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An Overview On Brain Targeting Drug Delivery System

By Shreeraj Shah - 01/06/2009 in

Latest Reviews 2009

Vol. 7 Issue 1 Brain targeting technology Colloidal drug carriers Liposomes Micelles Nanotechnology

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Author(s): Mitesh Jaypraka..., Jitendra Ramnar..., Shreeraj Shah


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Author(s): Mitesh Jaypraka... Jitendra Ramnar... Shreeraj Shah

Abstract:Target delivery of drug molecules to brain is one of the most challenging research areas in pharmaceutical sciences. The blood-brain barrier (BBB) represents an insurmountable obstacle for a large number of drugs, including antibiotics,antineoplastic agents, and a variety of central nervous system (CNS)-active drugs, especiallyneuropeptides. Therefore, various strategies have been proposed to improve the delivery of different drugs to this tissue which includesliposomes, colloidal drug carriers, micelles,chimeric peptide technology, intranasal and olfactory route of administration andnano technology. This review deals in brief about the status of the BBB, different pathologies of brain like neurodegenerative,cerebrovascular and inflammatory diseases. The first part of this article aims to review the strategies developed to circumvent the BBB and deliver drugs into the brain. The use ofnano technology andliposomes are discussed which are crucial part of this article as mainly used to target various CNS disorders. The later part of this article contains future aspects of brain drug targeting.

Keywords: Brain targeting technology, Colloidal drug carriers, Micelles,Liposomes,Nano Technology

Introduction:The global market for drugs for the central nervous system (CNS) is greatly under penetrated and would have to grow by over 500% just to be comparable to the global market for cardiovascular drugs. The principle reason for this under-development of the global brain drug market is that the great majority of drugs do not cross the brain capillary wall, which forms the blood brain barrier (BBB) in vivo. The blood-brain barrier (BBB) represents an insurmountable obstacle for a large number of drugs, including antibiotics,antineoplastic agents and a variety of central nervous system drugs (CNS)-active drugs, especiallyneuropeptides. It is located at the level of brain capillaries, where there is a convergence of different cell types; endothelial cells,pericytes,astrocytes andmicroglias (perivascular macrophages). The brain micro vessel endothelial cell (BMEC) that form the BBB, display important morphological characteristics such as the presence of tight junctions between the cells, the absence of fenestrations and a diminishedpinocytics activity, that together help to restrict the passage of compounds from the blood into the extra cellular environment of the brain.
[8, 9]

This barrier permits the exchange of

essential gases and nutrients between the bloodstream and the brain, while blocking larger entities such as microbes, immune cells and most drugs from entering. This barrier system is a perfectly logical arrangement, since the brain is the most sensitive and complex organ in the human body and it would not make sense for it to become the battleground of infection and immune response. This biological demilitarization zone is enforced by an elaborate and dense network of capillary vessels that feeds the brain and removes waste products.
[7, 9]

Each capillary vessel is bound by a single layer of endothelial cells, connected by

tight junction , thereby making it very difficult for most molecules to exit the capillaries and permeate into the brain. Tight junctions provide significanttransendothelial electrical resistance (TEER) to BMEC and impede the penetration of potential therapeutic agents such asoligonucleosides, antibodies, peptides and proteins. Furthermore, BMEC express a variety of enzymes, bothcytosolic and on the extra cellular membrane which also contribute to the restrictive nature of the BBB. P-glycoprotein (P-gp) is also present in the luminal plasma membrane of BMEC. This is an ATP-dependant efflux pump and a member of a family of intrinsic membrane proteins.
[4, 6]

P-gp is known to prevent the intracellular accumulation of an extensive variety of

chemotherapeutic agents and hydrophobic compounds. Under normal conditions the BBB acts as a barrier to toxic agents and safeguards the integrity of the brain. Nevertheless, several disorders and diseases can affect the brain leading to some loss of BBB integrity.
[16]

The major

neurological diseases affecting the brain may be categorized asneurodegerative,cerebrovascular, inflammatory (infections or autoimmune) and cancer.

Rate-limiting role of the BBB in brain drug development:Present-day incongruities in brain drug development are illustrated by a consideration of some of the characteristics of the CNS drug industry. Whereas 98% of all small-molecule drugs do not cross the BBB, and nearly 100% of large-molecule drugs do not cross the BBB, with some studies having co injectedPolysorbate 80, a detergent that can disrupt the BBB, with the drug as a stabilizing agent, and incorrectly attributing the detergent effects to their ownnanoparticles. In other studies, the large size of theliposomes that were used produced micro embolisms that gave a false impression of brain uptake.
[1]

Brain Targeting Technology:The usual noninvasive approach to solving the brain drug delivery problem isto lipidize the drug, The water -soluble parts of the drugs restricts BBB transport conversion of water-soluble drug into lipid-soluble pro drug is the traditional chemistry driven solution to the BBB problem.
[15]

Figure 1:- Outline of a program for developing BBB drug targeting strategies derived from either chemistry based or biology-based disciplines.

Strategies for drug delivery to the brain:Several drugs do not have adequate physiochemical characteristics such as high lipid solubility, low molecular size and positive charge which are essential to succeed in traversing BBB.

Disruption of the BBB: -

The thought behind this approach was to break down the barrier momentarily by injectingmannitol solution into arteries in the neck. The resulting high sugar concentration in brain capillaries takes up water out of the endothelial cells, shrinking them thus opening tight junction. The effect lasts for 20-30 minute, during which time drugs diffuse freely, that would not normally cross the BBB. This method permitted the delivery of chemotherapeutic agents in patients with cerebral lymphoma, malignantglioma and disseminated CNS germ cell tumors.
17] [4,

Physiological stress, transient increase in intracranial pressure, and unwanted delivery of

anticancer agents to normal brain tissues are the undesired side-effects of this approach in humans.

Intraventricular / Intrathecaldelivery : Here using a plastic reservoir which implanted subcutaneously in the scalp and connected to the ventricles within the brain by an outlet catheter. Drug injection into the CSF is a suitable strategy for sites close to the ventricles only.

Intra nasal drug delivery: After nasal delivery drugs first reach the respiratory epithelium, where compounds can be absorbed into the systemic circulation by Tran cellular and Para cellular passive absorption, carrier-mediated transport, and absorption throughtrancytosis.
[50, 53]

When a nasal drug

formulation is delivered deep and high enough into the nasal cavity, the olfactory mucosa may be reached and drug transport into the brain and/or CSF via the olfactory receptor neurons may occur.
[53, 55]

Possible systems for drug delivery:-

Colloidal drug carriers:Colloidal drug carrier systems such asmicellar solutions, vesicle and liquid crystal dispersions, as well asnanoparticle dispersions consisting of small particles of 10 400 nm diameter show great promise as drug delivery systems.
[5]

The goal is to obtain systems with optimized drug loading

and release properties, long shelf-life and low toxicity. The incorporated drug participates in the microstructure of the system, and may even influence it due to molecular interactions, especially if the drug possessesamphiphilic and/ormesogenic properties.
[5]

Figure 2:-Pharmaceutical carriers

Micelles:Micelles formed by self-assembly ofamphiphilic block copolymers (5-50 nm) in aqueous solutions are of great interest for drug delivery applications. [4]The drugs can be physically entrapped in the core of block copolymer micelles and transported at concentrations that can exceed their intrinsic water- solubility. Moreover, the hydrophilic blocks can form hydrogen bonds with the aqueous surroundings and form a tight shell around themicellar core. As a result, the contents of the hydrophobic core are effectively protected against hydrolysis and enzymatic degradation.
[7]

In addition, the corona may prevent recognition by thereticuloendothelial system and


[9]

therefore preliminary elimination of the micelles from the bloodstream.

The fact that their

chemical composition, total molecular weight and block length ratios can be easily changed, which allows control of the size and morphology of the micelles.Functionalization of block copolymers with cross linkable groups can increase the stability of the corresponding micelles and improve their temporal control.
[4, 7, 9]

Figure3:-Block copolymer micelles

Liposomes :Liposomes were first produced in England in 1961 by Alec D.Bangham.


[17]

One end of each

molecule is water soluble, while the opposite end is water insoluble. Water-soluble medications added to the water were trapped inside the aggregation of the hydrophobic ends; fat-soluble medications were incorporated into thephospholipid layer.
[22]

In some casesliposomes attach to cellular membranes and appear to fuse with them, releasing their or drugs into the cell.
[23]

In the case ofphagocytic cells, theliposomes are taken up,

thephospholipid walls are acted upon by organelles calledlysosomes, and the medication is released. Liposomal delivery systems are still largely experimental; the precise mechanisms of their action in the body are under study, as are ways in which to target them to specific diseased tissues. [6, 17-20, 22-27, 56-58]

Figure 4:- Liposomes, Micelles,Bilayer sheet

Nano technology:-

Nanoparticulate systems for braindelivery of drugs:One of the possibilities to deliver drugs to the brain is the employment ofnanoparticles.Nanopartiacles are polymeric particles made of natural or artificial polymers ranging in size between about 10 and 1000 nm (1 mm) .Drugs may be bound inform of a solid solution or dispersion or be adsorbed to the surface or chemically attached. Poly (butylcyanoacrylate)nanoparticles represent the onlynanoparticles that were so far successfully used for the in vivo delivery of drugs to the brain.
[8]

The first drug that was de-livered to the

brain usingnanoparticles was thehexapeptidedalargin (Tyr-D-Ala- Gly- Phe-Leu-Arg), aLeuenkephalin analogue withopioid activity. Nanoparticles andnanoformulations have already been applied as drug delivery systems with great success; andnanoparticulate drug delivery systems have still greater potential for many applications, including anti-tumors therapy, gene therapy, and AIDS therapy, radiotherapy, in the delivery of proteins, antibiotics,virostatics, and vaccines and as vesicles to pass the blood brain barrier.
[8, 9]

