Advanced Drug Delivery Reviews: Resham Bhattacharya, Priyabrata Mukherjee

Advanced Drug Delivery Reviews 60 (2008) 12891306
Contents lists available at ScienceDirect
Advanced Drug Delivery Reviews

j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / a d d r
Biological properties of naked metal nanoparticles

Resham Bhattacharya, Priyabrata Mukherjee
Department of Biochemistry and Molecular Biology, Department of Biomedical Engineering, College of Medicine, Mayo Clinic, Rochester, MN-55905, USA
A R T I C L E
I N F O
A B S T R A C T
Over the past few decades, inorganic nanoparticles, which exhibit signicantly distinct physical, chemical and biological properties from their bulk counterpart's, have elicited much interest. Discoveries in the past decade have demonstrated that the electromagnetic, optical and catalytic properties of noble-metal nanoparticles such as gold, silver and platinum, are strongly inuenced by shape and size. This has motivated an upsurge in research on the synthesis routes that allow better control of shape and size for various nanobiotechnological applications. Biomedical applications of metal nanoparticles have been dominated by the use of nanobioconjugates that started in 1971 after the discovery of immunogold labeling by Faulk and Taylor. Currently metal-based nanoconjugates are used in various biomedical applications such as probes for electron microscopy to visualize cellular components, drug delivery (vehicle for delivering drugs, proteins, peptides, plasmids, DNAs, etc), detection, diagnosis and therapy (targeted and non-targeted). However biological properties of bare-metal (naked) nanoparticles have remained largely unexplored. Therefore, in this review we discuss the novel biological properties and applications of three most widely used metal nanoparticles, namely, the nanoparticles of gold, silver and platinum. We describe the novel properties and use of these nanoparticles in angiogenesis and cancer related disorders. 2008 Elsevier B.V. All rights reserved.
Article history: Received 25 October 2007 Accepted 12 March 2008 Available online 10 April 2008 Keywords: Gold Silver Platinum Nanoparticles Angiogenesis Cancer Therapy
Contents 1. 2. 3. 4. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Medicinal application of gold: a historical overview . . . . . . . . . . . . . . . . . . . . . . . . Medicinal application of radioisotopes of colloidal gold . . . . . . . . . . . . . . . . . . . . . . . Angiogenesis and cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Physiological and pathological angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Angiogenic factors and cellular events . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Inhibitors of angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gold nanoparticles in cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Anti-angiogenic properties of gold nanoparticles. . . . . . . . . . . . . . . . . . . . . . . 5.1.1. Gold nanoparticles inhibit VEGF165-induced proliferation of HUVECs and bFGF-induced 5.1.2. Interaction of gold nanoparticles with heparin-binding domain . . . . . . . . . . . 5.1.3. Effect of gold nanoparticles on signaling events of VEGF165 . . . . . . . . . . . . . 5.1.4. Effect of gold nanoparticles on down stream signaling events of VEGF165 . . . . . . 5.1.5. Effect of gold nanoparticles on angiogenesis in vivo . . . . . . . . . . . . . . . . . Application of gold nanoparticles in cancer therapy . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Application of gold nanoparticles in ovarian cancer: angiogenesis in ovarian cancer . . . . . . 6.2. Effect of gold nanoparticles in mouse ovarian tumor model (MOT) . . . . . . . . . . . . . . Application of gold nanoparticles in multiple myeloma (MM) . . . . . . . . . . . . . . . . . . . . 7.1. Effect of gold nanoparticles on proliferation of multiple myeloma cells . . . . . . . . . . . . 7.2. Mechanism of inhibition: cell cycle analysis . . . . . . . . . . . . . . . . . . . . . . . . . 7.3. Internalization of gold nanoparticles by MM cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . proliferation of NIH3T3 cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1290 1290 1290 1291 1292 1292 1292 1293 1293 1293 1294 1295 1296 1296 1296 1296 1297 1297 1297 1298 1299
5.
6.
7.
This review is part of the Advanced Drug Delivery Reviews theme issue on Inorganic Nanoparticles in Drug Delivery. Corresponding author. Tel.: 1 507 284 8563; fax: +1 507 284 1767. E-mail address: Mukherjee.priyabrata@mayo.edu (P. Mukherjee). 0169-409X/$ see front matter 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.addr.2008.03.013
1290
R. Bhattacharya, P. Mukherjee / Advanced Drug Delivery Reviews 60 (2008) 12891306
Application of gold nanoparticles in B-chronic lymphocytic 8.1. Angiogenesis in B-CLL . . . . . . . . . . . . . . 8.2. Gold nanoparticles induce apoptosis in CLL-B cells . 8.3. Internalization of gold nanoparticles by CLL-B cells 9. Application of gold nanoparticles in arthritis . . . . . . . 10. Use of silver: a historical perspective. . . . . . . . . . . 10.1. Products containing silver ions . . . . . . . . . 10.2. Products containing nanocrystalline silver . . . . 10.3. Mechanism of anti-microbial effect of silver . . . 10.4. Side effects of silver . . . . . . . . . . . . . . 10.5. Silver nanoparticles interact with HIV-I . . . . . 11. Medicinal application of platinum nanoparticles . . . . . 12. Conclusion and future direction . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . .
8.
leukemia (B-CLL) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
. . . . . . . . . . . . . . .
1299 1299 1299 1300 1300 1300 1301 1301 1301 1301 1301 1302 1302 1302 1302
1. Introduction Over the past few decades, inorganic nanoparticles, whose structures exhibit signicantly novel and distinct physical, chemical, and biological properties, and functionality due to their nanoscale size, have elicited much interest. Nanostructure materials are attracting a great deal of attention because of their potential for achieving specic processes and selectivity, especially in biological and pharmaceutical applications [16]. At the nanoscale, the physical, chemical, and biological properties of materials differ fundamentally and often unexpectedly from their corresponding bulk counter part because of the quantum size effect e.g. gold nanoparticles (AuNPs) have wine red color whereas metallic gold is golden yellow and the color of the nanoparticles can be tailored by controlling their size and shape. Discoveries in the past decade have demonstrated that the electromagnetic, optical, and catalytic properties of noble-metal nanocrystals are strongly inuenced by shape and size [7,8]. This has motivated an upsurge in research on the synthesis routes that allow better control of shape and size for various nanotechnological applications. In medicine, nanotechnology has been explored for early detection, diagnosis and treatment of diseases [913]. Nanoparticles are the building blocks of nanotechnology. Although physicochemical properties of nanoparticles are well studied, their biological properties largely remain unexplored. In this review, we will discuss the biological properties of gold, silver and platinum nanoparticles that are widely used in various biomedical applications. 2. Medicinal application of gold: a historical overview Gold has a long history of use [14]. The therapeutic use of gold can be traced back to the Chinese in 2500 BC. Red colloidal gold is still in use today in India in the form of Ayurvedic medicine for rejuvenation and revitalization during old age under the name of Swarna Bhasma (Swarna meaning gold, Bhasma meaning ash) [15,16]. Mahdihassan has explored the historical use of gold in eastern traditions especially in India and China. In India cinnabar-gold is known as Makaradhwaja [17]. It is used as a drug for vigour of youth. Gold also has a long history of use in the western world as nervine, a substance that could revitalize people suffering from nervous conditions [18]. In the 16th century gold was recommended for the treatment of epilepsy [6]. In the beginning of the 19th century gold was the drug of choice for the treatment of syphilis [6]. The discovery by Robert Koch of bacteriostatic effect of gold cyanide towards the tubercle bacillus marked the beginning of the modern day medicinal use of gold. Following the discovery by Robert Koch, gold based therapy for tuberculosis was introduced in 1920s [6]. The major clinical uses of gold compounds are in the treatment of
rheumatic diseases including psoriasis, juvenile arthritis, planindromic rheutamitism and discoid lupus erythematosus [19,20]. Sodium aurothiomalate and aurothioglucose are two prime examples of gold thiolates mainly used for rheumatoid arthritis. These drugs are water soluble and administered as deep intramuscular injection. Following intramuscular injection these drugs get rapidly absorbed and the same time gold is rapidly cleared from the circulation and distributed to various organs such as kidney, liver, spleen, etc. The absorption of gold in the kidney causes nephrotoxicity, a major side effect. Other toxic reactions include mouth ulcers, skin reactions, blood disorder and liver toxicity. To overcome the poor pharmaco-kinetics and toxicity, second generation gold drug, auranon, was introduced in 1985 for arthritis. The presence of phosphine ligand makes auranon more lyophilic with better retention in the circulation. The absorption of gold in the kidney was also reduced with signicant reduction in the nephrotoxicity [21,22]. Antitumor activity of cis-platin was discovered in 1969 that prompted the investigation of other metal containing antitumor drugs. Gold has also been included in the search on the basis of three rationales [23] (i) both Pt(II) and Au(III) form analogous square planar complexes with d8 conguration of the central ions, (ii) analogy to the immunomodulatory effects of gold(I) antiarthritic agents and (iii) complexation of known antitumor agents with gold(I) and gold (III) to produce to compounds with enhanced activity. Auranon showed activity against HeLa cells in vitro and P388 cells in vivo. This discovery led to the screening of many phosphine containing gold drugs, of particular interest is bis(diphos)gold(I) complexes [22,24]. This complex showed promising antitumor properties but exhibited cardiovascular toxicity that precluded their use in clinical trials. The mechanisms of action of gold drugs are poorly understood. However it is believed nowadays that under biological conditions gold(I) and gold (III) species are reduced to gold(0), which may be the active species. There is hardly any report that describes the use of gold nanoparticles as an anticancer agent. However, recently we have shown for the rst time the anti-angiogenic property of gold nanoparticles. 3. Medicinal application of radioisotopes of colloidal gold Radioisotopes of gold have found wide application in the treatment of different types of cancer. Muller, a Swiss investigator, suggested that the injection of radiogold colloid directly into the body cavity might be an effective way of treating effusion caused by neoplasms. He is believed to be the rst to use radioactive gold in such a way. The predominant radiation from 198Au is a beta ray with very little penetration (maximum in water, 3.8 mm; mean 0.38 mm) with a halflife of 2.7 days. It produces a beta particle of 0.98 MeV and two gamma emissions of 0.12 and 0.41 MeV upon disintegration [25]. Its effect in
1291
the body is believed to be due to the beta emissions that have a low penetrating ability. The low penetrating ability of beta rays implies that bulk of the radiation will be localized to the site of injection without over-irradiating the neighboring normal tissues [26]. Therefore, intra-tumoral injection of 198Au is capable of delivering large amount of ionizing radiation within a tumor without damaging the normal tissues. There are several advantages of using radioactive gold over other internal sources of radiation such as radium needles or radon seeds [26]. The advantages lie in the physical properties of radiogold colloid; i) short half-life that permits the doses to be delivered within a brief period of time, ii) it is not necessary to remove the source of radiation as is the case with other sources, and iii) the radioactivity is contained in a liquid medium that makes it theoretically possible to inject many point sources of radiation throughout the tumor. There are some disadvantages as well, the most important one is probably the low penetration capability. The low penetration capability also implies that the area of the tumor which does not accumulate any radiogold colloid will receive none or an ineffective amount of beta radiation. It was shown that a cumulative survival of 96.3% was achieved in the treatment of stage Ia ovarian cancer with radiogold [27,28]. It has also been used in the prevention of Ehrlich ascites tumor by intraperitoneal injection of colloidal 198Au [29]. In the treatment of limited epithelial carcinoma of the ovary, 104 patients received intraperitoneal radio colloid [30]. Fifty six of these patients also received external beam radiation therapy to the pelvis. Five year actuarial no-evidence-of-disease survival rates were 95% for stage Iai, 82% for stage Iaii, 73% for stage Ib, 67% for Ic, 67% for Iia, 67% for Iib without gross residual tumor (GRT) and so on. Radioactive gold has also been used to prevent hepatic metastasis by intravenous administration [31]. Intracavitary colloidal gold treatment of effusions caused by malignant neoplasms in 24 patients indicates that this mode of treatment is of distinct palliative value in selected cases and control ascites accumulation in the peritoneal cavity. Furthermore, it causes less radiation sickness than conventional radiotherapy, it is simple to administer and unfavorable reactions appear to be minimal [25]. Radioactive colloidal gold has also been shown to produce uniform and consistent remissions in chronic leukemia in humans, both in the lymphogenous and myelogegenous forms of this disease [32,33]. Radioactive colloidal gold has also been used in the treatment of endometrial cancer as an adjuvant therapy and found to have benecial effect. However, with regard to acute leukemia in humans radiogold provides signicant but limited therapeutic efcacy [32]. Recently, gold nanoparticles have been used to increase the efcacy of radiotherapy in mice [34]. Mice bearing subcutaneous EMT-6 mammary carcinomas received a single intravenous injection of 1.9 nm gold particles (up to 2.7 g Au/kg body weight). The gold content of the tumor elevated by this treatment to 7 mg Au/g in tumor. The mice were then subjected to 250 kVp X-ray therapy for several minutes. One year survival rate was found to be 86% versus 20% with X-rays alone and 0% with gold alone. Previously, radioactive gold injections were used to prevent hepatic metastasis in rats. It was reported that 198Au injection within 10 min following tumor implantation can protect an animal from hepatic tumor growth without signicant liver toxicity [31]. Recently radioactive gold has been used in brachytherapy in the treatment of various types cancer. Brachytherapy is a form of radiation treatment in which radioactive sources are placed directly into the tumor [35,36]. It offers the advantage of maximizing radiation doses delivered to the tumor without damaging the surrounding normal tissues [37]. The idea of using brachytherapy in prostate cancer originated in 1952 when Flocks et al. injected colloidal gold radioisotope for prostate cancer [38]. Subsequently at Baylor College of Medicine, Eugene Carlton introduced the concept of implanting permanent radioactive gold seeds into the prostate gland [39]. Preliminary data obtained at Baylor College of Medicine suggests
that it can be performed with acceptable toxicity and is efcacious [35]. Brachytherapy using radioactive gold has also been applied in the treatment of bronchogenic carcinoma, nasopharyngeal carcinoma, head and neck cancers [37]. Recently, we have discovered the unique anti-angiogenic properties of gold nanoparticles and its application in a variety of cancers. Therefore, it is important to discuss, in brief, about angiogenesis and its role in cancer progression and metastasis. 4. Angiogenesis and cancer The concept that the tumor cells having the capability of continuously growing the capillary endothelium in vivo was suggested by Algire as early as 1945 [40]. This concept was further supported by Greene's observation that small tumors implanted in the anterior chamber of guinea pig eye would not grow because they could not vascularize. In the early 1970s Dr. J. Folkman rst isolated a soluble factor from human and animal neoplasms that was mitogenic for capillary endothelium. He showed that this factor induced growth of new capillaries and termed this factor as tumor angiogenesis factor (TAF) [40]. He demonstrated that solid tumors are angiogenic and require vascularization for growth [41,42]. Angiogenesis, the formation of new blood vessels from existing ones, plays an important role in the growth and spread of cancer. New blood vessels feed the cancer cells with oxygen and nutrients, allowing these cells to grow, invade nearby tissue, spread to other parts of the body, and form solid tumors (Fig. 1) [43]. In 1983, Dvorak and his co-workers described the partial purication of a protein able to induce vascular leakage when injected in guinea pig skin. They named it as vascular permeability factor and thought that this protein was responsible for the regulation of permeability (vascular leakiness) of tumor blood vessels [44]. However, in 1989, Ferara and others reported the purication of an endothelial specic mitogen and termed it vascular endothelial growth factor (VEGF) [45]. Cloning and expression of VEGF and VPF showed the involvement of the same molecule in their functions [46,47]. Here after we will use the term VEGF/VPF as a representation for vascular endothelial growth factor/vascular permeability factor. Several other members of the VEGF family have also been identied, including placental growth factor (PlGF), VEGF-B, VEGF-C and VEGF-D [4853]. Loss of a single VEGF allele results in embryonic lethality,
Fig. 1. The gure shows normal angiogenesis and tumor angiogenesis. Endothelial cells covering the innermost layer of the blood vessel are producing new capillaries.
1292
conrming its immense role in the appropriate development of vascular system [54,55]. 4.1. Physiological and pathological angiogenesis Angiogenesis can be divided in two types, normal angiogenesis and abnormal angiogenesis. Normal angiogenesis, also termed as physiological angiogenesis, begins in the developing fetus and continues after birth to form the normal blood vessels of the adult tissues. Normal blood vessels are distributed at regular and closely spaced intervals and are organized into hierarchy of elastic and muscular arteries, arterioles, capillaries, postcapillary venules and small and large rings [56]. On the other hand, blood vessels induced in pathological angiogenesis are highly abnormal and frequently, they are hyperpermeable to plasma and plasma proteins [5763]. They are structurally and functionally heterogeneous, non-uniformly distributed, branched irregularly and do not conform to a clear hierarchical fashion. 4.2. Angiogenic factors and cellular events Angiogenesis plays a central role both in organogenesis and tumorigenesis, it is important to know the factors that are responsible for such an effect. Since, there are a number of detailed reviews and reports in the literature about angiogenesis, here we will briey discuss about the factors and the signaling cascades involved in angiogenesis. The human VEGF gene is located in chromosome 6p21.3 and is organized in eight exons, separated by seven introns [64,65]. Alternative exon splicing results in the generation of at least four different molecular species, having respectively 121, 165, 189 and 206 amino acids, following signal sequence cleavage (VEGF121, VEGF165, VEGF189, VEGF206) [66]. VEGF165 is the most predominant isoform
produced by a wide variety of normal and transformed cells. VEGF165, the major isoform, is a basic, heparin-binding homodimeric glycoprotein of 45 kDa [67]. VEGF121 is weakly acidic and lacks the heparin-binding domain. VEGF189 and VEGF206 are more basic and have greater afnities to bind to heparin compared to VEGF165 [67,68]. There are mainly three high afnity tyrosine kinase receptors for VEGF/VPF family members. They include VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1) and VEGFR-3 (FLT-4). All are the members of large PDGF family (platelet-derived growth factor) [6971]. VEGFR-1 binds VEGF-A, VEGF-B and PlGF-1 and 2; VEGFR-2 binds VEGF-A and processed form of VEGF-C and D; VEGFR-3 binds unprocessed form of VEGF-C and VEGF-D [72]. In addition, there is another non-kinase receptor, neuropilin-1 (Nrp-1) that binds PlGF-2 and VEGF-165 but not VEGF-121 (Fig. 2) [73]. Mice null of any of the VEGF receptors are embryonic lethal as a result of early failures of vascular development [74,75]. Angiogenesis is a complex process. It is tightly regulated by a balance between endogenous pro-angiogenic growth factors like vascular endothelial growth factor (VEGF), placental growth factor (PLGF), platelet-derived growth factor (PDGF), tumor growth factorbeta (TGF-b) and angiopoietin-1 (Ang-1) and anti-angiogenic factors like thrombospondin-1 (TSP-1), somatostatin, endostatin, angiostatin, interleukins, interferons and tissue inhibitors of matrix metalloproteinases (TIMPs) [76,77]. For a detailed review on angiogenesis and cancer please refer to the following reviews [7882]. During tumor growth this balance is disrupted and the scale tips towards the tumorsecreted angiogenic growth factors that interact with their surface receptors expressed on endothelial cells (ECs) [83]. 4.3. Inhibitors of angiogenesis Different angiogenesis inhibitors may be categorized in different classes depending on their mode of action; (i) Agents that inhibit
Fig. 2. Different VEGF receptors (VEGFRs) and their respective ligands. The gure shows different domains (extracellular, transmembrane and intracellular) of VEGF receptors (VEGFR1, VEGFR2 and VEGFR3 and their respective ligands.
1293
endothelial cell proliferation or response. Such targets include endoglin, integrins, dominant negative receptors and agents that prevent the release or activation of FGF (broblast growth factor) [84]. Combrestatin phosphate which induces apoptosis in proliferating endothelial cells and causes tubulin destabilization [85]. Vitaxin, which is a humanized monoclonal antibody to alpha5-beta3 integrin present on endothelial cell surface and EMD 121974 a small molecule blocker of alpha5-beta3 integrins [8688]. (ii) Agents that block activation of angiogenesis. Such agents include Interferon alpha (demonstrated a 30% response rate in patients with AIDS-related Kaposi sarcoma and has shown to be active in treatment of hemangiomas, chronic myeloid leukemia, myeloma, melanoma, lymphoma and renal cell carcinoma [8991]), SU5416 (a small molecule blocker of VEGFR-2 signaling is in Phase II clinical trial for metastatic colorectal cancer, non-small cell lung cancer and von HippelLindau disease), SU6668 (a small molecule blocker of VEGF, FGF and PDGF receptor signaling is in Phase I trial for selected advanced tumors [92]), and humanized monoclonal antibody to VEGF (is now in clinical trials for a number of different cancers including metastatic renal cancer, advanced prostate cancer, non-small cell lung cancer, colorectal cancer and other solid cancers [93]); (iii) Agents that block extracellular matrix breakdown. Examples of such agents are MMP inhibitors (now in clinical trials), Marimastat (a synthetic inhibitor that blocks TNF-alpha convertase, has shown clinical activity when combined with chemotherapy in colorectal, ovarian, prostate, gastric and pancreatic cancer [94]), AG3340 (Phase I studies with in combination with other chemotherapeutic agents have been well tolerated in patients with advanced prostate and other solid tumors [95,96]), Bay12-9566 and MM1270 (synthetic MMP inhibitors, have undergone Phase I trials as single agents in pancreatic, ovarian and colorectal cancers). Although studies with anti-angiogenic molecules have been elegant and results encouraging yet these advances should be viewed with cautious optimism as side effects that occur in some patients include hypertension, thrombosis, proteinuria, and even fatal hemorrhage. 5. Gold nanoparticles in cancer All the anti-angiogenic molecules discovered and discussed so far are organic in nature. Recent reports also suggest that they have considerable toxicities such as gastrointestinal perforations [9799]. Therefore, avenues exist to explore the possibilities of searching for anti-angiogenic compounds that may be inorganic in nature and endowed with little or no side effects. Gold nanoparticle is an ideal model to explore such possibilities because (i) it is biocompatible. Biocompatibility of gold nanoparticles has been conrmed by various in vitro and in vivo experiments and use throughout the history of civilization [100105]; (ii) it is easy to synthesize and characterize due to the presence of surface plasmon resonance band; and more importantly, (iii) gold being a soft acid, is known to bind strongly with soft bases like thiols. Gold also binds moderately strongly with amine functionalities. The formation of goldthiol bond is the basis of the formation of self-assembled monolayer (SAM) on gold surfaces [2]. Proteins, by virtue of having cysteine and lysine residues, represent a unique ligand for binding to metal nanoparticles such as gold and alter their biological activities. Therefore, it makes a logical choice to test if binding to gold nanoparticles alters the activity of pro-angiogenic growth factors like VEGF165. Biological application of gold nanoparticles started in 1971 after the discovery of immunogold labeling [106]. Since then gold nanoparticles have been used in a number of biological applications mainly as a delivery vehicle or as a probe to visualize cellular compartments using electron microscopy. Many biomedical applications of gold nanoparticles require fabrication of nanoparticle surfaces with useful ligands. There has been signicant progress in the surface functionalization of gold nanoparticles in the form of monolayer protected gold clusters (MPCs) or mixed monolayer
protected clusters (MMPCs) [107109]. By using the above techniques nanoparticles can be rendered positively or negatively charged cluster by appropriate selection of ligand molecules. Moreover, it was elegantly reported by Rotello and his co-workers that proteins adsorbed onto the surface of MPCs or MMPCs loose their structural integrity [109]. Therefore, avenues exist also to explore MPCs or MMPCs to denature or inhibit the function of those proteins that are known to induce angiogenesis. Below we discuss such a novel application of naked gold nanoparticles in inhibiting the function of angiogenesis inducer proteins. 5.1. Anti-angiogenic properties of gold nanoparticles We have already discussed in the previous section that VPF/VEGFs are mitogenic for vascular endothelial cells [110] and act as potent angiogenic factors and blood vessel permeabilizing agents [46,111] in vivo. The signaling cascades in VEGF/VPF mediated angiogenesis are initiated after ligand binding to VEGFRs on endothelial cells. Therefore, blocking the interaction of VEGF/VPF with its receptors could be an efcient way of inhibiting angiogenesis. We have also discussed briey that there are mainly 4 isoforms of VEGF containing 121, 165, 189 and 206 amino acids and they are produced from a single gene as a result of alternate splicing. Interestingly, all of the above isoforms contain heparin-binding domain except VEGF121. Many anti-angiogenic approaches have been developed to block the interaction of VEGFs with their receptors in order to inhibit angiogenesis and tumor growth that include monoclonal antibodies targeting VEGF [112114] and the use of soluble decoy receptors blocking the binding of VEGF to its receptors [115]. Recently, we have reported that gold nanoparticles inhibit VPF/VEGF165 induced proliferation of endothelial cells [105]. It binds to VPF/VEGF165 to inhibit their activity. VPF/VEGF-165 is an endothelial cell (ECs) mitogen and a prime mediator of angiogenesis that plays a tremendous role in pathological neo-vascularization including rheumatoid arthritis, chronic inammation and neoplastic disorders. This is the rst example of an inorganic compound that is anti-angiogenic in nature and opens up a new area of research using inorganic nanoparticles as anti-angiogenic agent. Therefore, detailed discussion on the mechanism of its inhibitory effect is important so that similar strategies could be used to explore future inorganic antiangiogenic compounds. Gold nanoparticles used in this study were prepared by the reduction of aqueous chloroaurate ions with sodium and characterized using UVVisible spectroscopy (UVVis) and transmission electron microscopy (TEM). The characteristic SPR band of gold nanoparticles is clearly observed by UVVis suggesting the formation of spherical gold nanoparticles by this method (Fig. 3a). The TEM image of the gold nanoparticles clearly showed that gold nanoparticles of diameter ~ 5 nm were formed by this method (Fig. 3b). 5.1.1. Gold nanoparticles inhibit VEGF165-induced proliferation of HUVECs and bFGF-induced proliferation of NIH3T3 cells To determine whether gold nanoparticles had any effect on VEGF165 proliferation of HUVECs, VEGF165 was pre-incubated with various concentrations of gold nanoparticles (67, 335, 670 nM) overnight at 4 C and then added them to serum-starved HUVECs followed by [3H]-thymidine incorporation. It was found that gold nanoparticles inhibited VEGF165-induced proliferation (p b 0.0001). It was already discussed that VEGF165 has a heparin-binding domain. Therefore, it is also interesting to test whether heparin-binding domain of VEGFs plays any role in order to be inhibited by gold nanoparticles. However, it was found that gold nanoparticles did not inhibit non-heparin-binding VEGF121-induced proliferation of HUVEC cells. Gold nanoparticles were also found to be non-toxic to HUVECs where no inhibition in proliferation was observed in the only nanogold treated samples compared to the control (Fig. 4a). Thus, the inability of gold nanoparticles to inhibit the activity of VEGF121
1294
solution. This is the classical method of purifying heparin-binding proteins from non-heparin-binding ones. To prove that gold nanoparticles bind to the heparin-binding domain of VEGF165, gold nanoparticles at different concentrations (335, 670 and 1340 nM) were pre-incubated with VEGF165 overnight at 4 C. VEGF165 was then precipitated from this complex with a saturating concentration of heparin-sepharose. It was observed that in the absence of gold, all VEGF165 was bound to heparin-sepharose and was detected only in the precipitated fraction while none was detected in the supernatant fraction. The results of the pre-incubation experiments with heparinsepharose conclusively proved that VEGF165 in the supernatant fraction was in the gold-bound form and thus could not interact with the heparin-sepharose. From these results, it was concluded that gold nanoparticles inhibited VEGF165 from binding to heparin-sepharose because gold itself binds to VEGF165 through the heparin-binding domain. Direct binding of VEGF165 to gold nanoparticles was conrmed by XPS analysis. The presence of a single Au 4f7/2 peak at 83.9 eV clearly demonstrated only one form of Au present in solution and it is in the form of Au(0) [116119,104]. The presence of two sulfur peaks at 162.7 and 167.1 eV represented two chemically distinct sulfur species. The peak at 162.7 eV was assigned to gold-bound sulfur and peaks at higher BE were assigned to oxidized sulfur species such as in sulfones. The nitrogen 1s peak at 399.6 eV was likely due to unionized, nonprotonated nitrogen [104,120]. However, the possibility of gold
Fig. 3. UVVisible spectrum of gold nanoparticle and transmission electron micrograph (TEM) of gold nanoparticles. Subpanel (a) shows the UVVis spectrum of gold nanoparticles obtained by sodium borohydride method. The characteristic surface plasmon resonance band of gold nanoparticles ~ 512 nM is clearly visible. Subpanel (b) shows the TEM micrograph of gold nanoparticles conrming that the formation of spherical gold nanoparticles of ~ 5 nm was formed by this method [reproduced from Mukherjee, et al. Journal of Nanobiotechnology 2007, 5:4].