Nanoparticles provide massive advantages regarding drug targeting, delivery and release and, with their additional potential to combine diagnosis and therapy, emerge as one of the major tools innanomedicine.
[9]

The main goals are to improve their stability in the biological

environment, to mediate the bio-distribution of active compounds, improve drug loading, targeting, transport, release, and interaction with biological barriers. Thecytotoxicity ofnanoparticles or their degradation products remains a major problem, and improvements in biocompatibility obviously are a main concern of future research.
[10]

Nowadays nanotechnology is proved to be more efficient for enhancing drug delivery to brain. Thenanoparticles are the drug carrier system which is made from a broad number of materials such as poly (alkylcyanoacrylates) (pacas),polyacetates, polysaccharides, and copolymers. The methods of preparation ofnanoparticles, their characterization and medical application have been reviewed in details earlier (Kreuter, 1992;Barrattetal., 2001;Fattal andVauthier 2002).
10] [8,

The exact mechanism ofnanoparticle transport into brain is not understood, but it is thought to

depend on the particles size, material composition, and structure. In some cases it is reported to mimic molecules that would normally be transported to brain. For example,polysorbatecoatednanoparticles are thought to mimic low-density lipoprotein (LDL), allowing them to be transported across the capillary wall and into the brain by hitchingaride on the LDL receptor (Kreuter et al. 2002).
[8, 10]

The nanotechnology includes;1) Coatednanoparticles 2)Pegylatednanoparticles 3)Solid Lipidnanoparticles (SLN) 4)Nanogels

Advantages of nanotechnology :1) Due to their small sizenanoparticles penetrate into even small capillaries and are taken up within cells, allowing an efficient drug accumulation at the targeted sites in the body.
[10]

2) The use of biodegradable materials fornanoparticle preparation, allows sustained drug release at the targeted site after injection over a period of days or even weeks (Vinogradov et al. 2002).

Recent advances in nanotechnology:The research team of University of Michigan has developed a tool to diagnose and treat the most virulent forms of brain cancer. That is 20 to 200 nanometer diameternanoparticles; they dubbed Probes Encapsulated by Biologically Localized Embedding (pebbles). They designed the pebbles to carry a variety of agents on their surface, each with a unique function. The major potential advantage of using thesenanoparticles to treat cancer is of multifunctional. One target molecule immobilized on the surface could be used to help visualize the target using magnetic resonance imaging (MRI), while a third agent attached to the PEBBLE could deliver a destructive dose of drug or toxin to nearby cancer cells. All three functions can be combined in a single tiny polymerspere to make a potent weapon againstcancer.Kopelman introduced the common MRI contrast element gadolinium to the pebbles. When injected into thethe bloodstream, thenanoparticles travel their way through the bloodstream. And because they can transverse they have a targeting agent attached, the pebbles accumulate in the brain tumor enabling a clear MRI image within just a few hours.
[10]

Researchers incorporated a drug calledPhotofrin along with iron oxide intonanoparticles that would target cancerous brain tumors .Photofrin is a type of photodynamic therapy (PDT), in which the drug is drawn through the blood stream to tumors cells; a special type of laser light activates the drug to attack the tumor. Iron oxide is a contrast agent used to enhance magnetic resonance imaging (MRI)

Chimeric peptide technology:Chimeric peptides are formed when a drug that is normally not transported through the BBB is conjugated to a brain drug-targeting vector.
[11]

The latter is an endogenous peptide, modified

protein, orpeptidomimetic monoclonal antibody (mab) that undergoes RMT(Rapid metabolic transfer) through the BBB on endogenous receptor systems such as the insulin receptor or the tfr.Peptidomimeticmabs bind toexofacialepitopes on the BBB receptor that are removed from the endogenousligand binding site and piggyback across the BBB on the endogenous RMT system within the BBB, In this , a drug ismonobiotinylated in parallel with the production of a vector/ avid in or a vector/streptavidin (SA) fusion protein.
[11]

Thebiotinylated drug is produced in one

vial and the vector/avid in fusion protein is produced in another vial, and the 2 vials are mixed before administration.

Owing to the extremely high affinity of avid in or SA binding of biotin, there is instantaneous capture of thebiotinylatedneurotherapeutic agent by the vector/avid in or vector/SA fusion protein.
[16]

Monoclonal antibody/avid in andmab/SA fusion genes and fusion proteins are

produced with genetic engineering. Brain drug delivery in rats is possible with the OX26 mousemab to the rat tfr. Brain drug delivery in humans is possible with the genetically engineeredchimeric HIRmab. The activity of the genetically engineeredchimeric HIRmab is identical to that of the originalmurine HIRmab and thechimeric antibody is avidly taken up by the primate brain.
[33]

The brain uptake of the HIRmab in the rhesus monkey is 2% to 4% of the

injected dose which is a level of brain uptake that is 1 to 2 log orders greater than the brain uptake of aneuroactive small molecule such as morphine.
[11, 16, 33]

Neuroprotection with peptide radiopharmaceuticals:The practice of brain imaging uses small-molecule radio chemicals that bind to monoamine or amino acid neurotransmitter systems. Whereas there are less than a dozenmonoaminergic or aminoacidergic neurotransmitter systems, there are hundreds ofpeptidergic neurotransmission systems.
[40]

Therefore, the use of peptide radiopharmaceuticals could greatly increase the


[37]

diagnostic potential ofneuroimaging technology.

Potential candidates forneuroimaging include

epidermal growth factor (EGF) peptide radiopharmaceuticals for the early detection of brain tumors and A_ peptide radiopharmaceuticals as a diagnostic brain scan for Alzheimer disease. Many malignantgliomas over express the EGF receptor (EGF-R) and EGF are a potential peptide radiopharmaceutical for the imaging of brain tumors.
[34, 37, 40, 32]

ProteinNeurotherapeutic agent andneuroprotection in stroke:Virtually all small-moleculeneuroprotective agents have failed in clinical stroke trials because either (a) these molecules have unfavorable safety profiles or (b) the drugs do not cross the BBB. The therapeutic window forneuroprotection is the first 3 hours after stroke, and during this time, the BBB is intact.
[45]

The BBB is disrupted in later stages following stroke, but at this time,

chances forneuroprotection have been lost. Therefore, if effectiveneuroprotective agents for stroke are to be developed, these molecules must have favorable safety profiles and must be able to cross the BBB.
[41]

A modelneurotrophin, brain-derivedneurotrophic factor (BDNF), was

reformulated to enable BBB transport, and the BDNFchimeric peptide isneuroprotective following delayed intravenous administration in either regional or global brain ischemia.
[35, 36, 41,42-45]

Intranasal and olfactory rout of administration:-

Figure 5:- The olfactory bulb, olfactory mucosa, and olfactory nerve cells in humans.
[46]

Nasal transport routes:After nasal delivery drugs first reach the respiratory epithelium, where compounds can be absorbed into the systemic circulation utilizing the same pathways as any other epithelia in the body: Tran cellular and Para cellular passive absorption, carrier-mediated transport, and absorption throughtrancytosis. Although absorption across the respiratory epithelium is the major transport pathway for nasally-administered drugs and may represent a potentially timesaving route for the administration of certain systemic drugs delivered in cryonics medication protocols (e.g., epinephrine or vasopressin), problem of BBB-mediated exclusion of brain-therapeutic agents to be of greater immediate concern. Accordingly, the remainder of this article will deal primarily with the transport of drugs to the CNS by way of the olfactory epithelium.
[46]

When a nasal drug formulation is delivered deep and high enough into the nasal cavity, the olfactory mucosa may be reached and drug transport into the brain and/or CSF via the olfactory receptor neurons may occur. The olfactory pathways may be broadly classified into two possible routes: the olfactory nerve pathway (axonal transport) and the olfactory epithelial pathway. Axonal transport is considered a slow route whereby an agent enters the olfactory neuron viaendocytotic orpinocytotic mechanisms and travels to the olfactory bulb by utilizing the sameanterograde axonal transport mechanisms the cell uses to transport endogenous substances to the brain.
[53] [48]

Depending on the substance administered, axonal transport rates


[54]

range from 20-400 mm/day to a slower 0.1-4 mm/day.

The epithelial pathway is a

significantly faster route for direct nose-to-brain transfer, whereby compounds passparacellularly across the olfactory epithelium into theperineural space, which is continuous with the subarachnoid space and in direct contact with the CSF. Then the molecules can diffuse into the brain tissue or will be cleared by the CSF flow into the lymphatic vessels and subsequently into the systemic circulation.
[46-55]

Factors Affecting Nasal Drug Delivery to the Brain:The size of the molecule is the major determinant in whether a substance will be absorbed across the nasal respiratory epithelium and/or transported along the olfactory pathway. Fisher et al. Demonstrated an almost linear relationship between the log (molecular weight) and the log (% drug absorbed) of water-soluble compounds.
[51]

Other factors affecting delivery to the brain include the degree of dissociations andlipophilicity (higherlipophilicity results in better transport). Once a drug is in the brain, it can be further influenced by BBB efflux transporter systems like P-glycoprotein (P-gp). Graff and Pollack (2003), however, found that uptake into the brain was enhanced when drugs were administered in combination with the P-gp efflux inhibitor,rifampin.
[48, 49]

Nose-to-Brain Research:Researching nose-to-brain transfer of drugs in humans must, for obvious reasons, either employ indirect visualization of drug transfer (e.g., effects on event-related-potentials), measurement of drug concentrations in the CSF during surgery, or simple monitoring of CNS effects. Such studies have clearly indicated that drugs can be delivered to the brain in this manner, but they give no clear-cut evidence regarding the role of transfer. Because of this limitation, studies of the olfactory pathway as a conduit for transmission of drugs to the CNS have mostly made use of animals having substantially different ratios of olfactory-to-respiratory epithelium than humans.
[52]

However, the mechanisms of transfer remain the same and are worthy of thorough

investigation. To date, more than 50 drugs and drug-related compounds have been reported to reach the CNS after nasal administration in different species.
[49]

A growing number of recent reports have demonstrated the effectiveness of intranasal administration ofneuroprotective agents in decreasing ischemic brain injury. For example, Ying et al. (2007) recently reported that intranasal administration of NAD+ profoundly decreased brain injury in a rat model of transient focal ischemia. Similarly, Wei et al. (2007) showed that intranasal administration of the PARG inhibitor Gallo tannin decreased ischemic brain injury in rats. Such agents are believed to provideneuroprotection by diminishing or abolishing activation

of poly (ADP-ribose) polymerase-1 (PARP-1), which plays a significant role in ischemic brain damage. NAD+ was observed to reduce infarct formation by up to 86% even when administered at 2 hours after ischemic onset. Because PARP activation appears to be a downstream ischemic event, it may be worthwhile to also investigate the ability of IN (intranasal) administration of agents such asantiporters or NMDA receptor blockers to provideneuroprotection against the more upstream events of global ischemia such as membrane depolarization andexcitotoxicity.
[51]

Recent patents:-

No. 1 2 3 4 5 6 7 8

Document US20080235817 US20080234377 US20080234368 US20080234356 US20080234313 US20080234233 US20080234200 US20080233132

Document title Artificial mammalian chromosome Polyunsaturated fatty acids for treatment of dementia and pre-dementia related conditions Therapeutic compositions and methods of use 2-phenyl-3,3,3-trifluro-2-hydroxypropionic acid derivatives Novel inhibitors Medicament for treatment of neurodegenerative diseases Method of treatment of a metabolic disease using intranasal administration ofexendin peptide Multiple sclerosis therapy

Future aspects of brain targeting [2, 3, 12, 29, 30]:There are many technological challenges to be met, in developing the following techniques: " Nano - drug delivery systems that deliver large but highly localized quantities of drugs to specific areas to be released in controlled ways; " Controllable release profiles, especially for sensitive drugs; those are biocompatible and biodegradable; " Architectures / structures, such asbiomimetic polymers,nanotubes; " Technologies for self-assembly; " Functions ( active drug targeting, on-command delivery , intelligent drug release devices/bioresponsive triggered systems, self-regulated delivery systems, systems interacting with the body, smart delivery);
[13-15] [1]

" Materials fornanoparticles

" Virus-like systems for intracellular delivery; "Nanoparticles to improve devices such as implantable devices/nanochips fornanoparticle release, or multi reservoir drug delivery-chips;

" Nanoparticles for tissue engineering; e.g. For the delivery of cytokines to control cellular growth and differentiation, and stimulate regeneration; or for coating implants withnanoparticles in biodegradable polymer layers for sustained release; " Advanced polymeric carriers for the delivery of therapeutic peptide/proteins (biopharmaceutics), And also in the development of: Combined therapy and medical imaging, for example,nanoparticles for diagnosis and manipulation during surgery (e.g. Thermotherapy with magnetic particles);
[31]

" Universal formulation schemes that can be used as intravenous, intramuscular or per oral drugs " Cell and gene targeting systems. " User-friendly lab-on-a-chip devices for point-of-care and disease prevention and control at home. " Devices for detecting changes in magnetic or physical properties after specific binding ofligands on paramagneticnanoparticles that can correlate with the amount ofligand. " Better disease markers in terms of sensitivity and specificity.
[38, 39]

Conclusion:Brain Targeting has got the attention of the many researchers due to its application in various diseases related to CNS. Only few drugs can penetrate the BBB and enters the CNS, so various systems are developed for drug delivery. It emerges that the nanotechnology and by using other routes of drug administration like intra nasal technique drug can penetrate the BBB efficiently. Further the modified colloidal particles and various modifiedliposomes enhance exposure of the BBB due to prolonged blood circulation, which favors interaction and penetration into brain endothelial cells. This system has clinical benefits like reduced drug dose, decreased side effects, non invasive routes, and more patient compliance. We still require developing a cost effective system that can be used in various CNS disorders efficiently with minimum side effect.

Acknowledgements:We acknowledged our Director sir DR. K. PUNDARIKAKSHUDU and also very much thankful to Professor MR. B.M.PEERZADA and Professor MR. MANISH SHAH for giving constant support.

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32) Oldendorf WH. Brain uptake ofradiolabeled amino acids, amines, andhexoses after arterial injection . American Journal of Physiology.1971; 221:1629-1639. 33) Green NM. Avidin. Advanced Protein Chemistry.1975; 29:85-133. 34) Kurihara A,Pardridge WM. Imaging brain tumors by targeting peptide radiopharmaceuticals through the blood-brainbarrier .Cancer Res.1999;54:6159-6163. 35) Zhang Y,Pardridge WM. Conjugation of brain-derivedneurotrophic factor to a blood-brain barrier drug targeting system enablesneuroprotection in regional brain ischemia following intravenous injection of theneurotrophin . Brain Res. 2001;889:49-56. 36) Wu D, Pardridge WM. Neuroprotection with non-invasiveneurotrophin delivery to brain . ProcNatlAcadSci U S A.1999; 96:254-259. 37) Kurihara A,Pardridge WM. A_1-40 peptide radiopharmaceuticals for brainamyloid imaging: 111Inchelation, conjugation topolyethyleneglycol-biotin linkers, and autoradiography with Alzheimer s disease brain sections .Bioconjug Chem. 2000; 11:380-386. 38) Wong AJ,Bigner SH,Bigner DD,Kinzler KW, Hamilton SR, Vogelstein B. Increased expression of the epidermal growth factor receptor gene in malignantgliomas is invariably associated with gene amplification . ProcNatlAcadSci USA.1987;84:6899-6903. 39) Nishikawa R,Ji XD, Harmon RC, et al. A mutant epidermal growth factor receptor common in humanglioma confers enhancedtumorigenicity . ProcNatlAcadSci U S A.1994; 91:7727-7731. 40) Kurihara A,Deguchi Y,Pardridge WM. Epidermal growth factor radiopharmaceuticals: 111Inchelation, conjugation to a blood-brain barrier delivery vector via a biotin- polyethylene linker, pharmacokinetics, and in vivo imaging of experimental brain tumors .Bioconjug Chem.1999; 10:502-511. 41) Pardridge WM. Neuroprotection in stroke: is it time to consider large-molecule drugs . Drug Discovery Today.2001; 6:751-753. 42) Hefti F. Pharmacology ofneurotrophic factors . Annual Review Pharmacology & Toxicology.1997; 37:239-267. 43) Sakane T,Pardridge WM. Carboxyl-directedpegylation of brain-derivedneurotrophic factor markedly reduces systemic clearance with minimal loss of biologic activity .Pharm Res. 1997; 14:1085-1091. 44) Pardridge WM, Wu D,Sakane T. Combined use of carboxyl-directed proteinpegylation and vector-mediated blood-brain barrier drug delivery system optimizes brain uptake of brainderivedneurotrophic factor following intravenous administration .Pharm Res.1998; 15:576-582. 45) Zhang Y,Pardridge WM. Neuroprotection in transient focal brain ischemia following delayed, intravenous administration of BDNF conjugated to a blood-brain barrier drug targeting system . Stroke.2001;32:1378-1384.

46) Costantino H.R.,Lisbeth I., Brandt G., Johnson P.H., Quay S.C. (2007), Intranasal deliveryPhysicochemical and therapeutic aspects . International Journal of Pharmaceutics 337: 1-24. 47) Faber W.F. (1937), The nasal mucosa and the subarachnoid space . American Journal of Anatomy62: 121-148. 48) Jackson R.T., Tigges J., Arnold W. (1979), Subarachnoid space of the CNS, nasal mucosa and lymphatic system . Archives of Otolaryngology 105: 180-184. 49) Yoffey J.M. (1958), Passage of fluid and other substances through the nasal mucosa . Journal ofLaryngology and Otology 72: 377-383. 50) Illum L. (2004), Is nose-to-brain transport of drugs in man a reality? Journal of Pharmacy and Pharmacology56: 3-17. 51) Vyas T.K.,Salphati I., Benet L.Z. (2005), Intranasal drug delivery for brain targeting . Current Drug Delivery 2: 165-175. 52) Landau A.J.,Eberhardt R.T.,Frishman W.H. (1994), Intranasal delivery of cardiovascular agents: An innovative approach to cardiovascular pharmacotherapy . American Heart Journal 127: 1594-1599. 53) Yamada T. (2004), The potential of the nasal mucosa route for emergency drug administration via a high-pressure needleless injection system . Anesthesia Progress 51(2): 661. 54) Bleske B.E., Warren E.W., Rice T.L., Shea M.J.,Amidon G., Knight P. (1992), Comparison of intravenous and intranasal administration of epinephrine during CPR in a canine model . Annals of Emergency Medicine 21(9): 1125-1130. 55) chieny.W., Su K.S.E., Chang S.F. (1989), Nasal systemic drug delivery . Drugs and the pharmaceutical sciences. New York, Marcel Dekker, Inc. 56) http://www.avantilipids.com/Liposomes.asp 57) http://www.avantilipids.com/preparationofliposomes.html 58) http://www.avantilipids.com/preparationofmultilemellarliposomes.html

About Authors:

Shreeraj H. Shah Corresponding Author: Address: Dept. of Pharmaceutics, L.J. Institute of Pharmacy, Near Nagdev-Kalyan Mandir, S.G. Highway, Makarba, Ahmedabad-382 210, Gujarat, India.

Mitesh Jayprakash Shah E\22, Hariom Park , Opp. Gosha society, Near UDGUM school, Drive-in Road, Ahmadabad 380 054

Jitendra Ramnaresh Sharma 417, New Jashoda Nagar, b/h Phase-3, Vatwa, Ahmedabad,

GOOD REPRESENTATION.