suggested that the presence of heparin-binding domain was necessary in order to be inactivated by gold nanoparticles [105]. Similarly gold nanoparticles also inhibited bFGF, a heparin-binding growth factor, induced proliferation of NIH3T3 cells. However, it did not inhibit EGF induced proliferation. Gold nanoparticles were not toxic to 3T3 cell line as no inhibition in proliferation was observed in the only nanogold treated samples compared to the control. While bFGF is a heparin-binding growth factor, EGF is non-heparin-binding. Therefore, the inhibition of function of two heparin-binding growth factors namely VEGF165 and bFGF by gold nanoparticles and its inability to alter the activity of non-heparin-binding growth factors, namely VEGF121 and EGF clearly suggested that the heparin-binding domain plays a critical role to be inhibited by gold nanoparticles (Fig. 4b) [105]. 5.1.2. Interaction of gold nanoparticles with heparin-binding domain Since gold nanoparticles inhibited the function of heparin-binding growth factors, it is important to determine if gold nanoparticles interacted directly with the heparin-binding domain. Precipitation experiments with heparin-sepharose were performed to determine this interaction. Heparin-sepharose binds to the heparin-binding domain of a heparin-binding protein and precipitates it from the
Fig. 4. Effect of nanogold on growth factor-induced proliferation. [3H]-Thymidine incorporation is represented as fold stimulation. Subpanel (a), serum-starved HUVECs were stimulated withVEGF165/VEGF121 (10 ng/ml) that was pre-incubated with nanogold. Subpanel (b), serum-starved NIH3T3 cells were stimulated with 10 ng/ml bFGF/EGF preincubated gold. Average of three independent experiments, each one done in triplicate (reproduced from Mukherjee, P. et al. Clin Cancer Res 2005;11(9)May 1, 2005).
1295
nanoparticles binding to VEGF165 through nitrogen as well could not be ruled out. Hence it was concluded that the direct binding of VEGF165 to gold nanoparticles occurred through sulfur and/or nitrogen, both present in the heparin-binding domain of VEGF165. We have described earlier that angiogenesis plays a central role in the growth and progression of tumor [111]. This process is also important for the promotion and maintenance of other diseases like neoplasia and rheumatoid arthritis [121,122]. As there are several reports that indicate that gold salts can retard the progression of rheumatoid arthritis [123], we reasoned that gold nanoparticles might also inhibit angiogenesis. Because VEGF/VPF [46,110] and bFGF [111] are two critical cytokines for the induction of angiogenesis, we investigated whether non-toxic novel gold nanoparticles [100] being
used at present in several biomedical applications can inhibit the functions of these two important pro-angiogenic growth factors. 5.1.3. Effect of gold nanoparticles on signaling events of VEGF165 The very rst step in the angiogenic cascade involves ligand binding to VEGFRs on endothelial cells that lead to receptor phosphorylation and initiates the signaling events [124]. With the addition of nanogold at a concentration of 335670 nM, VEGF165induced phosphorylation of VEGFR-2 was profoundly inhibited in a dose dependent manner. Almost complete inhibition of VEGFR-2 phosphorylation was observed at 335 nM and 670 nM concentrations of nanogold. The results of receptor phosphorylation clearly suggested that gold nanoparticles bind directly to VEGF165 and
Fig. 5. Uptake of gold nanoparticles by HUVECs under serum free conditions. Subpanel (a) represents the TEM image of HUVECs treated with gold nanoparticles for 1 h under serum free condition, (b) and (c) are the higher magnication images of (a). Subpanel (d) represents the TEM image of HUVECs after 24 h treatment with gold nanoparticles under serum free conditions, (e) and (f) are the higher magnication images of (d).
1296
inhibited its interaction with cell surface receptors hence inhibiting phosphorylation. 5.1.4. Effect of gold nanoparticles on down stream signaling events of VEGF165 Since gold nanoparticles are acting extreme upstream of VEGF/VPF induced signaling, so all other signaling cascades are also expected to be inhibited. To further support the hypothesis that gold nanoparticles perform extreme upstream of VPF/VEGF induced signaling, gold nanoparticles were incubated with VPF/VEGF165 and tested its ability inhibit VEGF165 induced calcium release experiment from HUVECs. It was found that at a gold concentration of 67 nM ~34%, and complete inhibition at 335670 nM was observed (p b 0.05). The VEGF receptors on the HUVECs were still functional as evidenced by an increase in calcium release comparable to the control when VEGF was added after 300 s. These observations also clearly demonstrated that gold nanoparticles bind directly to VEGF165 and inhibited its signaling events but did not perturb the receptor functions [105]. In a similar fashion gold nanoparticles also inhibited the migration of HUVECs. Furthermore, it was found that gold nanoparticles were efciently taken up by HUVEC cells, localizations mainly in the endocytic compartments such as in late and early endosomes and lysozomes (Fig. 5). 5.1.5. Effect of gold nanoparticles on angiogenesis in vivo All the in vitro ndings should be tested and veried in vivo to check the feasibility of taking it to clinical trials. The efcacy of gold nanoparticles to inhibit VPF/VEGF165-induced permeability and angiogenesis in vivo was tested in a nude mouse ear model. An adenoviral vector (Ad-VEGF) expressing VEGF165 (the 164 amino acid isoform is most commonly expressed by tumors) driven by the cytomegalovirus promoter was introduced into the ears of nude mice. The resulting angiogenic response mimics that found in tumors, progressing through the steps of increased micro vascular permeability, tissue edema, brin deposition and formation of enlarged, thin-walled, pericytes poor mother vessels over the course of 13 weeks [60,61,125]. Ad-VEGF injected mice treated with gold nanoparticles developed lesser edema than mice treated with Ad-VEGF only (Fig. 6a,b,c). As shown, 30 min after injection of Evan's blue dye into the tail vein of these treated mice, a decrease in permeability was also observed (Fig. 6d,e) [105].
Taken together, the experiments and results discussed above showed that gold nanoparticles selectively inhibited VEGF165 and bFGF induced proliferation of HUVECs and broblasts, respectively. In a similar fashion gold nanoparticles also inhibited the activity of placental growth factor (PlGF) (unpublished data). Gold nanoparticles directly bind heparin-binding growth factors presumably through cysteine residues of the heparin-binding domain to inhibit growth factor mediated signaling. 6. Application of gold nanoparticles in cancer therapy The hypothesis that angiogenesis is required for the growth of solid tumors was proposed nearly 30 years ago [40,126128]. Numerous studies have revealed that an angiogenic switch can confer a tumor clone with an angiogenic phenotype via alteration of the expression levels between angiogenic (i.e., VEGF, basic broblast growth factor, bFGF, etc) and anti-angiogenic factors such as TSP-1 [77,83,129]. This latter angiogenic conversion leads to rapid growth and metastasis of solid tumors. There is a growing database on a diverse family of endogenous protein inhibitors of angiogenesis (i.e., thrombospondin, interferon, angiostatin, and endostatin). Increasing evidence indicates that there may be a ne balance between pro-angiogenic and the endogenous inhibitors in healthy individuals [83,129133]. Angiogenesis aids tumor growth by its perfusion effect, i.e., increasing the supply of oxygen and other essential nutrients or in solid tumor growth by a paracrine effect. This results in a positive-feedback loop that leads to rapid angiogenesis and tumor growth. Alternatively, human tumors and acute leukemia can use pro-angiogeneic factors as an autocrine loop to enhance their survival and/or metastatic potential [134136]. In this section application of gold nanoparticles in different types of cancers will be discussed. 6.1. Application of gold nanoparticles in ovarian cancer: angiogenesis in ovarian cancer Epithelial ovarian cancer is the most common malignancy of the female genital tract in western countries: 12% of all women develop EOC at some time during their lives [137]. This disease begins in and is limited to peritoneal cavity [138]. Unfortunately, the majority of epithelial ovarian cancers remain clinically undetected until patients have developed late stage disease.
Fig. 6. Effect of nanogold on angiogenesis in vivo in the ears of nude mice. Gross appearance of angiogenesis 7 days after injection of nanogold only (a), Ad-VEGF only (b), nanogold and Ad-VEGF (c). Effect of nanogold on permeability, Ad-VEGF only (d), nanogold and Ad-VEGF (e) (reproduced from Mukherjee, P. et al. Clin Cancer Res 2005;11(9)May 1, 2005).
1297
Several studies have indicated that VEGF regulated angiogenesis is an important component of ovarian cancer growth [139]. VEGF immunostaining has been demonstrated in the epithelial lining of benign ovarian neoplasms [139]. Microvascular density (MVD) and the degree of expression of VEGF and its receptors in ovarian tumors are directly correlated with poor prognosis, suggesting VEGF mediated angiogenesis, at least in part, inuence disease progression [140147]. These results suggest that growth of the peritoneal metastases is dependent on neovasculature and that VEGF may regulate angiogenesis in these deposits. Epithelial ovarian cancer is characterized by widespread intraperitoneal carcinoma and the formation of large volume of ascitic uid. In the ascitic uid of human ovarian cancer cell line OVCAR-5 grown in mice, VEGF concentrations of more than 6000 pg/ml were found whereas serum concentration was found to be only 30 pg/ml in the same animal [148]. When OVCAR-5 cells were grown in vitro, VEGF values in the conditioned medium reach greater that 1400 pg/ml, compared with less than 30 pg/ml for control medium without the tumor cells. In a patient with ovarian cancer, VEGF concentrations in the ascitic uid were greater that 13000 pg/ml [148]. Another group assessed the role of VEGF in the growth and ascites formation associated with ovarian cancer. The group used human ovarian carcinoma cell line SKOV-3 to develop an in vivo model of ovarian cancer in immunodecient mice that mimicked the intraperitoneal carcinoma and ascites production seen in women with this disease. The group then used a function blocking monoclonal antibody (A4.6.1) that block the access of VEGF to both of its receptors. A4.6.1 signicantly inhibited subcutaneous SKOV-3 tumor growth compared with controls. A4.6.1 completely inhibited ascites production in IP mice, although it only partially inhibited intraperitoneal tumor growth. However, when A4.6.1 treatment was stopped, IP mice rapidly developed ascites and became cachectic [144]. These data suggest that VEGF is essential for ascites formation. VEGF may play a major role in the progression of ovarian cancer by inuencing tumor growth through its promotion of tumor angiogenesis and ascites production through its stimulation of vascular permeability. All of the above studies point out the potential importance of targeting pathological angiogenesis to prevent metastases and progression of ovarian tumor. Anti-angiogenic properties of gold nanoparticles may be utilized to inhibit the progression of ovarian tumor growth and metastasis. 6.2. Effect of gold nanoparticles in mouse ovarian tumor model (MOT) The mouse ovarian tumor (MOT) model is a well-characterized transplantable ovarian carcinoma model. The tumor cells are maintained by serial passage in the peritoneal cavities of C3H female mice [125,149151]. This is a very aggressive form of tumor and all the animals die within 34 weeks after the implantation of the tumor cells due to huge ascites build up and metastasis (Fig. 7). It was elegantly shown by Nagy et al. that the VPF/VEGF165, secreted by tumor cells was mainly responsible for ascites accumulation in MOT model [125,149151]. We have found that the intraperitoneal injection of
Fig. 8. Effect of gold nanoparticles on ascites accumulation in vivo. For mouse ovarian tumor (MOT) experiments, 1 106 MOT cells were injected in the peritoneal cavity of C3H mice and treatment was started 2 days after the injection. Nanogold (1.3 mg) was injected to each mouse everyday over a period of 7 days. Mice were then sacriced and ascites uids collected. At least ve animals were used in each set. All experiments were done under protocols approved by the Beth Israel Deaconess Medical Center and the Mayo Clinic Institutional Animal Care and Use Committee. The gure clearly showing reduced ascites accumulation in nanogold treated mice [reproduced from Mukherjee, P. et al. Clin Cancer Res 2005;11(9)May 1, 2005].
gold nanoparticles reduced ascites accumulation in MOT model compared to non-treated tumor bearing animal (Fig. 8) [105]. Gold nanoparticles inhibited the function of growth factors such as VEGF165, bFGF secreted by MOT cells, thereby reducing permeability and hence reduced ascites accumulation. 7. Application of gold nanoparticles in multiple myeloma (MM) Multiple myeloma (MM) is a cancer of plasma cell (white blood cells that produce antibodies) malignancy that, despite intensive investigation, remains universally fatal [152]. The term multiple myeloma itself describes a characteristic feature of this disease. It is found in multiple sites in the bone marrow (myelo-) with accumulations of tumor (-oma) cells. Under normal condition plasma cells constitute about 1% of the cells in the bone marrow. However, in monoclonal multiple myeloma these cells are overproduced and may comprise of 1080% of the cells in the bone marrow. Clinically, it is characterized by high levels of paraproteins in blood and/or urine, lytic bone lesions, anemia, renal dysfunction and bone marrow plasmacytosis [153]. Elevated levels of many cytokines, including interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), insulin-like growth factor-I (IGF-I), CD40L, IFN-, and TNF- have been reported in the bone marrow microenvironment where multiple myeloma cells proliferate in vivo [154156]. These secreted factors provide critical signals required for multiple myeloma cell growth and survival [157]. Current treatments for this disease include combination chemotherapy with or without stem cell transplantation, use of alkylating agents, glucocorticosteroids and thalidomide [158]. Recently, FDA has approved a proteasome inhibitor, Bortezomib, for use in this disease [159,160]. However, none of these therapeutic modalities is curative and in most patients the disease will relapse necessitating further therapy. 7.1. Effect of gold nanoparticles on proliferation of multiple myeloma cells It is predicted that in 2007, 19,900 new cases of multiple myeloma will be diagnosed among which 10,790 will die from this disease. Therefore, new therapeutic approaches are urgently needed. We have already discussed that MM cells secrete angiogenic growth factors such as VEGF, bFGF. These growth factors are known to play important role in their survival [161166]. Furthermore, our group recently
Fig. 7. Mouse ovarian tumor model (MOT). The model is generated by serially transplanting MOT cells in the peritoneal cavity of 46 weeks C3H mice. The MOT cells are a kind gift from Prof. H. Dvorak, Harvard Medical School, Boston, MA. The picture showing the accumulation of ascites in the peritoneal cavity.
1298
demonstrated that gold nanoparticles have unique anti-angiogenic properties and they inhibit the function of heparin-binding growth factors [105]. Following that lead we tested the efcacy of gold nanoparticles to inhibit the proliferation of MM cells. We observed inhibition of proliferation in all the three cell lines (OPM-1, U-266 and RPMI-8266) in a dose dependent manner. We also studied in depth to nd out the mechanism of such action of gold nanoparticles (Fig. 9) [167]. 7.2. Mechanism of inhibition: cell cycle analysis To nd out the mechanism of gold nanoparticle induced inhibition of proliferation, we performed cell cycle analysis. The cell cycle in