Submitted by ks kumar upadhyayula on Sun, 01/18/2009 - 02:57.

3 YOUR WAY OF APPROACH TOWARDS TOPIC IS REALLY AWESOME AND THE WAY OF REPRESENTATION IS GIVING A GOOD WAY TO LEARN MORE.THE LINKS ARE MORE HELPING TO KNOW EXTRA INFORMATION.

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Dear Shah you are working

Submitted by Dixon Thomas on Fri, 01/16/2009 - 15:35.

4 Dear Shah you are working pretty well with publications. I appreciate your enthusiasum DIXON THOMAS

MDCP, BELA POST KERALA, INDIA 671321

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THANK YOU VERY MUCH

Submitted by Shreeraj Shah on Sat, 01/17/2009 - 11:17.

THANK YOU VERY MUCH

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excellent

Submitted by Vijaya Ratna on Thu, 01/15/2009 - 14:55.

5 Excellent handling of a very important topic. Definitely more attention must be shown to targeting brain. Diagrams are very good.

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THANKS A LOT MAM FOR

Submitted by Shreeraj Shah on Fri, 01/16/2009 - 13:19.

THANKS A LOT MAM FOR COMPLIMENTS AND ENCOURAGEMENT

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April 11th, 2008 at 7:59 pm

Targeting Delivery for Nanoparticles


in: Breakthrough Thinking, Health & Fitness, Medical Breakthrough, New Discoveries, People Making a Difference, business

Conventional chemotherapy can wreak havoc on healthy tissue, causing painful side effects, and its not always effective. Nanotechnology-based methods to deliver these drugs only to cancerous cells have shown promise, but they dont work for all cancers. Now a handful of research groups are developing more-complex approaches that use microscopic carriers to deliver a variety of particlesincluding drugs, molecular tags that target tumors, and imaging agents to monitor and destroy cancer cells. In theory, these microscopic delivery vehicles would evade the bodys defenses and target blood vessels near a tumor, then release their payload.

Micro Carriers: These microscopic discs, made of porous silicon, can be used to deliver nanoparticles to tumors to treat cancer. While the technology is still in its early stages, researchers at the University of Texas in Houston have taken a first step by engineering tiny discs of porous silicon that can be used to deliver two types of nanoparticles simultaneously. Mauro Ferrari, a professor of biomedical engineering, fabricated porous silicon using previously developed methods and then used photolithography to carve out tiny structures shaped like red blood cells, but about half the size. (Computer models suggest that the structures will tend to hug the inside of blood vessel walls, a crucial property for targeted delivery.) Ferrari and collaborators then loaded the pores with quantum dots and carbon nanotubes. When administered to cells growing in a dish, the silicon carriers begin to break down, releasing their cargo over the course of several hours. The cells then absorbed the nanoparticles, which accumulated in distinct areas inside the cells. The work was published last month in the journal Nature Nanotechnology. Ferraris approach, and others like it, might overcome some of the drawbacks of current nanotechnology-based drug delivery. In one current technology, hollow, nanoscopic containers called liposomes or micelles are loaded with a drug and injected into the bloodstream. Since the blood vessels that feed tumors tend to be leaky, these nanoparticles tend to accumulate more in tumors than in other tissue. The approach has been approved for use in treating breast cancer and ovarian cancer. But not all tumors have leaky vasculature, Ferrari says, limiting the applications of this approach. His system, on the other hand, can be targeted to cancer cells using antibodies and other targeting molecules, eliminating the need to rely on leaky blood vessels. Others are already trying a similar approachusing targeting molecules attached to nanoparticlesand, in some cases, are about to begin clinical trials. But unlike liposomes, which can carry significant drug payloads, these nanoparticles only carry a relatively small amount of drug on their surface. Whats more, many of the particles can be trapped or destroyed by the bodys defenses, making it difficult to deliver an effective dose. In Ferraris approach, the microscopic silicon carrier would protect the nanoparticles and deliver them in large numbers to the vicinity of the tumor, increasing the chances that the drugs will reach the cancer cells in large amounts. Multistage approaches such as Ferraris are still at an early stage. Robert Langer, a professor of chemical engineering at MIT, calls it a nice approach, but points to the need to demonstrate its effectiveness in animals and clinical trials. Other experts disagree whether silicon will be an effective delivery material. James Baker, a physician and professor of biologic nanotechnology at the University of Michigan, says stiff, microscopic particles will likely be trapped in narrow blood vessels. But Michael Sailor, a professor of chemistry and biochemistry at the University of California at San Diego and another leader in the field of multistage delivery, says that silicon particles could be injected close to the tumor, eliminating the need for them to travel through the bloodstream. If successful, the relatively large microscopic carrier particles could be used as a generic transport for a variety of combinations of drugs and nanoparticles selected for specific types of tumors. This approach could also make it possible to use drugs that have been dismissed for being too easily degraded in the body or too toxic to deliver using conventional approaches. It is an attack that holds much promise, says James Tour, a

professor of chemistry at Rice University who hopes this approach could be used to deliver some of the tumor-targeting nanoparticles he is developing. Its not a sure win, but there is cautious optimism. Via Technology Review You must be logged in to post a comment.

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Nanotechnology could offer an alternative to brain surgery

(Nanowerk News) If you had brain tumor, would you rather receive your medicine through an injection in the arm or have a hole drilled in your skull? Even if you opted for the 'hole-in-the-skull' method, brain cancers are often inoperable due to their location within critical brain regions or because they are too small to detect. Nanotechnology offers a vision for a 'smart' drug approach to fighting tumors: the ability of nanoparticles to locate cancer cells and destroy them with single-cell precision. One of the most important applications for such nanoparticulate drug delivery could be the delivery of the drug payload into the brain. However, crossing the brains protective shield, the blood-brain barrier, is a considerable challenge. Novel targeted nanoparticulate drug delivery systems that are able to cross this barrier bring us closer to this vision of brain cancer destroying drugs. A tight seal of endothelial cells lines the blood vessels in the brain and acts as a barrier to protect its cells. This is known as the blood-brain barrier (BBB). BBB strictly limits transport into the brain through both physical (tight junctions) and metabolic (enzymes) barriers and keeps most substances, such as chemicals and large biomolecules, out of the brain. The challenge in treating most brain disorders is overcoming the difficulty of delivering therapeutic agents to specific regions of the brain by crossing the BBB. The problem is the BBB does not differentiate what it keeps out. With very few exceptions, only nonionic and low molecular weight molecules soluble in fat clear the BBB. For instance, alcohol, caffeine, nicotine and antidepressants meet these criteria. However, large molecules needed to deliver drugs cannot cross it. "The delivery of peptides into the brain is a challenge that is not adressed with classical pharmaceutical formulations, since the blood brain barrier doesn't allow the easy diffusion of such molecules." Dr. Patrick Couvreur explained to Nanowerk. Couvreur, the director of the Center for Pharamceutical Studies at the Universit Paris Sud, together with an international group of researchers, describes novel nanoparticles that are able to transport drugs into the brain ("Development and Brain Delivery of Chitosan-PEG Nanoparticles Functionalized with the Monoclonal Antibody OX26"). The development of carrier nanoparticles able to penetrate the BBB, as done by this research group, is an important step towards detection and therapeutic treatment of diseases in the brain. BBB investigation is an ever growing and dynamic field studied by pharmacologists, neuroscientists, pathologists, physiologists, and clinical practitioners. "The chitosan-based immuno-nanoparticles we have developed" says Couvreur "allow transport across the BBB by combining two factors: 1) the ability of cationic (with a full positive charge) chitosan to interact with the negative charges of the brain endothelium and 2) the affinity of the monoclonal antibody OX26 for the transferrin receptor."

Transmission electron micrographs showing nanoparticles in the brain interstitium (original magnification 5000); (Reprinted with permission from American Chemical Society) The researchers hypothized that transferrin receptor (TfR), which is highly concentrated in the BBB, may trigger receptor-mediated transport across the BBB. Transferrin itself is limited as a brain drug transport vector since the transferrin receptors are almost saturated under physiologic conditions. However, the antibodies that bind to TfR have been shown to selectively target BBB endothelium due to the high levels of TfR expressed by these cells. Therefore, these antibodies are potential carriers for the delivery of therapeutic agents to the central nervous systems. In particular, a mouse monoclonal antibody, OX26, with a high abundance of transferrin receptors at the brain microvascular endothelium has been detected and was used in the experiments. Consequently, the researchers designed chitosan (CS) nanospheres conjugated with poly(ethylene glycol) (PEG) bearing the OX26 monoclonal antibody. The nanoparticles were injected intravenously to mice. The results showed that an important amount of nanoparticles were located in the brain. Raoul Kopelman and his group at the University of Michigan designed nanoparticles they dubbed Probes Encapsulated by Biologically Localized Embedding (PEBBLEs) to carry a variety of agents on their surface, each with a unique function. The particles consist of an iron oxide core that serves as an MRI contrast agent. Attached to them are copies of a cancer-targeting peptide called F3, as well as a light-absorbing compound called photofrin that kills cells when hit with red light. When Kopelmans team used their PEBBLEs to treat rats previously injected with cancer cells inside their brains they saw very clear results: A single IV injection of a targeted therapeutic nanoparticle dose, coupled with a single 5 min photodynamic therapy treatment, leads not only to an increase in the rat survival rate but accomplishes complete tumor remission.

The PEBBLE platform for the detection and treatment of cancer (Image: Kopelman Laboratory) The targeted treatments using nanoparticles may offer a number of advantages, not only over surgery but also over traditional chemotherapy. In chemotherapy, the drugs indiscrimenately permeate cells throughout the body to damage their DNA and prevent rapid growth, and are only moderately more toxic to cancer cells over normal cells. Nanoparticulate drug delivery, on the other hand, is highly localized to the cancer target, and does no or very little damage to surrounding healthy tissue. By Michael Berger, Copyright 2007 Nanowerk LLC

Nanotech that Heals Brain Damage

In a recent post I described a peptide bio-gel that promotes cell growth, and acts as a three dimensional scaffold for tissue healing and cell culture. Now a cognitive science researcher at MIT has developed a liquid solution of peptide chains that self assembles into nano-fibres inside damaged brain. These nano-fibres then form a scaffold for the re-growth of severed nerves--an incredible achievement in the central nervous system. Here is the report: Although victims of stroke and traumatic brain and spinal cord injuries

sometimes recover through rehabilitation, they often have permanent disabilities, in part, because scar tissue and regulatory chemicals in the brain slow nerve growth, preventing nerve tissue from repairing itself. Now a treatment that has restored lost vision in lab animals appears to overcome these obstacles, allowing a mass of nerve cells to regrow after being cut. "We think this is the basis of reconstructive brain surgery -- which is something nobody has ever heard of before," says Rutledge Ellis-Behnke, a researcher on the project and a brain and cognitive sciences researcher at MIT. The treatment, described online this week in the Proceedings of the National Academy of Sciences and performed at MIT, Hong Kong University, and Fourth Military Medical University in China, may be available to humans in trials in as little as three years if all goes well in large-animal studies, the researchers say. In their experiments, the researchers first cut into a brain structure that conveys signals for vision, causing the small lab animals to be blinded in one eye. They then injected a clear fluid containing chains of amino acids into the damaged area. Once in the environment of the brain, these chains, called peptides, bind to one another, assembling into nano-scale fibers that bridge the gap left by the damage. The mesh of fibers prevents scar tissue from forming and may also encourage cell growth (the researchers are still investigating the mechanisms involved). As a result, nerve cells restored severed connections, allowing 75 percent of the animals to see well enough to detect and turn toward food. The treatment restored around 30,000 nerve connections, compared with 25-30 connections made possible in other experimental treatments, Ellis-Behnke says. Read the rest here. Repairing damage in the brain and spinal cord has always been virtually impossible, due to the resistance to regrowth of CNS neurons. Clearly something

in the peptide fibres encourages the nerves to regrow, and reconnect. Just like something in the peptide gel of the tissue scaffold in the earlier article encourages cultured cells to grow. In those two research projects, we can see the beginnings of the development of both the growing of artificial replacement organs, and the repair of central nervous system damage in the brain and spinal cord. Now we need to watch for research that replicates these findings, and takes them further.
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NCI Alliance for Nanotechnology in Cancer | Monthly Feature | December 2005

Nanotechnology Tackles Brain Cancer

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Brain cancer can be counted among the most deadly and intractable diseases. Often diagnosed after a patient exhibits symptoms such as nausea, dizziness,

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uncharacteristic behavior changes, or paralysis, the growing mass of a brain tumor will continue to squeeze out normal tissue and degrade the brains function if left untreated. But treatment is elusive. Tumors may be embedded in regions of the brain that are critical to orchestrating the bodys vital functions, while they shed cells to invade other parts of the brain, forming more tumors too small to detect using conventional imaging techniques. Brain cancers location and ability to spread quickly makes treatment with surgery or radiation like fighting an enemy hiding out among minefields and caves, and explains why the term brain cancer is all too often associated with the word inoperable. Making treatment even more challenging, there is a system of blood vessels and protective cells in the brain the blood-brain barrier that admits only essential nutrients and oxygen, and keeps out everything else, including about 95 percent of all drugs. This natural barrier puts serious limits on how much a patient can benefit from traditional chemotherapy and new cancer drugs. In an ideal situation, we would have a smart drug that could cross the blood-brain barrier, zero in on the cancer cells, mark their location clearly for surgery, or destroy them with such precision that it would leave surrounding, normal brain cells intact. Until now, such a scenario seemed so far-fetched. But using nanotechnology, NCIsupported researchers at the University of Michigan, the University of Washington, the University of Texas M. D. Anderson Cancer Center, Virginia Polytechnic Institute, and Virginia Commonwealth University are creating ultrasmall particles that can target and destroy cancer cells in the brain, even those in tumors too small to be removed surgically. Back To Top

Getting Into the Brain Ticket Required


Among the properties of nanoparticles that make them ideal candidates for recognizing and treating brain cancer, their ability to deliver a wide variety of payloads across the blood-brain barrier is perhaps the most important. Understanding how some nanoparticles achieve this special permission to enter the brain requires a closer look at how the blood-brain barrier works. The blood-brain barrier permits the exchange of essential nutrients and gases between the bloodstream and the brain, while blocking larger entities such as microbes, immune cells and most drugs from entering. This barrier system is a perfectly logical arrangement, since the brain is the most sensitive and complex organ in the human body and it would not make sense for it to become the battleground of infection and immune response. This biological demilitarization zone is enforced by an elaborate and dense network of capillary vessels that feeds the brain and removes waste products. Each capillary vessel is bound by a single layer of endothelial cells, connected by tight junctions, thereby making it very difficult for most molecules to exit the capillaries and permeate into the brain. Outside of the central nervous system, capillaries have fenestra (the latin for window), which are the cracks between the cells in the vessel wall. Both small and large molecules and even cells can leave the capillary and enter into the surrounding

tissue. Instead of leaking material, brain capillary walls closely regulate the flow of material using molecular pumps and receptors that recognize and transport nutrients such as glucose, nucleosides, and specific proteins into the brain. In other words, substances need to be pre-recognized to enter. So what allows some nanoparticles to get into the brain? Nanoparticles that successfully cross the barrier are often coated with polyethylene glycol (PEG), polysorbate, or other polymer or surfactant (a detergent-like substance). The exact mechanism of nanoparticle transport into the brain is not fully understood, but it is thought to depend on the particles size, material composition, and structure. In some cases, it appears that a specialized coating of polymer or surfactant allows nanoparticles to mimic molecules that would normally be transported into the brain. For example, polysorbate-coated nanoparticles are thought to mimic low-density lipoproteins (LDL), allowing them to be transported across the capillary wall and into the brain by hitching a ride on the LDL receptor.1 Back To Top In another example, nanoparticles were decorated with opioid peptides, short pieces of protein that act as natural painkillers. The opioid peptides bind to specific receptors on the capillary walls, which help carry the nanoparticles into the brain.2 In other cases, no special tricks are needed: larger tumors can disrupt the local vasculature, creating leaky vessels through which nanoparticles and other molecules can easily penetrate. Once inside the brain, a nanoparticle can deliver a wide variety of payloads to detect and treat cancer.

Throwing PEBBLEs at Brain Cancer


When the team of Raoul Kopelman, Ph.D., at the University of Michigan, thought of a tool to diagnose and treat the most virulent forms of brain cancer, they thought of pebbles. That is, 20 to 200 nanometer diameter nanoparticles they dubbed Probes Encapsulated by Biologically Localized Embedding (PEBBLEs).3 Kopelman designed the PEBBLEs to carry a variety of agents on their surface, each with a unique function. Therein lies another major potential advantage of using nanoparticles to treat cancer: multifunctionality. One target molecule immobilized on the surface could guide the PEBBLE to a tumor. Another agent could be used to help visualize the target using magnetic resonance imaging (MRI), while a third agent attached to the PEBBLE could deliver a destructive dose of drug or toxin to nearby cancer cells. All three functions can be combined in a single tiny polymer sphere to make a potent weapon against cancer (See Figure 1).

Figure 1 The power of PEBBLEs is in their multifunctionality. One tiny polymer sphere can contain a targeting agent that guides the particle to cancer cells, a protective coating (PEG) that might also help it cross the blood-brain barrier, photodynamic molecules that catalyze the conversion of oxygen to highly reactive oxygen singlets, magnetically dense metals for MRI contrast imaging, and a fluorescent beacon to visually pinpoint the nanoparticles location. (Courtesy: Raoul Kopelman, Ph.D., University of Michigan)

Back To Top Kopelman introduced the common MRI contrast element gadolinium to the PEBBLEs. When injected into the bloodstream, the nanoparticles wend their way through the bloodstream. But because they can transverse the blood-brain barrier, and because they have a targeting agent attached, the PEBBLEs accumulate in the brain tumor enabling a clear MRI image within just a few hours. The next functional step is a remarkable feat of nano-engineering. Each PEBBLE carries a photocatalyst . When stimulated by a light source through a micrometersized fiber-optic probe inserted into the skull, the photocatalyst converts oxygen into a so-called singlet state, which effectively bleaches and destroys nearby cells. The PEBBLEs are inert and harmless until the light is turned on. Used in combination with MRI imaging, one could now kill cancer cells at will, while tracking the effectiveness of the treatment with imaging. The targeted treatments using nanoparticles may offer a number of advantages over traditional chemotherapy. In chemotherapy, the drugs permeate cells throughout the body to damage their DNA and prevent rapid growth, and are only moderately more toxic to cancer cells over normal cells. That is why patients suffer so many side effects of chemotherapy including nausea, hair loss, and anemia. In contrast, PEBBLEs are highly localized to the cancer target, and do very little damage to surrounding healthy tissue. PEBBLEs and other nanoparticle drugs could also avoid another serious problem

occurring in traditional chemotherapy for some cancers, over 50 percent of patients become non-responsive to treatment due to the development of multi-drug resistance (MDR). MDR occurs when cancer cells mutate and begin to pump the chemotherapy drugs back out before they can destroy the cell. The cancer becomes immune to the drug. But PEBBLEs act on the outside of the cell, and the toxic payload of oxygen that they deliver acts quickly, without giving the cancer much chance to survive and develop resistance. In rat models of a type of brain cancer called 9L-gliosarcoma, PEBBLE-based treatment can significantly increase survival time. Patients with this particularly aggressive form of cancer rarely live more than four months after diagnosis without treatment. For rats, the clock runs out in about five days. When rats were treated with PEBBLEs targeted to 9L-gliosarcoma tumors, some were still thriving after two months, and an MRI image of their brain revealed that the tumors had been eliminated. Kopelman and collaborators (including Martin Philbert, Ph.D., at the University of Michigan School of Public Health), hope ultimately to prove the utility and safety of this approach to treating brain cancer in humans. Back To Top