eukaryotes is mainly classied into four phases, G1-phase (Gap phase) where growth and preparation of the chromosomes for replication occurs, S-phase (synthesis phase) where synthesis of DNA and centrosomes takes place, G2-phase where preparation for mitosis occurs and M-phase where mitosis takes place, the cell dividing into two daughter cells each with a complete set of genes. Therefore, the inhibition in proliferation should be reected in the cell cycle and smaller population would be expected in the S-phase and higher population in the G1-phase [168]. Cell cycle analysis revealed an increase in the percentage of cells in the G1-phase and a signicant decrease in percentage of cells in the Sphase in all of the gold nanoparticles treated cells as compared to the untreated cells (Fig. 9) [167].
Fig. 9. The proliferation of myeloma cells after 48 h in the presence of gold nanoparticles, as determined from a [3H]-thymidine incorporation assay. ac) The proliferation of OPM-1, U-266, and RPMI-8266 cells, respectively, at different concentrations of gold nanoparticles. Cell cycle analysis of myeloma cells after 48 h in the presence of gold nanoparticles, as determined from PI staining, is shown in (df). df) Cell cycle analysis of OPM-1, U-266, and RPMI-8266 cells, respectively, at different concentrations of gold nanoparticles (Resham Bhattacharya, Chitta Ranjan Patra, Rajanshu Verma, Shaji Kumar, Philip R. Greipp, and Priyabrata Mukherjee, Adv. Mater. 2007, 19, 711716, Copyright Wiley-VCH Verlag GmbH & Co. KGaA. Reproduced with permission).
1299
The cell cycle is tightly regulated by interplay of many proteins. Key among these is the cyclins, which are expressed and then degraded in a concerted fashion to drive the stages of the cell cycle. Cyclins combine with cyclin dependent kinases (cdks) to form activated kinases that phosphorylate targets leading to cell cycle regulation. p21 and p27 are two proteins that are expressed in the G1-phase of the cell cycle and inhibit cdk4 and cdk2 respectively [169]. There are numerous reports that in a variety of cancers including multiple myeloma reduced expression of p21 and p27 correlate with poor prognosis and enhanced tumorigenic potential [170172]. To nd out the levels of p21 and p27 in gold nanoparticles treated and nontreated control samples we performed the western blot analysis for these two proteins and found out that gold nanoparticles upregulated both the cell cycle inhibitor proteins p21 and p27 in a dose dependent manner [167]. 7.3. Internalization of gold nanoparticles by MM cells It is also important to know whether MM cells internalize the gold nanoparticles that in turn, may have such an inhibitory effect. TEM pictures of all the cell lines showed the presence of gold nanoparticles at the cell surface, inside the cell in double membrane layered earlyendosome like structures away from the nucleus and late-endosome like structures close to the nucleus [167]. Whether the pattern of internalization and locations of the gold nanoparticles inside the cells have any inuence in the inhibition of proliferation of MM cells is still not clear and needs further investigation. The mechanism of upregulation of p21 and p27 by gold nanoparticles treatment is unique and currently under investigation. Recently, we have demonstrated that gold nanoparticles posses antiangiogenic properties. Moreover, MM cells secrete a number of growth factors and cytokines such as IL-6, VEGF, basic broblast growth factor (bFGF), IGF-I, CD40L, IFN- [152,156,173]. These factors provide critical signals for multiple myeloma cell growth and survival. We speculate that in MM gold nanoparticles inhibit the function of heparin-binding growth factors/proteins such as VEGF, bFGF that provide the critical signals for cell proliferation. This inhibition of activity in turn may lead to the upregulation of cell cycle inhibitor proteins such as p21 and p27 and hence inhibition in proliferation. However, other mechanisms of inhibition of proliferation cannot be ruled out. This study is unique in that it bridges the eld of nanoscience and technology with the therapy in multiple myeloma and opens up the opportunity of utilizing the technological advances of nanoscience in the treatment of MM. In future, opportunities exist to explore the optoelectronic properties of gold nanoparticles in the treatment of multiple myeloma [167]. 8. Application of gold nanoparticles in B-chronic lymphocytic leukemia (B-CLL) B-CLL is the most common leukemia in the Western world [174 177] with the predominance of the disease in males (2:1 male to female ratio). The clinical course is variable with a median survival of 5 to 7 years, but patients with advanced stage disease may survive only 1.5 to 2 year. Eventually, 70% of all CLL patients will require therapy and a subgroup of patients (~25%) will experience aggressive disease or may undergo transformation to a more undifferentiated leukemia or lymphoma. While chemotherapy may be effective, it is not curative and often does not result in sustained clinical responses. It is estimated that 15,340 men and women (8960 men and 6380 women) will be diagnosed with and 4500 men and women will die of chronic lymphocytic leukemia in 2007. Chronic lymphocytic leukemia (CLL) is a cancer characterized by the over production of lymphocytes (a type of white blood cells) by bone marrow [178181]. The spongy inner mass of bones is the bone marrow that produces the blood cells. White blood cells originate
from the marrow and circulate in the blood. B-Chronic lymphocytic leukemia (CLL) affects B-lymphocytes and causes immune suppression and inltration of malignant cells into organs. Chronic lymphocytic leukemia starts in the bone marrow, but it can spread to other organs. It does not usually form a solid mass or tumor. While chemotherapy (purine nucleosides) with or without antibodies such as rituximab (so called chemoimmunotherapy) may be very effective, it is not curative and often does not result in sustained clinical responses [179181]. We believe that additional approaches to therapy will emerge by more fully detailing the mechanisms of apoptosis in CLL-B cells. This insight should lead to approaches that can facilitate higher levels of apoptosis in CLL-B cells and perhaps be used with traditional approaches used in the treatment of CLL. 8.1. Angiogenesis in B-CLL Our studies in B-CLL assessed the degree of bone marrow angiogenesis, and we measured pro-angiogenic factors including VEGF and bFGF [182]. We detected abnormal angiogenesis in marrow sections of B-CLL patients and signicantly higher levels of bFGF and VEGF in the urine of many B-CLL patients. The combination of increased marrow vascularity and abnormal levels of vascular factors in the urine of B-CLL patients strongly suggested to us that the abnormal angiogenesis is an important biologic component of this disease. In support, it was found that abnormal marrow angiogenesis was positively associated with advancing stage of their disease [182]. Earlier studies had shown that clonal B cells in B-CLL can synthesize bFGF and VEGF [183185]. In clonal cells from B-CLL patients with high-risk disease, the median level of intracellular bFGF was approximately 4 times higher than in clonal cells from patients with less disease. In addition, this study found that clonal B cells with higher levels of bFGF were resistant to the apoptotic effects of the drug udarabine [183]. This latter study strongly suggested that angiogenic factors are capable of modulating CLL-B cell drug resistance. Other studies, including our own, have shown that CLL-B cells synthesize and release VEGF isoforms121 and 165 [185]. These isoforms are able to bind avidly to the VEGF receptors, VEGFR-1 and VEGFR-2. 8.2. Gold nanoparticles induce apoptosis in CLL-B cells Fig. 10 describes the effect of gold nanoparticles alone in the induction of apoptosis in CLL-B cells. The amount of gold nanoparticles used is exactly the same as in the respective doses of Au-AbVF. From this gure it is clear that 3 (P1, P2, P3) samples responded to the exposure to gold nanoparticles alone with increases in apoptosis (~ 5060% apoptosis was observed) in a dose dependent manner (Fig. 10). Among the remaining 4 samples, 2 did not respond at all (P6, P7) and lesser levels of apoptosis induction were observed for the remaining 2 samples (P4, P5). The apoptosis induction observed in the case of control gold nanoparticles (Au treatment group) on CLL-B cells is not surprising as we have shown previously that the gold nanoparticles posses unique anti-angiogenic properties [104,105]. Recently, it has been reported that gold nanoparticles inhibit the function of heparin-binding growth factors such as VEGF165, BFGF and posses anti-angiogenic properties. Therefore, gold nanoparticles alone without any modication can inhibit the function of some of the growth factors secreted by the CLL-B cells and hence the induction of apoptosis [105]. Time dependent apoptosis was observed for P1 and P3 where maximum apoptosis was observed at 72 h, however P2, P4 and P7 did not respond with apoptosis induction to the gold nanoparticles. For P5 and P6, time dependent apoptosis was observed for rst 48 h, however, no apoptosis was observed at 72 h [104]. We believe that these residual B cells were resistant to the nonconjugated Au nanoparticles. The degree of apoptosis observed from the treatment with gold nanoparticles alone is not unexpected due to the anti-angiogenic properties of gold nanoparticles, as described above.
1300
Fig. 10. Dose dependent effect of Au nanoparticles in the induction of apoptosis in CLL-B cells. Cells were treated with 1, 5 and 25 g of Au for 72 h followed by measurement of apoptosis using annexin PI. The % apoptosis was calculated after normalizing the apoptosis in the control cells (no treatment group) to zero [reproduced from Mukherjee, et al. Journal of Nanobiotechnology 2007, 5:4].
8.3. Internalization of gold nanoparticles by CLL-B cells It is also important to know the fate of the nanoparticles after the treatment. Do the cells internalize the particles or do the particles remain bound to the cell membrane? To address these issues transmission electron microscopy of the cells treated with gold nanoparticles alone and with Au-AbVF for 1 h is performed. The 1 h treatment duration was chosen based on previously reported literature on the internalization of gold nanoparticles as longer time points did not increase gold uptake nor does it alter the pattern of internalization [13,102,103,167]. Nanoconjugates were found at the cell periphery (within uncoated tubules and vacuoles). Gold nanoparticles were also detected within larger endocytic compartments of diverse morphology. These include peripherally both early and late endosomes and lysozomes. Similar pattern of internalization was observed when the cells were treated with gold nanoparticles alone. However, in this case, the number of gold nanoparticles taken up by the cells was found to be much lower than the previous case and lots of aggregated gold nanoparticles were seen [104]. 9. Application of gold nanoparticles in arthritis It is now recognized that angiogenesis plays a key role in the formation and maintenance of pannus in rheumatoid arthritis (RA) [122,186]. The new blood capillaries promote synovial inammation by transporting the inammatory cells to the site of synovitis in RA. It is found that VEGF levels in serum, synovial uid (SF) and in inamed synovium of RA patients are elevated [187,188]. Therefore, antiangiogenic therapy could be a potential treatment options for RA. Following our lead on anti-angiogenic properties of gold nanoparticles and the role of angiogenesis in RA, researchers in Taiwan tested the efcacy of gold nanoparticles to ameliorate collagen-induced arthritis (CIA) in rats [189]. The authors prepared ~13 nM gold nanoparticles using citrate reduction method and tested their ability to inhibit VEGF/ VPF induced proliferation and migration of HUVECs. They also used PEGcoated gold nanoparticles as control for naked gold nanoparticles. The authors found signicant inhibition in VEGF induced proliferation and migration of HUVECs in presence of naked nanogold but not in presence of PEG-coated gold nanoparticles. To further test the efcacy of nanogold in preclinical RA model, the authors generated the CIA model in 8-weeks old SpragueDawley rats. They were injected intradermally with 400 g and 240 g of bovine type II collagen. Injection of nanogold or peg-
coated nanogold was initiated 7 and 10 days post induction of CIA. With the help of clinical and radiographic assessment the authors conrmed that nanogold administration resulted in a signicant reduction of joint inammation. Furthermore, immunohistochemical staining revealed a signicant decrease in macrophage inltration into the synovium of rats with CIA in the nanogold treated group compared to PBS and PEG-gold treated group. These results further support the benecial effect of nanogold in the treatment of arthritis. This is an important study that describes the application of bare gold nanoparticles in rheumatoid arthritis which is currently incurable. 10. Use of silver: a historical perspective The antibacterial property of silver has been known for thousands of years with the ancient Greeks cooking from silver pot. The antimicrobial properties of silver were utilized as early as 1000 BC to keep water safe [190]. The Greeks and others used silver vessels for drinking water and other liquids. Alexander the Great used to drink only from silver vessels [191]. This is recently attributed to the anti-microbial activities of released Ag+ ions. The rst recorded medicinal use of silver goes back to 8th century. In 980 AD Avicenna used silver as a blood purier, for bad breath and for heart palpitations [190]. A detailed account on the early uses of silver is reviewed in an article by Klasen [192]. Silver nitrate was used to treat ulcers in 17th and 18th century. Silver nitrate pencils formed part of the standard surgical equipment in the 19th century. J. N. Rust was one of the rst to use dilute silver nitrate solution for fresh burns. The use of silver for burn patients completely disappeared around world war II [192]. At present use of silver is reemerging as a viable treatment for infections encountered in burns due to the stimulus publication by Moyer et al. [193196]. More recently silver is used as a biocide to prevent infection in burns, traumatic wounds and diabetic ulcers [191]. Other uses include coating of catheters and other medical devices implanted on/within the body [197,191]. It is also used as a water disinfectant [198]. Most of the silver products available in the market today are to counter infections in burns, open wounds and chronic ulcers and are mainly characterized by the presence of Ag+ ions. The gold standard in topical burn treatment is silver sulfadiazine (Flammazine, Smith and Nephew Health care Limited, Hull, Canada), silver sulfadiazine/ chlorhexidine (Silverex, Motiff Laboratories Pvt. Ltd. Kare Health Specialities, Verna, Goa), silver sulfadiazine with cerium nitrate (FlammaceriumR, Solvay, Brussels, Belgium), and silver sulfadiazine
1301
impregnated lipidocolloid wound dressing Urgotul SSD (Laboratories, Chenova, France) [198]. Research has shown that impregnating other materials with silver nanoparticles is a practical way to exploit the germ ghting properties of silver. Different silver products that are used to treat infection can be broadly classied in two categories depending on the presence of either (1) silver ion or (2) silver nanoparticles. 10.1. Products containing silver ions Silvazine contains 1% silver sulfadiazine used as a biocide [191,199]. Flammazine contains silver nitrate is used as an antibacterial agent for topical treatment of burns and wounds [191,198]. Silverex is a formulation of silver sulfadiazine used as an antibacterial agent used in burn wounds [191,198]. However, the use of the products described above results in the formation of cream dehydrates. To reapply, this thin layer must be removed by taking multiple baths or showers and then reapplied [191,198,199]. To overcome these difculties silver coated dressings were developed to provide long sustained release of silver to a wound site. These dressings are based on the use of nanocrystalline silver. Some examples are described below. 10.2. Products containing nanocrystalline silver Dressings containing nanocrystalline silver: The most important feature in these products is the incorporation of silver within the dressing rather than being applied as separate silver compounds [191,198,199]. Here silver is delivered to the wound by the dressing. Some examples of silver dressing containing nanocrystalline silver are given below; i) Acticoat-7: This is a dressing marketed by Smith and Newphew in UK. This dressing consists of polyethyelene mesh coated with nanocrystalline silver (b 20 nM). The silver nanoparticles provide an initial large amount of silver to the wound followed by a sustained release. ii) Actisorb Silver 220: This is another dressing containing nanocrystalline silver marketed by Johnson & Johnson, New Brunswick, NJ, USA. In this formulation nanocrystalline silver is bound to charcoal dressing. Actisorb functions by adsorbing bacteria to the charcoal dressing where it is killed by silver. iii) Aquacel-Ag hydrober: Marketed by Convatec, Skillman, NJ, USA. This is a carboxymethylcellulose dressing impregnated with silver nanoparticles. It functions by slowly releasing silver ions upon hydration.