The Illuminated Brain


Unfortunately, the most common form of primary brain cancer, glioblastoma, is also the most aggressive and lethal. Glioblastoma tumors emerge rapidly and spread throughout the brain. About 20,000 Americans are diagnosed each year, and more than half of those patients will die within 18 months. Surgery is limited in its effectiveness because it is difficult to differentiate visually between cancerous and normal brain tissue, and any cancer cells left behind are likely to proliferate and form new tumors. In order to improve the odds of eliminating all the cancer during surgery and avoid removing healthy brain tissue, researchers have devised a number of fluorophores, or glowing molecules that mark the tumor boundaries for removal. But the fluorescent probes are difficult to locate and use within the brain during surgery. A multidisciplinary team at the University of Washington and the Fred Hutchinson Cancer Research Center in Seattle, wanted to see if surgical outcomes could be improved by a single probe that accurately marks the location of a tumor in pre-operative MRI scans, while guiding the surgeon to those same locations in the exposed brain. To materials scientist Miqin Zhang, Ph.D., radiologist Raymond Sze, M.D., and oncologist Jim Olson, M.D., nanotechnology was the perfect solution for creating such a multifunctional probe.4 Starting with a 10 nanometer diameter iron oxide core that serves as an MRI contrast material, Zhang and colleagues coated the nanoparticles with polyethylene glycol and modified them with a fluorescent molecule called Cy5.5. Cy5.5 gives off light at near-infrared wavelengths, which unlike visible light can penetrate several centimeters through brain tissue (See Figure 2).

Figure 2 Schematic diagram for synthesis of nanoparticle-chlorotoxin (NPC) and NPC-Cy5.5 conjugates. NPC-Cy5.5 is able to bind to and fluorescently illuminate glioblastoma tumors. (Reprinted with permission from ref. 4; Copyright 2005 American Chemical Society)

In order to selectively light up glioma tumors through imaging, a targeting agent had to be attached. Zhang and colleagues selected chlorotoxin, a peptide derived from the venom of the giant Israeli scorpion, which binds specifically to a tumor surface marker found in the vast majority of gliomas. At 15 nanometers, the final particle size and composition gave it the best chance for crossing the blood-brain barrier, and homing in on its target. Tested on cultured cells, the nanoparticles performed remarkably well (See Figure 3). Studies clearly demonstrated uptake by glioma cells, but not healthy brain cells, and the nanoprobes were readily detectable by both MRI and near-infrared fluorescence. More work remains to be done in animal studies, but Zhang and coworkers are driven by a vision that some day a surgeon will be able to use MRI to map out a surgical plan, and then have a visual guide for that plan in real time, while operating on the brain.

Figure 3 Fluorescent microscope images showing 9L-gliosarcoma cells light up with chorotoxin-linked nanoparticles (red dots in B) but not when exposed to nanoparticles without the chlorotoxin targeting agent (A). (Reprinted with permission from ref. 4; Copyright 2005 American Chemical Society)

Back To Top According to Chun Li, Ph.D., at the University of Texas M. D. Anderson Cancer Center, and Eastman Kodak, near-infrared emitting nanoparticles could be a valuable tool for outlining the margins of a tumor, and helping the surgeon to avoid cutting into healthy tissue. Better cameras and detection methods will be needed before these nanoparticles are used in a real operation, but a photographic

technology expert such as Eastman Kodak seems ideal to address these challenges. Kodaks engineering and chemistry teams are backed by a long history of expertise in dye chemistry. The company is supplying high-quality near-infrared emitting nanoparticles with well-controlled properties. Lis multidisciplinary approach, pooling the expertise of engineers, chemists, and biologists, is a good example of the multidisciplinary research collaborations needed to move nanotechnology research forward in the area of cancer.

Buckyballs Pack Heat


In the 1970s, a new variety of carbon was discovered that formed hollow nanometerscale cage-like spheres. They were called buckminsterfullerenes or buckyballs, after the architect who built domed structures of a similar shape, and were hypothesized to have great potential for their ability to carry atoms and molecules with useful properties. Then in 1999, Virginia Tech chemists Harry Dorn, Ph.D. and Harry Gibson, Ph.D. created the first buckyballs encapsulating rare earth metals, the kind that can easily be recognized as a contrast agent for MRI. The attachment of targeting agents to the outside of the carbon cage allowed the buckyballs to accumulate in tumors. Now, Panos Fatouros, Ph.D., and neurosurgeon William Broaddus, M.D., Ph.D., both at Virginia Commonwealth University, are collaborating with Dorn and Gibson on a project using buckyballs to improve the ability of MRIs to locate brain tumors, and deliver a payload of radiation to destroy them. Experiments on rats have shown that buckyballs packed with the MRI contrast metal gadolinium can increase the sensitivity of MRI detection by at least 40-fold. This level of precision is reaching a point at which cancer cells that have spread beyond the margins of the tumor may become visible. Stray cells, left behind after surgery, are thought to be responsible for tumor relapse. Finding and removing these cells could improve a patient's chance of survival. Fatouros and colleagues have created a modified version of the buckyballs with a fluorescent metal atom called terbium. A glowing buckyball could guide surgeons to remove tumors with greater precision. Addition of yet another metal, lutetium, would deliver a lethal dose of radiation to the cancer cells, including those missed by the surgeon. The research is about three to five years away from testing in humans, but the possibilities seem remarkable.

Detect, Treat, Track


There is a growing consensus that brain cancer is a problem in need of a radically different solution, and that nanotechnology fits the bill. Functionalized nanoparticles could provide precision detection, targeted treatment, and real-time tracking that conventional technology lacks. For a disease in which only 5 percent to 32 percent of patients are likely to survive after five years, large hope is riding on the potential success of small technology. Back To Top

Brain Cancer Facts 5-7

Brain cancer is a complex disease, classified into 120 different types. Socalled non-malignant (benign) brain tumors can be just as life-threatening as malignant tumors, as they squeeze out normal brain tissue and disrupt function. The glioma family of tumors comprise 44.4% of all brain tumors. Glioblastoma is the most common glioma at 51.9%, followed by astrocytoma at 21.6%. Brain tumors are the leading cause cancer death in children under the age of 20. They are the second leading cause of cancer death among 20-29 year old males. Metastatic brain tumors result from cancer that spreads from other parts of the body into the brain. About 10-15% of people with cancer will eventually develop metastatic brain tumors. The five-year survival rate following diagnosis of a primary malignant brain tumor is about 32.7%. The five-year survival rate for some forms of cancer, such as glioblastoma, can be as low as 5%.

References
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Kreuter J, Shamenkov D, Petrov V, Ramge P, Cychutek K, Koch-Brandt C, Alyautdin R. Apolipoprotein-mediated transport of nanoparticle-bound drugs across the blood-brain barrier. J Drug Target 10(4):317-25 (2002)
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Costantino L , Gandolfi F, Tosi G, Rivasi F, Vandelli MA, Forni F. Peptidederivatized biodegradable nanoparticles able to cross the blood-brain barrier. J Control Release 108(1):84-96 (2005)
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Kopelman R, Philbert M, Koo YEL, Moffat BA, Reddy GR, P. McConville, Hall DE, Chenevert TL, Bhojani MS, Buck SM, Rehemtulla A, Ross BD. Multifunctional Nanoparticle Platforms for In Vivo MRI Enhancement and Photodynamic Therapy of a Rat Brain Cancer. J. of Magnetism and Magnetic Materials 293:404-410 (2005)

Veiseh O, Sun C, Gunn J, Kohler N, Gabikian P, Lee D, Bhattarai N, Ellenbogen R, Sze R, Hallahan A, Olson J, Zhang M. Optical and MRI multifunctional nanoprobe for targeting gliomas. Nano Lett. 5(6):1003-8 (2005)
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Jemal A, Murray T, Samuels A, Cancer Statistics, 2003. CA: A Cancer Journal for Clinicians 53(1):5-26 (2003)
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Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L, Edwards BK (eds.) Seer Cancer Statistics Review, 1973-1999: National Cancer Institute, Bethesda, MD (2002)
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Primary Brain Tumors in the United States Statistical Report 2002-2003. Central Brain Tumor Registry of the United States (CBTRUS) Back To Top Home | Text-Only Version | Contact Us | Policies | Accessibility | RSS | Advanced Search | Site Map Home | Images Version | Contact Us | Policies | Accessibility | RSS | Advanced Search | Site Map A Service of the National Cancer Institute

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February 2008 Nanotechnology Advances Brain Cancer Detection and Therapy

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Brain cancer is one of the most aggressive and lethal of malignancies, made even more difficult to treat by the fact that most anticancer drugs have a hard time even getting to the tumors. Now, studies by three different groups of researchers show that targeted nanoparticles hold promise for solving this delivery problem. In a report published in the journal Small, a team of investigators led by Miqin Zhang, Ph.D., principal investigator (PI) of the Nanotechnology Platform for Pediatric Brain Cancer Imaging and Therapy at the University of Washington, and Jim Olson, M.D., of the Fred Hutchinson Cancer Research Center, describes its development of an iron oxide nanoparticle targeted to glioblastoma cells and shows that brain tumors in animal models take up these nanoparticles. The researchers start with iron oxide nanoparticles coated with PEG and add a targeting molecule known as chlorotoxin. Chlorotoxin is a peptide isolated from scorpions and has been shown

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to have high selectivity for binding strongly to gliomas and other malignancies, including prostate cancer, sarcoma, and intestinal cancer. The investigators first tested this nanoparticle construct in glioma cells growing in culture, showing that the nanoparticle was internalized rapidly. More importantly, the nanoparticles ended up in the cells cytoplasm rather than remaining confined within uptake vesicles known as endosomes. In contrast, nanoparticles lacking chlorotoxin showed almost no uptake by glioma cells. The researchers also showed in these experiments that they could detect the internalized nanoparticles using magnetic resonance imaging (MRI). On the basis of these results, the investigators examined whether these nanoparticles would target gliomas implanted in mice. By 3 hours after injection, tumors were readily apparent in MRI scans and were easily distinguished from surrounding healthy tissue. The researchers also found that maximal signal enhancement occurred approximately 12 hours after injection. A thorough examination of tissues from kidney, liver, and spleen showed no signs of acute toxicity from the nanoparticles. In a second paper, published in the journal Biomaterials, Victor Yang, Ph.D., and colleagues at the University of Michigan showed that they could use a magnetic field to target iron oxide nanoparticles to gliomas implanted in the brains of mice. In this study, the investigators used commercially available iron oxide nanoparticles coated with starch. After placing tumor-bearing animals so that their heads rested between the poles of an electromagnet, the researchers injected nanoparticles into the animals tail veins. After 30 minutes, the researchers then placed the animals into a small-bore MRI system. MRI scans obtained 1 and 3 hours after injection showed significant accumulation of the nanoparticles within the tumors. Shin-Ichi Miyatake, M.D., Ph.D., of Osaka Medical College in Japan led another team of investigators that developed a tumor-targeted liposome that was able to deliver high concentrations of boron to brain tumors for boron-neutron capture therapy, which in turn enhanced the survival of animals with implanted human brain tumors. They created the delivery vehicle first by forming PEG-coated liposomes loaded with sodium borocaptate and then attaching transferrin, a well-studied tumor targeting agent, to the PEG coating. Researchers then loaded boron into liposomes coated with PEG. Studies using glioma cells growing in culture showed that liposomes were internalized within 12 hours, concentrating in the cell nucleus. Neutron irradiation was lethal to the cells. In contrast, little effect was seen when cells were treated with an untargeted liposome or a targeted liposome lacking boron prior to neutron irradiation. The researchers then injected the targeted liposomes into mice with tumors growing on one side of their brains. Boron accumulated in the tumors within 6 hours and remained there for at least 72 hours after administration, whereas very little boron accumulated in the opposite brain hemisphere. Neutron irradiation produced a marked effect on the treated animals, significantly increasing the time of survival. The work from Drs. Zhang and Olson and their colleagues is detailed in the paper In vivo MRI detection of gliomas by chlorotoxin-conjugated superparamagnetic

nanoprobes. This work was funded by the NCIs Alliance for Nanotechnology in Cancer. An investigator from the Childrens National Medical Center in Washington, DC, also participated in this study. An abstract of this paper is available through PubMed. View abstract The work from Dr. Yang and collaborators is described in the paper Iron oxide nanoparticles as a drug delivery vehicle for MRI monitored magnetic targeting of brain tumors. This research was funded by the NCI. Investigators from chemicell GmbH in Berlin, Germany, and from Tianjin University in China also participated in this study. An abstract of this paper is available through PubMed. View abstract The work from Dr. Miyatake and colleagues appears in the paper Tumor-specific targeting of sodium borocaptate (BSH) to malignant glioma by transferrin-PEG liposomes: a modality for boron neutron capture therapy. Investigators from Hiroshima International University, Teikyo University, the Japan Atomic Energy Research Institute, and Kyoto University, all in Japan, also participated in this study. An abstract of this paper is available through PubMed. View abstract Home | Text-Only Version | Contact Us | Policies | Accessibility | RSS | Advanced Search | Site Map Home | Images Version | Contact Us | Policies | Accessibility | RSS | Advanced Search | Site Map A Service of the National Cancer Institute

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Nanotechnology Advances Brain Cancer Detection And Therapy


Feb 15th, 2008 by Kathy URL: http://nanowerk.com/news/newsid=4558.php (Nanowerk News) Brain cancer is one of the most aggressive and lethal of malignancies, made even more difficult to treat by the fact that most anticancer drugs have a hard time even getting to the tumors. Now, studies by three different groups of researchers show that targeted nanoparticles hold promise for solving this delivery problem. In a report published in the journal Small (In Vivo MRI Detection of Gliomas by Chlorotoxin-Conjugated Superparamagnetic Nanoprobes), a team of investigators led by Miqin Zhang, Ph.D., principal investigator (PI) of the Nanotechnology Platform for Pediatric Brain Cancer Imaging and Therapy at the University of Washington, and Jim Olson, M.D., of the Fred Hutchinson Cancer Research Center, describes its development of an iron oxide nanoparticle targeted to glioblastoma cells and shows that brain tumors in animal models take up these nanoparticles. The researchers start with iron oxide nanoparticles coated with PEG and add a targeting molecule known as chlorotoxin. Chlorotoxin is a peptide isolated from scorpions and has been shown to have high selectivity for binding strongly to gliomas and other malignancies, including prostate cancer, sarcoma, and intestinal cancer. The investigators first tested this nanoparticle construct in glioma cells growing in culture, showing that the nanoparticle was internalized rapidly. More importantly, the nanoparticles ended up in the cells cytoplasm rather than remaining confined within uptake vesicles known as endosomes. In contrast, nanoparticles lacking chlorotoxin showed almost no uptake by glioma cells. The researchers also showed in these experiments that they could detect the internalized nanoparticles using magnetic resonance imaging (MRI). On the basis of these results, the investigators examined whether these nanoparticles would target gliomas implanted in mice. By 3 hours after injection, tumors were readily apparent in MRI scans and were easily distinguished from surrounding healthy tissue. The researchers also found that maximal signal enhancement occurred approximately 12 hours after injection. A thorough examination of tissues from kidney, liver, and spleen showed no signs of acute toxicity from the nanoparticles.

In a second paper, published in the journal Biomaterials (Iron oxide nanoparticles as a drug delivery vehicle for MRI monitored magnetic targeting of brain tumors), Victor Yang, Ph.D., and colleagues at the University of Michigan showed that they could use a magnetic field to target iron oxide nanoparticles to gliomas implanted in the brains of mice. In this study, the investigators used commercially available iron oxide nanoparticles coated with starch. After placing tumor-bearing animals so that their heads rested between the poles of an electromagnet, the researchers injected nanoparticles into the animals tail veins. After 30 minutes, the researchers then placed the animals into a small-bore MRI system. MRI scans obtained 1 and 3 hours after injection showed significant accumulation of the nanoparticles within the tumors. Shin-Ichi Miyatake, M.D., Ph.D., of Osaka Medical College in Japan led another team of investigators that developed a tumor-targeted liposome that was able to deliver high concentrations of boron to brain tumors for boron-neutron capture therapy, which in turn enhanced the survival of animals with implanted human brain tumors (Tumor-specific targeting of sodium borocaptate (BSH) to malignant glioma by transferrin-PEG liposomes: a modality for boron neutron capture therapy). They created the delivery vehicle first by forming PEG-coated liposomes loaded with sodium borocaptate and then attaching transferrin, a well-studied tumor targeting agent, to the PEG coating. Researchers then loaded boron into liposomes coated with PEG. Studies using glioma cells growing in culture showed that liposomes were internalized within 12 hours, concentrating in the cell nucleus. Neutron irradiation was lethal to the cells. In contrast, little effect was seen when cells were treated with an untargeted liposome or a targeted liposome lacking boron prior to neutron irradiation. The researchers then injected the targeted liposomes into mice with tumors growing on one side of their brains. Boron accumulated in the tumors within 6 hours and remained there for at least 72 hours after administration, whereas very little boron accumulated in the opposite brain hemisphere. Neutron irradiation produced a marked effect on the treated animals, significantly increasing the time of survival. Posted in News, Research

2 Responses to Nanotechnology Advances Brain Cancer Detection And Therapy


1. on 25 Apr 2008 at 11:29 am1Lene Lyssand

Hi, Reading your article, I have a general question of when this study will be introduced as an accepted way of treatment for brain cancer patients and which brain cancer patients will be able to benefit from it? Let me give you some more background information to my two questions above. My mother was just diagnosed with geotropic astrocytoma brain cancer. She was

diagnosed on Wednesday 04/23/2008 - following the results from an MRI she took 7 weeks ago. However, she was first diagnosed in 1997 and she has had two brain surgeries since then. With the current diagnosis she will have her third surgery within the next 6 weeks. The tumor is located in the right part of her brain above her ear. During her first operation in 1997 she was awake during surgery in order for the surgeon to work with her to find out how much he could remove of the tumor and surrounding tissue to cause minimal or none paralysis and/or speech impediments. Today, her left fingers tips and part of her upper lip is semi-paralyzed, but other than that this surgery did not give her any side effects except tiredness. During the second surgey, two years ago now, she was not awake during the operation. Now, the tumor is back and seems to be getting more aggressive. The MRI shows that the size of the tumor is 4 x 2 cm in diameter and the doctors in at Haukeland Hospital in Norway are going to using the same procedure as they did in the previous surgeries. I am wondering, can Nanotechnology be something for my mother or is it still in research mode? At the Haukeland Hospital in Bergen Norway they also offer some therapy that is similar to the cyber knife, but the doctors say Nanotechnology is not ready for actual human therapy yet. My mother has heard about Nanotechnology and is very excited about what it can do for cancer patients. Can Nanotechnology do something for my mother in 2008? I would be very pleased if you could put me in contact with someone who can support me in finding alternative methods to brain surgery as the invasive surgery is putting a heavy toll on patients that go through multiple brain surgeries effecting the patients physical health in the aftermath of surgery. I apologize if this is the wrong forum to raise the above questions, but I would highly appreciate it if you could direct me so someone who can support and advice me in this matter. Thank you! Lene Lyssand (Currently in Colorado)
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Nanotechnology Tackles Brain Cancer