iv) Silverlon: This is marketed by Argentum Medical, Chicago, USA. This is a polymeric fabric coated with nanocrystalline silver by autocatalytic electroless chemical plating. This is a three dimensional fabric with large surface area and exibility. It is reported that silver products containing nanocrystalline silver kill microbes more rapidly and completely than products where silver remains in the cationic form. 10.3. Mechanism of anti-microbial effect of silver In order to have bactericidal effect silver must be released into the solution. The efcacy of the solution is dependent on the concentration and shape of silver ions present. Additionally, silver interacts with structural proteins and preferentially binds with DNA bases to inhibit replication [191,199]. Furthermore, bactericidal effect of silver has also been attributed to inactivation of the enzyme phosphomannose isomerase. 10.4. Side effects of silver In minute concentrations silver is non-toxic to human cells. The epidemiological history of silver has established non-toxicity in normal use [191,199]. There has been a continuous debate on the advantages and disadvantages of the use of silver products in health care and medicine [191]. Probably, one of the most reported side effects of silver products is argyria. Argyria occurs when sub-dermal silver deposits in skin microvessels resulting in an irreversible gray to black coloration of the skin [200,201]. This permanent discoloration is not physically harmful but remains an inherent serious cosmetic problem [191]. There are also some reports of kidney toxicity and cytotoxicity [202]. Liver toxicity has also been observed following acute silver toxicity due to nanocrystalline silver [203]. Allergic reaction has also been noted in a small population of patients treated topically with silver nitrate [204]. However, it is important to note here that despite decades of use, the evidence of toxicity of silver is still not clear and silver sulfadiazine remains the main topical product used in burn [198,191]. 10.5. Silver nanoparticles interact with HIV-I Recently it was reported by Elechiguerra et al. that silver nanoparticles in a size range 110 nM bind with HIV-I in a size dependent fashion [205]. They also maintain a spatial relationship that can be explained with the help of structural information of HIV-1 envelope (Fig. 11). The exterior surface of HIV-1 is composed of two
Fig. 11. AADF images of the HIV-1 virus. a) HAADF image of an HIV-1 virus exposed to BSA-conjugated silver nanoparticles. Inset shows the regular spatial arrangement between groups of three nanoparticles. b) HAADF image of HIV-1 viruses without silver nanoparticle treatment. Inset highlights the regular spatial arrangement observed on the surface of the untreated HIV-1 virus [reproduced from Jose Luis Elechiguerra et al. Journal of Nanobiotechnology 2005, 3:6].
1302
subunits. The gp120 surface glycoprotein subunit is exposed to the exterior, whereas the gp41 transmembrane glycoprotein subunit spans the viral membrane and connects the gp120 subunit to the interior p17 matrix protein [206208]. The main function of gp120 is to bind with CD4 receptor sites on host cells [208]. The authors have shown that silver nanoparticles inhibit HIV-1 infection in CD4+MT-2 cells and cMAGI HIV-1 reporter cells. For nanoparticles preparation with various surface modications, they have shown that silver concentrations over 25 g/ml signicantly inhibited HIV-1 infection. Bare silver nanoparticles showed superior effect, whereas surface modication with BSA and PVP showed moderate effect. This is a promising study that explores potential use of silver nanoparticles towards millions of people suffering from AIDs. 11. Medicinal application of platinum nanoparticles Medicinal application of bare platinum nanoparticles is rare. Medicinal application of platinum is mainly dominated by use of platinum compounds and not nanoparticles, the most famous and well studied is cis-platin (cis-Diamminedichloroplatinum) [209,210]. The interest in platinum based compounds as antitumor agent was prompted with a discovery by Rosenberg in 1960 that platinum complexes inhibit cell division [211,212]. Cis-Diamminedichloroplatinum(II) (cis-[PtCl2(NH3)2]) and cis-diaminetetrachloroplatinum(IV) (cis-[PtCl4(NH3)2]). In 1978, cis-platin was approved for the treatment of testicular and ovarian cancer. It is now one of the three most widely used antitumor drugs in the world and has annual sales of approximately half a billion US dollar [210]. Most biomedical applications of platinum nanoparticles have been in combination with other nanoparticles, either in the form of an alloy, or coreshell or bimetallic nanoclusters [213]. Yolkshell nanocrystals of FePt@CoS2 have been found to be more potent in killing HeLa cells compared to cis-platin [214]. The IC50 value of FePt@CoS2 is found to be 35.5 4.7 ng of Pt/ml for HeLa cells, whereas, it is 230 ng of Pt/ml in case of cis-platin. This type of engineered nanomaterials may ultimately lead to the development of new types of nanodrugs with improved cytotoxicity towards the malignant cells. Platinum nanoparticles were also used in combination with multi-walled carbon nanotubes (MWCNTs) for fabricating sensitivity-enhanced electrochemical DNA biosensor. Due to the ability of carbon nanotubes to promote electron-transfer reactions, the high catalytic activities of platinum nanoparticles for chemical reactions, the sensitivity of presented electrochemical DNA biosensors was remarkably improved. The detection limit of the method for target DNA was 1.0 1011 mol l 1 [215]. Recently a group has reported synthesis of carboxy-terminated platinum nanoparticles attached to a NO donor (MPC-3). These entities are water soluble and are able to supply NO under the control of visible light stimuli [216]. 12. Conclusion and future direction We discussed in this review some novel and unique biological properties of metal nanoparticles of gold, silver and platinum. These nanoparticles have the properties to interact specically with selected proteins and inhibit their activities. Since many diseases such as cancer, arthritis, macular degeneration, etc, are dependent on angiogenesis, these discoveries open new possibilities to inactivate the function of disease inducing protein by metal nanoparticles and surface modied metal nanoparticles. It would also be important to investigate what the effect of the protein structure and charge would have on such interaction with metal nanoparticles, in general. Is it the net charge of the protein important to be inactivated by gold nanoparticles or is it distribution of charge on the heparin-binding domain/protein that plays the crucial role? Or are the cysteine residues in the heparin-binding domain important? If so, is it a single residue or a collection of cysteine residues that form a binding motif
for gold nanoparticles? Is it dependent on the size of the gold nanoparticles or on the nature of the nanoparticles? Is it dependent on protein structure? Same questions are also applicable for other metal nanoparticles including silver and platinum. Would we be able to synthesize or design nanoparticles that will sense and deactivate protein function more effectively and specically? Such structurebased design, detection, and deactivation will lead to new therapeutic strategies for those incurable diseases that were unimaginable before. Acknowledgements This work is supported by 2A3450 (CLL-Global foundation), RAF20P (Hem-malignancy program at Mayo Clinic) and State-1 grant to PM. References
[1] P. Alivisatos, The use of nanocrystals in biological detection, Nat. Biotechnol. 22 (2004) 4752. [2] J.C. Love, L.A. Estroff, J.K. Kriebel, R.G. Nuzzo, G.M. Whitesides, Self-assembled monolayers of thiolates on metals as a form of nanotechnology, Chem. Rev. 105 (2005) 11031169. [3] C.A. Mirkin, T.A. Taton, Semiconductors meet biology, Nature 405 (2000) 626627. [4] S. Nie, Y. Xing, G.J. Kim, J.W. Simons, Nanotechnology applications in cancer, Annu. Rev. Biomed. Eng. 9 (2007) 257288. [5] M.D. Wang, D.M. Shin, J.W. Simons, S. Nie, Nanotechnology for targeted cancer therapy, Expert. Rev. Anticancer Ther. 7 (2007) 833837. [6] M.C. Daniel, D. Astruc, Gold nanoparticles: assembly, supramolecular chemistry, quantum-size-related properties, and applications toward biology, catalysis, and nanotechnology, Chem. Rev. 104 (2004) 293346. [7] C. Burda, X. Chen, R. Narayanan, M.A. El-Sayed, Chemistry and properties of nanocrystals of different shapes, Chem. Rev. 105 (2005) 10251102. [8] P. Mulvaney, Surface plasmon spectroscopy of nanosized metal particles, Langmuir 12 (1996) 788798. [9] C.C.M. You, O.R. Gider, B. Ghosh, S.P. Kim, I. Erdogan, B. Krovi, S.A. Bunz, U.H.F. Rotello, V.M., Detection and identication of proteins using nanoparticle? Fluorescent polymer chemical nose sensors, Nature Nanotech. 2 (2007) 318323. [10] G. Han, P. Ghosh, V.M. Rotello, Functionalized gold nanoparticles for drug delivery, Nanomedical 2 (2007) 113123. [11] L.R. Hirsch, J.B. Jackson, A. Lee, N.J. Halas, J.L. West, A whole blood immunoassay using gold nanoshells, Anal. Chem. 75 (2003) 23772381. [12] L.R. Hirsch, R.J. Stafford, J.A. Bankson, S.R. Sershen, B. Rivera, R.E. Price, J.D. Hazle, N.J. Halas, J.L. West, Nanoshell-mediated near-infrared thermal therapy of tumors under magnetic resonance guidance, Proc. Natl. Acad. Sci. U. S. A. 100 (2003) 1354913554. [13] R. Bhattacharya, C.R. Patra, A. Earl, S. Wang, A. Katarya, L. Lu, J.N. Kizhakkedathu, M.J. Yaszemski, P.R. Greipp, D. Mukhopadhyay, P. Mukherjee, Attaching folic acid on gold nanoparticles using noncovalent interaction via different polyethylene glycol backbones and targeting of cancer cells, Nanomedical 3 (2007) 224238. [14] G.J. Higby, Gold in medicine: a review of its use in the West before 1900, Gold Bull. 15 (1982) 130140. [15] S. Mahdihassan, Colloidal gold as an alchemical preparation, Janus 58 (1971) 112118. [16] S. Mahdihassan, The tradition of alchemy in India, Am. J. Chin. Med. 9 (1981) 2333. [17] S. Mahdihassan, Cinnabar-gold as the best alchemical drug of longevity, called Makaradhwaja in India, Am. J. Chin. Med. 13 (1985) 93108. [18] S.P. Fricker, R.G. Buckley, Comparison of two colorimetric assays as cytotoxicity endpoints for an in vitro screen for antitumour agents, Anticancer Res. 16 (1996) 37553760. [19] I.C. Shaw, Gold-based therapeutic agents, Chem. Rev. 99 (1999) 25892600. [20] D.T. Felson, J.J. Anderson, R.F. Meenan, The comparative efcacy and toxicity of second-line drugs in rheumatoid arthritis. Results of two metaanalyses, Arthritis. Rheum. 33 (1990) 14491461. [21] S.J. Berners-Price, G.R. Girard, D.T. Hill, B.M. Sutton, P.S. Jarrett, L.F. Faucette, R.K. Johnson, C.K. Mirabelli, P.J. Sadler, Cytotoxicity and antitumor activity of some tetrahedral bis(diphosphino)gold(I) chelates, J. Med. Chem. 33 (1990) 13861392. [22] S.J. Berners-Price, P.J. Sadler, Interaction of the antitumor Au(I) complex [Au(Ph2P (CH2)2PPh2)2]Cl with human blood plasma, red cells, and lipoproteins: 31P and 1H NMR studies, J. Inorg. Biochem. 31 (1987) 267281. [23] I. Haiduc, C. Silvestru, Rhodium, iridium, copper and gold antitumor organometallic compounds (review), In Vivo 3 (1989) 285293. [24] S.J. Berners-Price, R.E. Norman, P.J. Sadler, The autoxidation and proton dissociation constants of tertiary diphosphines: relevance to biological activity, J. Inorg. Biochem. 31 (1987) 197209. [25] G.A. Andrews, S.W. Root, H.D. Kerman, R.R. Bigelow, Intracavitary colloidal radiogold in the treatment of effusions caused by malignant neoplasms, Ann. Surg. 137 (1953) 375381. [26] H.B. Wheeler, W.E. Jaques, T.W. Botsford, Experiences with the use of radioactive colloidal gold in the treatment of cancer, Ann. Surg. 141 (1955) 208217.
R. Bhattacharya, P. Mukherjee / Advanced Drug Delivery Reviews 60 (2008) 12891306 [27] H.J. Buchsbaum, W.C. Keetel, H.B. Latourette, The use of radioisotopes as adjunct therapy of localized ovarian cancer, Semin. Oncol. 2 (1975) 247251. [28] H.J. Buchsbaum, W.C. Keettel, Radioisotopes in treatment of stage Ia ovarian cancer, Natl. Cancer Inst. Monogr. 42 (1975) 127128. [29] E.E. Rogoff, R. Romano, E.W. Hahn, The prevention of Ehrlich ascites tumor using intraperitoneal colloidal 198Au. Dose vs. size of inoculum, Radiology 114 (1975) 225226. [30] R.D. Pezner, K.R. Stevens Jr., D. Tong, C.V. Allen, Limited epithelial carcinoma of the ovary treated with curative intent by the intraperitoneal installation of radiocolloids, Cancer 42 (1978) 25632571. [31] A.E. Alfonso, A. Hassan, B. Gardner, S. Stein, J. Patti, N.A. Solomon, J. McCarthy, J. Steigman, Prevention of hepatic metastases by intravenous radioactive gold, Cancer Res. 38 (1978) 27402744. [32] P.F. Hahn, H.E. Skipper, E.L. Carothers, L.J. Bernard, The effect of radioactive colloidal metallic gold in the treatment of acute AK-4 leukemia in mice, Cancer 4 (1951) 634636. [33] P.F. Hahn, E.L. Carothers, Radioactive metallic gold colloids coated with silver and their distribution in the lung and its lymphatics following intra-pulmonary administration; therapeutic implications in primary lung and bronchiogenic tumors, Br. J. Cancer 5 (1951) 400404. [34] J.F. Hainfeld, D.N. Slatkin, H.M. Smilowitz, The use of gold nanoparticles to enhance radiotherapy in mice, Phys. Med. Biol. 49 (2004) N309N315. [35] E.B. Butler, P.T. Scardino, B.S. Teh, B.M. Uhl, W.G. Guerriero, C.E. Carlton, B.M. Berner, W.S. Dennis, L.S. Carpenter, H.H. Lu, J.K. Chiu, T.S. Kent, S.Y. Woo, The Baylor College of Medicine experience with gold seed implantation, Semin. Surg. Oncol. 13 (1997) 406418. [36] C.C. Wang, J. Busse, M. Gitterman, A simple afterloading applicator for intracavitary irradiation of carcinoma of the nasopharynx, Radiology 115 (1975) 737738. [37] H. Ashamalla, S. Raa, B. Zaki, N.C. Ikoro, P. Ross, Radioactive gold grain implants in recurrent and locally advanced head-and-neck cancers, Brachytherapy 1 (2002) 161166. [38] R.H. Flocks, H.D. Kerr, H.B. Elkins, D. Culp, Treatment of carcinoma of the prostate by interstitial radiation with radio-active gold (Au 198): a preliminary report, J. Urol. 68 (1952) 510522. [39] W.G. Guerriero, C.E. Carlton Jr., P.T. Hudgins, Combined interstitial and external radiotherapy in the denitive management of carcinoma of the prostate, Cancer 45 (1980) 19221923. [40] J. Folkman, E. Merler, C. Abernathy, G. Williams, Isolation of a tumor factor responsible for angiogenesis, J. Exp. Med. 133 (1971) 275288. [41] J. Folkman, Tumor angiogenesis, Adv. Cancer Res. 19 (1974) 331358. [42] J. Folkman, Tumor angiogensis: role in regulation of tumor growth, Symp. Soc. Dev. Biol. 30 (1974) 4352. [43] F. Bussolino, A. Mantovani, G. Persico, Molecular mechanisms of blood vessel formation, Trends. Biochem. Sci. 22 (1997) 251256. [44] D.R. Senger, S.J. Galli, A.M. Dvorak, C.A. Perruzzi, V.S. Harvey, H.F. Dvorak, Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites uid, Science 219 (1983) 983985. [45] N. Ferrara, W.J. Henzel, Pituitary follicular cells secrete a novel heparin-binding growth factor specic for vascular endothelial cells, Biochem. Biophys. Res. Commun. 161 (1989) 851858. [46] D.W. Leung, G. Cachianes, W.J. Kuang, D.V. Goeddel, N. Ferrara, Vascular endothelial growth factor is a secreted angiogenic mitogen, Science 246 (1989) 13061309. [47] P.J. Keck, S.D. Hauser, G. Krivi, K. Sanzo, T. Warren, J. Feder, D.T. Connolly, Vascular permeability factor, an endothelial cell mitogen related to PDGF, Science 246 (1989) 13091312. [48] D. Maglione, V. Guerriero, G. Viglietto, P. Delli-Bovi, M.G. Persico, Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor, Proc. Natl. Acad. Sci. U. S. A. 88 (1991) 92679271. [49] B. Olofsson, K. Pajusola, A. Kaipainen, G. von Euler, V. Joukov, O. Saksela, A. Orpana, R.F. Pettersson, K. Alitalo, U. Eriksson, Vascular endothelial growth factor B, a novel growth factor for endothelial cells, Proc. Natl. Acad. Sci. U. S. A. 93 (1996) 25762581. [50] V. Joukov, K. Pajusola, A. Kaipainen, D. Chilov, I. Lahtinen, E. Kukk, O. Saksela, N. Kalkkinen, K. Alitalo, A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases, Embo J. 15 (1996) 1751. [51] J. Lee, A. Gray, J. Yuan, S.M. Luoh, H. Avraham, W.I. Wood, Vascular endothelial growth factor-related protein: a ligand and specic activator of the tyrosine kinase receptor Flt4, Proc. Natl. Acad. Sci. U. S. A. 93 (1996) 19881992. [52] M.G. Achen, M. Jeltsch, E. Kukk, T. Makinen, A. Vitali, A.F. Wilks, K. Alitalo, S.A. Stacker, Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4), Proc. Natl. Acad. Sci. U. S. A. 95 (1998) 548553. [53] N. Ferrara, T. Davis-Smyth, The biology of vascular endothelial growth factor, Endocr. Rev. 18 (1997) 425. [54] N. Ferrara, K. Carver-Moore, H. Chen, M. Dowd, L. Lu, K.S. O'Shea, L. PowellBraxton, K.J. Hillan, M.W. Moore, Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene, Nature 380 (1996) 439442. [55] P. Carmeliet, V. Ferreira, G. Breier, S. Pollefeyt, L. Kieckens, M. Gertsenstein, M. Fahrig, A. Vandenhoeck, K. Harpal, C. Eberhardt, C. Declercq, J. Pawling, L. Moons, D. Collen, W. Risau, A. Nagy, Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele, Nature 380 (1996) 435439. [56] H.F. Dvorak, Angiogenesis: update 2005, J. Thromb. Haemost. 3 (2005) 18351842. [57] H.F. Dvorak, Rous-Whipple Award Lecture. How tumors make bad blood vessels and stroma, Am. J. Pathol. 162 (2003) 17471757.
1303
[58] T.W. Secomb, M.A. Konerding, C.A. West, M. Su, A.J. Young, S.J. Mentzer, Microangiectasias: structural regulators of lymphocyte transmigration, Proc. Natl. Acad. Sci. U. S. A. 100 (2003) 72317234. [59] L.F. Brown, K.T. Yeo, B. Berse, T.K. Yeo, D.R. Senger, H.F. Dvorak, L. van de Water, Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing, J. Exp. Med. 176 (1992) 13751379. [60] J.A. Nagy, E. Vasile, D. Feng, C. Sundberg, L.F. Brown, M.J. Detmar, J.A. Lawitts, L. Benjamin, X. Tan, E.J. Manseau, A.M. Dvorak, H.F. Dvorak, Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis, J. Exp. Med. 196 (2002) 14971506. [61] J.A. Nagy, E. Vasile, D. Feng, C. Sundberg, L.F. Brown, E.J. Manseau, A.M. Dvorak, H.F. Dvorak, VEGF-A induces angiogenesis, arteriogenesis, lymphangiogenesis, and vascular malformations, Cold Spring Harb. Symp. Quant. Biol. 67 (2002) 227237. [62] G. Ren, L.H. Michael, M.L. Entman, N.G. Frangogiannis, Morphological characteristics of the microvasculature in healing myocardial infarcts, J. Histochem. Cytochem. 50 (2002) 7179. [63] P. Carmeliet, D. Collen, Role of vascular endothelial growth factor and vascular endothelial growth factor receptors in vascular development, Curr. Top. Microbiol. Immunol. 237 (1999) 133158. [64] V. Vincenti, C. Cassano, M. Rocchi, G. Persico, Assignment of the vascular endothelial growth factor gene to human chromosome 6p21.3, Circulation 93 (1996) 14931495. [65] E. Tischer, R. Mitchell, T. Hartman, M. Silva, D. Gospodarowicz, J.C. Fiddes, J.A. Abraham, The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing, J. Biol. Chem. 266 (1991) 1194711954. [66] K.A. Houck, N. Ferrara, J. Winer, G. Cachianes, B. Li, D.W. Leung, The vascular endothelial growth factor family: identication of a fourth molecular species and characterization of alternative splicing of RNA, Mol. Endocrinol. 5 (1991) 18061814. [67] K.A. Houck, D.W. Leung, A.M. Rowland, J. Winer, N. Ferrara, Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms, J. Biol. Chem. 267 (1992) 2603126037. [68] J.E. Park, G.A. Keller, N. Ferrara, The vascular endothelial growth factor (VEGF) isoforms: differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF, Mol. Biol. Cell. 4 (1993) 13171326. [69] N. Ferrara, H.P. Gerber, J. LeCouter, The biology of VEGF and its receptors, Nat. Med. 9 (2003) 669676. [70] T. Veikkola, K. Alitalo, VEGFs, receptors and angiogenesis, Semin. Cancer Biol. 9 (1999) 211220. [71] J. Folkman, M. Klagsbrun, Angiogenic factors, Science 235 (1987) 442447. [72] T.T. Rissanen, J.E. Markkanen, M. Gruchala, T. Heikura, A. Puranen, M.I. Kettunen, I. Kholova, R.A. Kauppinen, M.G. Achen, S.A. Stacker, K. Alitalo, S. Yla-Herttuala, VEGF-D is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses, Circ. Res. 92 (2003) 10981106. [73] S. Soker, S. Takashima, H.Q. Miao, G. Neufeld, M. Klagsbrun, Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specic receptor for vascular endothelial growth factor, Cell 92 (1998) 735745. [74] H.F. Dvorak, J.A. Nagy, D. Feng, L.F. Brown, A.M. Dvorak, Vascular permeability factor/vascular endothelial growth factor and the signicance of microvascular hyperpermeability in angiogenesis, Curr. Top. Microbiol. Immunol. 237 (1999) 97132. [75] L.F. Brown, M. Detmar, K. Claffey, J.A. Nagy, D. Feng, A.M. Dvorak, H.F. Dvorak, Vascular permeability factor/vascular endothelial growth factor: a multifunctional angiogenic cytokine, Exs 79 (1997) 233269. [76] M.K. Gupta, R.Y. Qin, Mechanism and its regulation of tumor-induced angiogenesis, World J. Gastroenterol. 9 (2003) 11441155. [77] P. Nyberg, L. Xie, R. Kalluri, Endogenous inhibitors of angiogenesis, Cancer Res. 65 (2005) 39673979. [78] J. Folkman, Angiogenesis: an organizing principle for drug discovery? Nat. Rev. Drug. Discov. 6 (2007) 273286. [79] J. Folkman, Angiogenesis, Annu Rev Med 57 (2006) 118. [80] M.L. Iruela-Arispe, H.F. Dvorak, Angiogenesis: a dynamic balance of stimulators and inhibitors, Thromb. Haemost. 78 (1997) 672677. [81] N. Ferrara, R.S. Kerbel, Angiogenesis as a therapeutic target, Nature 438 (2005) 967974. [82] N. Ferrara, The role of VEGF in the regulation of physiological and pathological angiogenesis, Exs (2005) 209231. [83] J. Folkman, D. Hanahan, Switch to the angiogenic phenotype during tumorigenesis, Princess Takamatsu Symp. 22 (1991) 339347. [84] T. Yoshida, Y. Kaneko, A. Tsukamoto, K. Han, M. Ichinose, S. Kimura, Suppression of hepatoma growth and angiogenesis by a fumagillin derivative TNP470: possible involvement of nitric oxide synthase, Cancer Res. 58 (1998) 37513756. [85] Y. Sheng, J. Hua, K.G. Pinney, C.M. Garner, R.R. Kane, J.A. Prezioso, D.J. Chaplin, K. Edvardsen, Combretastatin family member OXI4503 induces tumor vascular collapse through the induction of endothelial apoptosis, Int. J. Cancer 111 (2004) 604610. [86] G.C. Tucker, Alpha v integrin inhibitors and cancer therapy, Curr. Opin. Investig. Drugs. 4 (2003) 722731. [87] J.A. Posey, M.B. Khazaeli, A. DelGrosso, M.N. Saleh, C.Y. Lin, W. Huse, A.F. LoBuglio, A pilot trial of Vitaxin, a humanized anti-vitronectin receptor (anti alpha v beta 3) antibody in patients with metastatic cancer, Cancer. Biother. Radiopharm. 16 (2001) 125132. [88] T. Taga, A. Suzuki, I. Gonzalez-Gomez, F.H. Gilles, M. Stins, H. Shimada, L. Barsky, K.I. Weinberg, W.E. Laug, alpha v-Integrin antagonist EMD 121974 induces
1304
R. Bhattacharya, P. Mukherjee / Advanced Drug Delivery Reviews 60 (2008) 12891306 apoptosis in brain tumor cells growing on vitronectin and tenascin, Int. J. Cancer 98 (2002) 690697. L.M. Evans, L.M. Itri, M. Campion, R. Wyler-Plaut, S.E. Krown, J.E. Groopman, H. Goldsweig, P.A. Volberding, S.B. West, R.T. Mitsuyasu, et al., Interferon-alpha 2a in the treatment of acquired immunodeciency syndrome-related Kaposi's sarcoma, J. Immunother. 10 (1991) 3950. M.A. Fischl, D.M. Finkelstein, W. He, W.G. Powderly, P.L. Triozzi, R.T. Steigbigel, A phase II study of recombinant human interferon-alpha 2a and zidovudine in patients with AIDS-related Kaposi's sarcoma. AIDS Clinical Trials Group, J. Acquir. Immune. Dec. Syndr. Hum. Retrovirol. 11 (1996) 379384. A.K. Morris, A.W. Valley, Overview of the management of AIDS-related Kaposi's sarcoma, Ann. Pharmacother. 30 (1996) 11501163. K. Yorozuya, T. Kubota, M. Watanabe, H. Hasegawa, S. Ozawa, M. Kitajima, L.M. Chikahisa, Y. Yamada, TSU-68 (SU6668) inhibits local tumor growth and liver metastasis of human colon cancer xenografts via anti-angiogenesis, Oncol. Rep. 14 (2005) 677682. L.M. Ellis, Bevacizumab, Nat. Rev. Drug. Discov. Suppl (2005) S8S9. W.P. Steward, Marimastat (BB2516): current status of development, Cancer Chemother. Pharmacol. 43 (Suppl) (1999) S56S60. G.H. Ripple, G. Wilding, Drug development in prostate cancer, Semin. Oncol. 26 (1999) 217226. K.D. Tutsch, R.Z. Arzoomanian, D. Alberti, M.B. Tombes, C. Feierabend, H.I. Robins, D.R. Spriggs, G. Wilding, Phase I clinical and pharmacokinetic study of an onehour infusion of ormaplatin (NSC 363812), Invest. New Drugs 17 (1999) 6372. G.F. Woude, G.J. Kelloff, R.W. Ruddon, H.M. Koo, C.C. Sigman, J.C. Barrett, R.W. Day, A.P. Dicker, R.S. Kerbel, D.R. Parkinson, W.J. Slichenmyer, Reanalysis of cancer drugs: old drugs, new tricks, Clin. Cancer Res. 10 (2004) 38973907. R.S. Kerbel, Antiangiogenic drugs and current strategies for the treatment of lung cancer, Semin. Oncol. 31 (2004) 5460. R.S. Kerbel, B.A. Kamen, The anti-angiogenic basis of metronomic chemotherapy, Nat. Rev. Cancer 4 (2004) 423436. J.F. Hainfeld, D.N. Slatkin, T.M. Focella, H.M. Smilowitz, Gold nanoparticles: a new X-ray contrast agent, Br. J. Radiol. 79 (2006) 248253. C.M. Goodman, C.D. McCusker, T. Yilmaz, V.M. Rotello, Toxicity of gold nanoparticles functionalized with cationic and anionic side chains, Bioconjug. Chem. 15 (2004) 897900. R.J. Esther, R. Bhattacharya, M. Ruan, M.E. Bolander, D. Mukhopadhyay, G. Sarkar, P. Mukherjee, Gold nanoparticles do not affect the global transcriptional program of human umbilical vein endothelial cells: a DNA-microarray analysis, J. Biomed. Nanotech. 3 (2005) 328335. E.E. Connor, J. Mwamuka, A. Gole, C.J. Murphy, M.D. Wyatt, Gold nanoparticles are taken up by human cells but do not cause acute cytotoxicity, Small 1 (2005) 325327. P. Mukherjee, R. Bhattacharya, N. Bone, Y.K. Lee, C.R. Patra, S. Wang, L. Lu, C. Secreto, P.C. Banerjee, M.J. Yaszemski, N.E. Kay, D. Mukhopadhyay, Potential therapeutic application of gold nanoparticles in B-chronic lymphocytic leukemia (BCLL): enhancing apoptosis, J. Nanobiotechnology 5 (2007) 4. P. Mukherjee, R. Bhattacharya, P. Wang, L. Wang, S. Basu, J.A. Nagy, A. Atala, D. Mukhopadhyay, S. Soker, Antiangiogenic properties of gold nanoparticles, Clin. Cancer Res. 11 (2005) 35303534. W.P. Faulk, G.M. Taylor, An immunocolloid method for the electron microscope, Immunochemistry 8 (1971) 10811083. R. Balasubramanian, R. Guo, A.J. Mills, R.W. Murray, Reaction of Au(55)(PPh(3)) (12)Cl(6) with thiols yields thiolate monolayer protected Au(75) clusters, J. Am. Chem. Soc. 127 (2005) 81268132. R. Guo, Y. Song, G. Wang, R.W. Murray, Does core size matter in the kinetics of ligand exchanges of monolayer-protected Au clusters? J. Am. Chem. Soc. 127 (2005) 27522757. N.O. Fischer, C.M. McIntosh, J.M. Simard, V.M. Rotello, Inhibition of chymotrypsin through surface binding using nanoparticle-based receptors, Proc. Natl. Acad. Sci. U S A 99 (2002) 50185023. D.R. Senger, C.A. Perruzzi, J. Feder, H.F. Dvorak, A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines, Cancer Res. 46 (1986) 56295632. W. Risau, Mechanisms of angiogenesis, Nature 386 (1997) 671674. J. Folkman, Antiangiogenesis in cancer therapyendostatin and its mechanisms of action, Exp. Cell. Res. 312 (2006) 594607. J. Folkman, R. Kalluri, Cancer without disease, Nature 427 (2004) 787. N. Ferrara, R.D. Mass, C. Campa, R. Kim, Targeting VEGF-A to treat cancer and agerelated macular degeneration, Annu. Rev. Med. 58 (2007) 491504. H. Zeng, D. Zhao, D. Mukhopadhyay, Flt-1-mediated down-regulation of endothelial cell proliferation through pertussis toxin-sensitive G proteins, beta gamma subunits, small GTPase CDC42, and partly by Rac-1, J. Biol. Chem. 277 (2002) 40034009. K.L. Prime, G.M. Whitesides, Self-assembled organic monolayers: model systems for studying adsorption of proteins at surfaces, Science 252 (1991) 11641167. I.M. Tidswell, T.A. Rabedeau, P.S. Pershan, J.P. Folkers, M.V. Baker, G.M. Whitesides, Wetting lms on chemically modied surfaces: an X-ray study, Phys. Rev. B Condens. Matter. 44 (1991) 1086910879. G.M. Whitesides, J.P. Mathias, C.T. Seto, Molecular self-assembly and nanochemistry: a chemical strategy for the synthesis of nanostructures, Science 254 (1991) 13121319. R.R. Siegel, P. Harder, R. Dahint, M. Grunze, F. Josse, M. Mrksich, G.M. Whitesides, On-line detection of nonspecic protein adsorption at articial surfaces, Anal. Chem. 69 (1997) 33213328. A. Kumar, H. Joshi, R. Pasricha, A.B. Mandale, M. Sastry, Phase transfer of silver nanoparticles from aqueous to organic solutions using fatty amine molecules, J. Colloid. Interface. Sci. 264 (2003) 396401. [121] P. Carmeliet, R.K. Jain, Angiogenesis in cancer and other diseases, Nature 407 (2000) 249257. [122] A.E. Koch, Angiogenesis as a target in rheumatoid arthritis, Ann. Rheum. Dis. 62 (Suppl 2) (2003) ii60ii67. [123] T. Pincus, G. Ferraccioli, T. Sokka, A. Larsen, R. Rau, I. Kushner, F. Wolfe, Evidence from clinical trials and long-term observational studies that disease-modifying anti-rheumatic drugs slow radiographic progression in rheumatoid arthritis: updating a 1983 review, Rheumatology (Oxford) 41 (2002) 13461356. [124] S. Basu, J.A. Nagy, S. Pal, E. Vasile, I.A. Eckelhoefer, V.S. Bliss, E.J. Manseau, P.S. Dasgupta, H.F. Dvorak, D. Mukhopadhyay, The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor, Nat. Med. 7 (2001) 569574. [125] J.A. Nagy, M.S. Meyers, E.M. Masse, K.T. Herzberg, H.F. Dvorak, Pathogenesis of ascites tumor growth: brinogen inux and brin accumulation in tissues lining the peritoneal cavity, Cancer Res. 55 (1995) 369375. [126] J. Folkman, D. Hanahan, Switch to the angiogenic phenotype during tumorigenesis, Princess Takamatsu Symp. 22 (1991) 339347. [127] K. Sugimachi, S. Tanaka, T. Terashi, K. Taguchi, T. Rikimaru, The mechanisms of angiogenesis in hepatocellular carcinoma: angiogenic switch during tumor progression, Surgery 131 (2002) S135S141. [128] F. Tosetti, R. Benelli, A. Albini, The angiogenic switch in solid tumors: clinical implications, Suppl. Tumori. 1 (2002) S9S11. [129] T.M. Mundel, R. Kalluri, Type IV collagen-derived angiogenesis inhibitors, Microvasc. Res. (2007). [130] M. Sund, Y. Hamano, H. Sugimoto, A. Sudhakar, M. Soubasakos, U. Yerramalla, L.E. Benjamin, J. Lawler, M. Kieran, A. Shah, R. Kalluri, Function of endogenous inhibitors of angiogenesis as endothelium-specic tumor suppressors, Proc. Natl. Acad. Sci. U. S. A. 102 (2005) 29342939. [131] A. Sudhakar, P. Nyberg, V.G. Keshamouni, A.P. Mannam, J. Li, H. Sugimoto, D. Cosgrove, R. Kalluri, Human alpha1 type IV collagen NC1 domain exhibits distinct antiangiogenic activity mediated by alpha1beta1 integrin, J. Clin. Invest. 115 (2005) 28012810. [132] Y. Hamano, R. Kalluri, Tumstatin, the NC1 domain of alpha3 chain of type IV collagen, is an endogenous inhibitor of pathological angiogenesis and suppresses tumor growth, Biochem. Biophys. Res. Commun. 333 (2005) 292298. [133] Y. Hamano, H. Sugimoto, M.A. Soubasakos, M. Kieran, B.R. Olsen, J. Lawler, A. Sudhakar, R. Kalluri, Thrombospondin-1 associated with tumor microenvironment contributes to low-dose 50 cyclophosphamide-mediated endothelial cell apoptosis and tumor growth suppression, Cancer Res. 64 (2004) 15701574. [134] F. de Fraipont, M. El Ati, C. Gicquel, X. Bertagna, E.M. Chambaz, J.J. Feige, Expression of the angiogenesis markers vascular endothelial growth factor-A, thrombospondin-1, and platelet-derived endothelial cell growth factor in human sporadic adrenocortical tumors: correlation with genotypic alterations, J. Clin. Endocrinol. Metab. 85 (2000) 47344741. [135] T.A. Baudino, C. McKay, H. Pendeville-Samain, J.A. Nilsson, K.H. Maclean, E.L. White, A.C. Davis, J.N. Ihle, J.L. Cleveland, c-Myc is essential for vasculogenesis and angiogenesis during development and tumor progression, Genes Dev. 16 (2002) 25302543. [136] O.V. Volpert, R.M. Alani, Wiring the angiogenic switch: Ras, Myc, and Thrombospondin-1, Cancer Cell. 3 (2003) 199200. [137] B. Czernobilsky, R. Moll, G. Leppien, G. Schweikhart, W.W. Franke, Desmosomal plaqueassociated vimentin laments in human ovarian granulosa cell tumors of various histologic patterns, Am. J. Pathol. 126 (1987) 476486. [138] E.S. Bamberger, C.W. Perrett, Angiogenesis in epithelian ovarian cancer, Mol. Pathol. 55 (2002) 348359. [139] J.D. Gordon, S. Mesiano, C.J. Zaloudek, R.B. Jaffe, Vascular endothelial growth factor localization in human ovary and fallopian tubes: possible role in reproductive function and ovarian cyst formation, J. Clin. Endocrinol. Metab. 81 (1996) 353359. [140] G.M. Abu-Jawdeh, J.D. Faix, J. Niloff, K. Tognazzi, E. Manseau, H.F. Dvorak, L.F. Brown, Strong expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in ovarian borderline and malignant neoplasms, Lab. Invest. 74 (1996) 11051115. [141] C.A. Boocock, D.S. Charnock-Jones, A.M. Sharkey, J. McLaren, P.J. Barker, K.A. Wright, P.R. Twentyman, S.K. Smith, Expression of vascular endothelial growth factor and its receptors t and KDR in ovarian carcinoma, J. Natl. Cancer. Inst. 87 (1995) 506516. [142] K. Reynolds, F. Farzaneh, W.P. Collins, S. Campbell, T.H. Bourne, F. Lawton, A. Moghaddam, A.L. Harris, R. Bicknell, Association of ovarian malignancy with expression of platelet-derived endothelial cell growth factor, J. Natl. Cancer Inst. 86 (1994) 12341238. [143] P.J. Paley, K.A. Staskus, K. Gebhard, D. Mohanraj, L.B. Twiggs, L.F. Carson, S. Ramakrishnan, Vascular endothelial growth factor expression in early stage ovarian carcinoma, Cancer 80 (1997) 98106. [144] S. Mesiano, N. Ferrara, R.B. Jaffe, Role of vascular endothelial growth factor in ovarian cancer: inhibition of ascites formation by immunoneutralization, Am. J. Pathol. 153 (1998) 12491256. [145] T.A. Olson, D. Mohanraj, L.F. Carson, S. Ramakrishnan, Vascular permeability factor gene expression in normal and neoplastic human ovaries, Cancer Res. 54 (1994) 276280. [146] S. Yamamoto, I. Konishi, M. Mandai, H. Kuroda, T. Komatsu, K. Nanbu, H. Sakahara, T. Mori, Expression of vascular endothelial growth factor (VEGF) in epithelial ovarian neoplasms: correlation with clinicopathology and patient survival, and analysis of serum VEGF levels, Br. J. Cancer 76 (1997) 12211227. [147] S. Yamamoto, I. Konishi, Y. Tsuruta, K. Nanbu, M. Mandai, H. Kuroda, K. Matsushita, A.A. Hamid, Y. Yura, T. Mori, Expression of vascular endothelial
[89]
[90]
[91] [92]
[93] [94] [95] [96]
[97]
[98] [99] [100] [101]
[102]
[103] [104]
[105]
[106] [107]
[108]
[109]
[110]
[111] [112] [113] [114] [115]
[116] [117]
[118] [119]
[120]
R. Bhattacharya, P. Mukherjee / Advanced Drug Delivery Reviews 60 (2008) 12891306 growth factor (VEGF) during folliculogenesis and corpus luteum formation in the human ovary, Gynecol. Endocrinol. 11 (1997) 371381. N. McClure, D.L. Healy, P.A. Rogers, J. Sullivan, L. Beaton, R.V. Haning Jr., D.T. Connolly, D.M. Robertson, Vascular endothelial growth factor as capillary permeability agent in ovarian hyperstimulation syndrome, Lancet 344 (1994) 235236. J.A. Nagy, K.T. Herzberg, J.M. Dvorak, H.F. Dvorak, Pathogenesis of malignant ascites formation: initiating events that lead to uid accumulation, Cancer Res. 53 (1993) 26312643. J.A. Nagy, E.M. Masse, K.T. Herzberg, M.S. Meyers, K.T. Yeo, T.K. Yeo, T.M. Sioussat, H.F. Dvorak, Pathogenesis of ascites tumor growth: vascular permeability factor, vascular hyperpermeability, and ascites uid accumulation, Cancer Res. 55 (1995) 360368. J.A. Nagy, E.S. Morgan, K.T. Herzberg, E.J. Manseau, A.M. Dvorak, H.F. Dvorak, Pathogenesis of ascites tumor growth: angiogenesis, vascular remodeling, and stroma formation in the peritoneal lining, Cancer Res. 55 (1995) 376385. T. Hideshima, J.E. Bradner, J. Wong, D. Chauhan, P. Richardson, S.L. Schreiber, K.C. Anderson, Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma, Proc. Natl. Acad. Sci. U. S. A. 102 (2005) 85678572. M. Attal, J.L. Harousseau, T. Facon, F. Guilhot, C. Doyen, J.G. Fuzibet, M. Monconduit, C. Hulin, D. Caillot, R. Bouabdallah, L. Voillat, J.J. Sotto, B. Grosbois, R. Bataille, Single versus double autologous stem-cell transplantation for multiple myeloma, N. Engl. J. Med. 349 (2003) 24952502. S. Singhal, J. Mehta, Novel therapies in multiple myeloma, Int. J. Hematol. 77 (2003) 226231. T. Hideshima, K.C. Anderson, Molecular mechanisms of novel therapeutic approaches for multiple myeloma, Nat. Rev. Cancer 2 (2002) 927937. T. Hideshima, C. Mitsiades, G. Tonon, P.G. Richardson, K.C. Anderson, Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets, Nat. Rev. Cancer 7 (2007) 585598. M. Altun, P.J. Galardy, R. Shringarpure, T. Hideshima, R. LeBlanc, K.C. Anderson, H.L. Ploegh, B.M. Kessler, Effects of PS-341 on the activity and composition of proteasomes in multiple myeloma cells, Cancer Res. 65 (2005) 78967901. H. Yasui, T. Hideshima, N. Raje, A.M. Roccaro, N. Shiraishi, S. Kumar, M. Hamasaki, K. Ishitsuka, Y.T. Tai, K. Podar, L. Catley, C.S. Mitsiades, P.G. Richardson, R. Albert, V. Brinkmann, D. Chauhan, K.C. Anderson, FTY720 induces apoptosis in multiple myeloma cells and overcomes drug resistance, Cancer Res. 65 (2005) 74787484. P.G. Richardson, C. Mitsiades, Bortezomib: proteasome inhibition as an effective anticancer therapy, Future Oncol. 1 (2005) 161171. A. Badros, N. Gahres, Bortezomib, thalidomide, and dexamethasone for relapsed multiple myeloma: add it up and wait, Clin. Adv. Hematol. Oncol. 3 (2005) 916917 discussion 918. K. Podar, K.C. Anderson, Inhibition of VEGF signaling pathways in multiple myeloma and other malignancies, Cell Cycle 6 (2007) 538542. K. Podar, M.S. Raab, G. Tonon, M. Sattler, D. Barila, J. Zhang, Y.T. Tai, H. Yasui, N. Raje, R.A. DePinho, T. Hideshima, D. Chauhan, K.C. Anderson, Up-regulation of c-Jun inhibits proliferation and induces apoptosis via caspase-triggered c-Abl cleavage in human multiple myeloma, Cancer Res. 67 (2007) 16801688. K. Podar, M.S. Raab, J. Zhang, D. McMillin, I. Breitkreutz, Y.T. Tai, B.K. Lin, N. Munshi, T. Hideshima, D. Chauhan, K.C. Anderson, Targeting PKC in multiple myeloma: in vitro and in vivo effects of the novel, orally available small-molecule inhibitor enzastaurin (LY317615.HCl), Blood 109 (2007) 16691677. K. Podar, N. Raje, K.C. Anderson, Inhibition of the TGF-beta signaling pathway in tumor cells, Recent Results Cancer Res. 172 (2007) 7797. K. Podar, P.G. Richardson, D. Chauhan, K.C. Anderson, Targeting the vascular endothelial growth factor pathway in the treatment of multiple myeloma, Expert. Rev. Anticancer. Ther. 7 (2007) 551566. K. Podar, Y.T. Tai, B.K. Lin, R.P. Narsimhan, M. Sattler, T. Kijima, R. Salgia, D. Gupta, D. Chauhan, K.C. Anderson, Vascular endothelial growth factor-induced migration of multiple myeloma cells is associated with beta 1 integrin- and phosphatidylinositol 3-kinase-dependent PKC alpha activation, J. Biol. Chem. 277 (2002) 78757881. R. Bhattacharya, C.R. Patra, R. Verma, S. Kumar, P.R. Greipp, P. Mukherjee, Gold nanoparticles inhibit the proliferation of multiple myeloma cells, Adv. Mater. 19 (2007) 711716. R. Bhattacharya, N. Kang-Decker, D.A. Hughes, P. Mukherjee, V. Shah, M.A. McNiven, D. Mukhopadhyay, Regulatory role of dynamin-2 in VEGFR-2/KDRmediated endothelial signaling, Faseb J. 19 (2005) 16921694. J. Slingerland, M. Pagano, Regulation of the cdk inhibitor p27 and its deregulation in cancer, J. Cell Physiol. 183 (2000) 1017. W.H. Park, E.S. Kim, B.K. Kim, Y.Y. Lee, Monensin-mediated growth inhibition in NCIH929 myeloma cells via cell cycle arrest and apoptosis, Int. J. Oncol. 23 (2003) 197204. M. Boccadoro, G. Morgan, J. Cavenagh, Preclinical evaluation of the proteasome inhibitor bortezomib in cancer therapy, Can. Cell. Int. 5 (2005) 18. P.R. Greipp, J. San Miguel, B.G. Durie, J.J. Crowley, B. Barlogie, J. Blade, M. Boccadoro, J.A. Child, H. Avet-Loiseau, R.A. Kyle, J.J. Lahuerta, H. Ludwig, G. Morgan, R. Powles, K. Shimizu, C. Shustik, P. Sonneveld, P. Tosi, I. Turesson, J. Westin, International staging system for multiple myeloma, J. Clin. Oncol. 23 (2005) 34123420. T. Hideshima, D. Chauhan, R. Schlossman, P. Richardson, K.C. Anderson, The role of tumor necrosis factor alpha in the pathophysiology of human multiple myeloma: therapeutic applications, Oncogene 20 (2001) 45194527. F. Caligaris-Cappio, Biology of chronic lymphocytic leukemia, Rev. Clin. Exp. Hematol. 4 (2000) 521.
1305
[148]
[149]
[150]
[151]
[152]
[153]
[154] [155] [156]
[157]
[158]
[159] [160]
[161] [162]
[163]
[164] [165]
[166]
[167]
[168]
[169] [170] [171] [172]
[173]
[174]
[175] B.D. Cheson, Emerging therapies and future directions in chronic lymphocytic leukaemiachemotherapy, Hematol. Cell. Ther. 42 (2000) 4147. [176] F. Caligaris-Cappio, Biology of chronic lymphocytic leukemia, Rev. Clin. Exp. Hematol. 4 (2000) 521. [177] B.D. Cheson, Emerging therapies and future directions in chronic lymphocytic leukaemiachemotherapy, Hematol. Cell. Ther. 42 (2000) 4147. [178] C.S. Zent, N.E. Kay, Advances in the understanding of biology and prognosis in chronic lymphocytic leukemia, Curr. Oncol. Rep. 6 (2004) 348354. [179] N.E. Kay, S.M. Geyer, T.G. Call, T.D. Shanafelt, C.S. Zent, D.F. Jelinek, R. Tschumper, N.D. Bone, G.W. Dewald, T.S. Lin, N.A. Heerema, L. Smith, M.R. Grever, J.C. Byrd, Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows signicant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia, Blood 109 (2007) 405411. [180] T.D. Shanafelt, T.E. Witzig, S.R. Fink, R.B. Jenkins, S.F. Paternoster, S.A. Smoley, K.J. Stockero, D.M. Nast, H.C. Flynn, R.C. Tschumper, S. Geyer, C.S. Zent, T.G. Call, D.F. Jelinek, N.E. Kay, G.W. Dewald, Prospective evaluation of clonal evolution during long-term follow-up of patients with untreated early-stage chronic lymphocytic leukemia, J. Clin. Oncol. 24 (2006) 46344641. [181] C.S. Zent, T.G. Call, W.J. Hogan, T.D. Shanafelt, N.E. Kay, Update on risk-stratied management for chronic lymphocytic leukemia, Leuk. Lymphoma 47 (2006) 17381746. [182] A.R. Kini, N.E. Kay, L.C. Peterson, Increased bone marrow angiogenesis in B cell chronic lymphocytic leukemia, Leukemia 14 (2000) 14141418. [183] T. Menzel, Z. Rahman, E. Calleja, K. White, E.L. Wilson, R. Wieder, J. Gabrilove, Elevated intracellular level of basic broblast growth factor correlates with stage of chronic lymphocytic leukemia and is associated with resistance to udarabine, Blood 87 (1996) 10561063. [184] A. Konig, T. Menzel, S. Lynen, L. Wrazel, A. Rosen, A. Al-Katib, E. Raveche, J.L. Gabrilove, Basic broblast growth factor (bFGF) upregulates the expression of bcl-2 in B cell chronic lymphocytic leukemia cell lines resulting in delaying apoptosis, Leukemia 11 (1997) 258265. [185] H. Chen, A.T. Treweeke, D.C. West, K.J. Till, J.C. Cawley, M. Zuzel, C.H. Toh, In vitro and in vivo production of vascular endothelial growth factor by chronic lymphocytic leukemia cells, Blood 96 (2000) 31813187. [186] J. Folkman, Angiogenesis in cancer, vascular, rheumatoid and other disease, Nat. Med. 1 (1995) 2731. [187] R.A. Fava, N.J. Olsen, G. Spencer-Green, K.T. Yeo, T.K. Yeo, B. Berse, R.W. Jackman, D. R. Senger, H.F. Dvorak, L.F. Brown, Vascular permeability factor/endothelial growth factor (VPF/VEGF): accumulation and expression in human synovial uids and rheumatoid synovial tissue, J. Exp. Med. 180 (1994) 341346. [188] S.S. Lee, Y.S. Joo, W.U. Kim, D.J. Min, J.K. Min, S.H. Park, C.S. Cho, H.Y. Kim, Vascular endothelial growth factor levels in the serum and synovial uid of patients with rheumatoid arthritis, Clin. Exp. Rheumatol. 19 (2001) 321324. [189] C.Y. Tsai, A.L. Shiau, S.Y. Chen, Y.H. Chen, P.C. Cheng, M.Y. Chang, D.H. Chen, C.H. Chou, C.R. Wang, C.L. Wu, Amelioration of collagen-induced arthritis in rats by nanogold, Arthritis Rheum. 56 (2007) 544554. [190] A. Wadhera, M. Fung, Systemic argyria associated with ingestion of colloidal silver, Dermatol. Online. J. 11 (2005) 12. [191] S. Silver, L.T. Phung, G. Silver, Silver as biocides in burn and wound dressings and bacterial resistance to silver compounds, J. Ind. Microbiol. Biotechnol. (2006). [192] H.J. Klasen, Historical review of the use of silver in the treatment of burns. I. Early uses, Burns 26 (2000) 117130. [193] C.A. Moyer, A treatment of burns, Trans. Stud. Coll. Physicians Philadelphia 33 (1965) 53103. [194] C.A. Moyer, Some effects of 0.5 per cent silver nitrate and high humidity upon the illness associated with large burns, J. Natl. Med. Assoc. 57 (1965) 95100. [195] C.A. Moyer, L. Brentano, D.L. Gravens, H.W. Margraf, W.W. Monafo Jr., Treatment of large human burns with 0.5 per cent silver nitrate solution, Arch. Surg. 90 (1965) 812867. [196] H.J. Klasen, A historical review of the use of silver in the treatment of burns. II. Renewed interest for silver, Burns 26 (2000) 131138. [197] R.O. Darouiche, Anti-infective efcacy of silver-coated medical prostheses, Clin. Infect. Dis. 29 (1999) 13711377 quiz 1378. [198] B.S. Atiyeh, M. Costagliola, S.N. Hayek, S.A. Dibo, Effect of silver on burn wound infection control and healing: review of the literature, Burns 33 (2007) 139148. [199] S. Silver, Bacterial silver resistance: molecular biology and uses and misuses of silver compounds, FEMS Microbiol. Rev. 27 (2003) 341353. [200] C.M. Payne, C. Bladin, A.C. Colchester, J. Bland, R. Lapworth, D. Lane, Argyria from excessive use of topical silver sulphadiazine, Lancet 340 (1992) 126. [201] A.T. Wan, R.A. Conyers, C.J. Coombs, J.P. Masterton, Determination of silver in blood, urine, and tissues of volunteers and burn patients, Clin. Chem. 37 (1991) 16831687. [202] G. Chaby, V. Viseux, J.F. Poulain, B. De Cagny, J.P. Denoeux, C. Lok, Topical silver sulfadiazine-induced acute renal failure, Ann. Dermatol. Venereol. 132 (2005) 891893. [203] M. Trop, Silver-coated dressing acticoat caused raised liver enzymes and argyrialike symptoms in burn patient, J. Trauma. 61 (2006) 1024. [204] K. Dunn, V. Edwards-Jones, The role of Acticoat with nanocrystalline silver in the management of burns, Burns 30 (Suppl 1) (2004) S1S9. [205] J.L. Elechiguerra, J.L. Burt, J.R. Morones, A. Camacho-Bragado, X. Gao, H.H. Lara, M.J. Yacaman, Interaction of silver nanoparticles with HIV-1, J. Nanobiotechnol. 3 (2005) 6. [206] M.J. Forster, B. Mulloy, M.V. Nermut, Molecular modelling study of HIV p17gag (MA) protein shell utilising data from electron microscopy and X-ray crystallography, J. Mol. Biol. 298 (2000) 841857. [207] L.O. Arthur, J.W. Bess Jr., R.C. Sowder II, R.E. Benveniste, D.L. Mann, J.C. Chermann, L.E. Henderson, Cellular proteins bound to immunodeciency viruses: implications for pathogenesis and vaccines, Science 258 (1992) 19351938.
1306
R. Bhattacharya, P. Mukherjee / Advanced Drug Delivery Reviews 60 (2008) 12891306 [212] B. Rosenberg, L. Vancamp, T. Krigas, Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode, Nature 205 (1965) 698699. [213] C.M. Welch, R.G. Compton, The use of nanoparticles in electroanalysis: a review, Anal. Bioanal. Chem. 384 (2006) 601619. [214] J. Gao, G. Liang, B. Zhang, Y. Kuang, X. Zhang, B. Xu, FePt@CoS(2) yolkshell nanocrystals as a potent agent to kill HeLa cells, J. Am. Chem. Soc. 129 (2007) 14281433. [215] X. Wang, F. Liu, G.T.A. Senthil, X. Jing, K. Singh, V.R. Yazdanpanah, N. Bruque, R.R. Pandey, R. Lake, M. Ozkan, K.L. Wang, C.S. Ozkan, Carbon nanotube-DNA nanoarchitectures and electronic functionality, Small 2 (2006) 13561365. [216] E.B. Caruso, S. Petralia, S. Conoci, S. Giuffrida, S. Sortino, Photodelivery of nitric oxide from water-soluble platinum nanoparticles, J. Am. Chem. Soc. 129 (2007) 480481.
[208] C.K. Leonard, M.W. Spellman, L. Riddle, R.J. Harris, J.N. Thomas, T.J. Gregory, Assignment of intrachain disulde bonds and characterization of potential glycosylation sites of the type 1 recombinant human immunodeciency virus envelope glycoprotein (gp120) expressed in Chinese hamster ovary cells, J. Biol. Chem. 265 (1990) 1037310382. [209] M.D. Hall, H.R. Mellor, R. Callaghan, T.W. Hambley, Basis for design and development of platinum(IV) anticancer complexes, J. Med. Chem. 50 (2007) 34033411. [210] E. Wong, C.M. Giandomenico, Current status of platinum-based antitumor drugs, Chem. Rev. 99 (1999) 24512466. [211] B. Rosenberg, L. Van Camp, E.B. Grimley, A.J. Thomson, The inhibition of growth or cell division in Escherichia coli by different ionic species of platinum(IV) complexes, J. Biol. Chem. 242 (1967) 13471352.

Advanced Drug Delivery Reviews: Resham Bhattacharya, Priyabrata Mukherjee

Загружено:

Сведения о документе

Исходное описание:

Оригинальное название

Авторское право

Доступные форматы

Поделиться этим документом

Поделиться или встроить документ

Параметры публикации

Этот документ был вам полезен?

Это неприемлемый материал?

Авторское право:

Доступные форматы

Advanced Drug Delivery Reviews: Resham Bhattacharya, Priyabrata Mukherjee

Загружено:

Авторское право:

Доступные форматы

Advanced Drug Delivery Reviews 60 (2008) 12891306

Contents lists available at ScienceDirect

Advanced Drug Delivery Reviews

Biological properties of naked metal nanoparticles

R. Bhattacharya, P. Mukherjee / Advanced Drug Delivery Reviews 60 (2008) 12891306

R. Bhattacharya, P. Mukherjee / Advanced Drug Delivery Reviews 60 (2008) 12891306

R. Bhattacharya, P. Mukherjee / Advanced Drug Delivery Reviews 60 (2008) 12891306

R. Bhattacharya, P. Mukherjee / Advanced Drug Delivery Reviews 60 (2008) 12891306

R. Bhattacharya, P. Mukherjee / Advanced Drug Delivery Reviews 60 (2008) 12891306

R. Bhattacharya, P. Mukherjee / Advanced Drug Delivery Reviews 60 (2008) 12891306

R. Bhattacharya, P. Mukherjee / Advanced Drug Delivery Reviews 60 (2008) 12891306

R. Bhattacharya, P. Mukherjee / Advanced Drug Delivery Reviews 60 (2008) 12891306

R. Bhattacharya, P. Mukherjee / Advanced Drug Delivery Reviews 60 (2008) 12891306

R. Bhattacharya, P. Mukherjee / Advanced Drug Delivery Reviews 60 (2008) 12891306

R. Bhattacharya, P. Mukherjee / Advanced Drug Delivery Reviews 60 (2008) 12891306

R. Bhattacharya, P. Mukherjee / Advanced Drug Delivery Reviews 60 (2008) 12891306

R. Bhattacharya, P. Mukherjee / Advanced Drug Delivery Reviews 60 (2008) 12891306

[93] [94] [95] [96]

[98] [99] [100] [101]

[111] [112] [113] [114] [115]

[154] [155] [156]

[169] [170] [171] [172]

Вам также может понравиться