Jan 26, 2006 NCI-supported researchers are creating ultrasmall particles that can target and destroy cancer cells in the brain, even those in tumors too small to be removed surgically. Nanotechnology From the Lab to the Land Announcements

Brain cancer can be counted among the most deadly and intractable diseases. Often diagnosed after a patient exhibits symptoms such as nausea, dizziness, uncharacteristic behavior changes, or paralysis, the growing mass of a brain tumor will continue to squeeze out normal tissue and degrade the brains function if left untreated. But treatment is elusive. Tumors may be embedded in regions of the brain that are critical to orchestrating the bodys vital functions, while they shed cells to invade other parts of the brain, forming more tumors too small to detect using conventional imaging techniques. Brain cancers location and ability to spread quickly makes treatment with surgery or radiation like fighting an enemy hiding out among minefields and caves, and explains why the term brain cancer is all too often associated with the word inoperable. Making treatment even more challenging, there is a system of blood vessels and protective cells in the brain the blood-brain barrier that admits only essential nutrients and oxygen, and keeps out everything else, including about 95 percent of all drugs. This natural barrier puts serious limits on how much a patient can benefit from traditional chemotherapy and new cancer drugs. In an ideal situation, we would have a smart drug that could cross the bloodbrain barrier, zero in on the cancer cells, mark their location clearly for surgery, or destroy them with such precision that it would leave surrounding, normal brain cells intact. Until now, such a scenario seemed so far-fetched. But using nanotechnology, NCI-supported researchers at the University of Michigan, the University of Washington, the University of Texas M. D. Anderson Cancer Center, Virginia Polytechnic Institute, and Virginia Commonwealth University are creating ultrasmall particles that can target and destroy cancer cells in the brain, even those in tumors too small to be removed surgically.

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Getting Into the Brain Ticket Required

Among the properties of nanoparticles that make them ideal candidates for recognizing and treating brain cancer, their ability to deliver a wide variety of payloads across the blood-brain barrier is perhaps the most important. Understanding how some nanoparticles achieve this special permission to enter the brain requires a closer look at how the blood-brain barrier works. The blood-brain barrier permits the exchange of essential nutrients and gases Single Wall Carbon Nanotubebetween the bloodstream and the brain, while blocking larger entities such as Based Structural Health microbes, immune cells and most drugs from entering. This barrier system is a Monitoring Sensing Materials A. Neal Watkins et perfectly logical arrangement, since the brain is the most sensitive and complex NASA Langley Research al. Center organ in the human body and it would not make sense for it to become the Nanotech Proceedings battleground of infection and immune response. This biological demilitarization zone is enforced by an elaborate and dense network of capillary vessels that feeds the brain and removes waste products. Each capillary vessel is bound by a single layer of endothelial cells, connected by tight junctions, thereby making it very difficult for most molecules to exit the capillaries and permeate into the brain. Access 3,064 pages of Outside of the central nervous system, capillaries have fenestra (the latin for the latest peer-reviewed

window), which are the cracks between the cells in the vessel wall. Both small and large molecules and even cells can leave the capillary and enter into the surrounding tissue. Instead of leaking material, brain capillary walls closely regulate the flow of material using molecular pumps and receptors that recognize and transport nutrients such as glucose, nucleosides, and specific proteins into the brain. In other words, substances need to be pre-recognized to enter. So what allows some nanoparticles to get into the brain? Nanoparticles that successfully cross the barrier are often coated with polyethylene glycol (PEG), polysorbate, or other polymer or surfactant (a detergent-like substance). The exact mechanism of nanoparticle transport into the brain is not fully understood, but it is thought to depend on the particles size, material composition, and structure. In some cases, it appears that a specialized coating of polymer or surfactant allows nanoparticles to mimic molecules that would normally be transported into the brain. For example, polysorbate-coated nanoparticles are thought to mimic low-density lipoproteins (LDL), allowing them to be transported across the capillary wall and into the brain by hitching a ride on the LDL receptor. In another example, nanoparticles were decorated with opioid peptides, short pieces of protein that act as natural painkillers. The opioid peptides bind to specific receptors on the capillary walls, which help carry the nanoparticles into the brain. In other cases, no special tricks are needed: larger tumors can disrupt the local vasculature, creating leaky vessels through which nanoparticles and other molecules can easily penetrate. Once inside the brain, a nanoparticle can deliver a wide variety of payloads to detect and treat cancer.
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Throwing PEBBLEs at Brain Cancer


When the team of Raoul Kopelman, Ph.D., at the University of Michigan, thought of a tool to diagnose and treat the most virulent forms of brain cancer, they thought of pebbles. That is, 20 to 200 nanometer diameter nanoparticles they dubbed Probes Encapsulated by Biologically Localized Embedding (PEBBLEs). Kopelman designed the PEBBLEs to carry a variety of agents on their surface, each with a unique function. Therein lies another major potential advantage of using nanoparticles to treat cancer: multifunctionality. One target molecule immobilized on the surface could guide the PEBBLE to a tumor. Another agent could be used to help visualize the target using magnetic resonance imaging (MRI), while a third agent attached to the PEBBLE could deliver a destructive dose of drug or toxin to nearby cancer cells. All three functions can be combined in a single tiny polymer sphere to make a potent weapon against cancer. Kopelman introduced the common MRI contrast element gadolinium to the PEBBLEs. When injected into the bloodstream, the nanoparticles wend their way through the bloodstream. But because they can transverse the blood-brain
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barrier, and because they have a targeting agent attached, the PEBBLEs accumulate in the brain tumor enabling a clear MRI image within just a few hours. The next functional step is a remarkable feat of nano-engineering. Each PEBBLE carries a photocatalyst . When stimulated by a light source through a micrometer-sized fiber-optic probe inserted into the skull, the photocatalyst converts oxygen into a so-called singlet state, which effectively bleaches and destroys nearby cells. The PEBBLEs are inert and harmless until the light is turned on. Used in combination with MRI imaging, one could now kill cancer cells at will, while tracking the effectiveness of the treatment with imaging. The targeted treatments using nanoparticles may offer a number of advantages over traditional chemotherapy. In chemotherapy, the drugs permeate cells throughout the body to damage their DNA and prevent rapid growth, and are only moderately more toxic to cancer cells over normal cells. That is why patients suffer so many side effects of chemotherapy including nausea, hair loss, and anemia. In contrast, PEBBLEs are highly localized to the cancer target, and do very little damage to surrounding healthy tissue. PEBBLEs and other nanoparticle drugs could also avoid another serious problem occurring in traditional chemotherapy for some cancers, over 50 percent of patients become non-responsive to treatment due to the development of multi-drug resistance (MDR). MDR occurs when cancer cells mutate and begin to pump the chemotherapy drugs back out before they can destroy the cell. The cancer becomes immune to the drug. But PEBBLEs act on the outside of the cell, and the toxic payload of oxygen that they deliver acts quickly, without giving the cancer much chance to survive and develop resistance. In rat models of a type of brain cancer called 9L-gliosarcoma, PEBBLE-based treatment can significantly increase survival time. Patients with this particularly aggressive form of cancer rarely live more than four months after diagnosis without treatment. For rats, the clock runs out in about five days. When rats were treated with PEBBLEs targeted to 9L-gliosarcoma tumors, some were still thriving after two months, and an MRI image of their brain revealed that the tumors had been eliminated. Kopelman and collaborators (including Martin Philbert, Ph.D., at the University of Michigan School of Public Health), hope ultimately to prove the utility and safety of this approach to treating brain cancer in humans.

The Illuminated Brain


Unfortunately, the most common form of primary brain cancer, glioblastoma, is also the most aggressive and lethal. Glioblastoma tumors emerge rapidly and spread throughout the brain. About 20,000 Americans are diagnosed each year, and more than half of those patients will die within 18 months. Surgery is limited in its effectiveness because it is difficult to differentiate visually between cancerous and normal brain tissue, and any cancer cells left behind are likely to proliferate and form new tumors. In order to improve the odds of eliminating all the cancer during surgery and avoid removing healthy brain tissue, researchers

have devised a number of fluorophores, or glowing molecules that mark the tumor boundaries for removal. But the fluorescent probes are difficult to locate and use within the brain during surgery. A multidisciplinary team at the University of Washington and the Fred Hutchinson Cancer Research Center in Seattle, wanted to see if surgical outcomes could be improved by a single probe that accurately marks the location of a tumor in pre-operative MRI scans, while guiding the surgeon to those same locations in the exposed brain. To materials scientist Miqin Zhang, Ph.D., radiologist Raymond Sze, M.D., and oncologist Jim Olson, M.D., nanotechnology was the perfect solution for creating such a multifunctional probe. Starting with a 10 nanometer diameter iron oxide core that serves as an MRI contrast material, Zhang and colleagues coated the nanoparticles with polyethylene glycol and modified them with a fluorescent molecule called Cy5.5. Cy5.5 gives off light at near-infrared wavelengths, which unlike visible light can penetrate several centimeters through brain tissue. In order to selectively light up glioma tumors through imaging, a targeting agent had to be attached. Zhang and colleagues selected chlorotoxin, a peptide derived from the venom of the giant Israeli scorpion, which binds specifically to a tumor surface marker found in the vast majority of gliomas. At 15 nanometers, the final particle size and composition gave it the best chance for crossing the blood-brain barrier, and homing in on its target. Tested on cultured cells, the nanoparticles performed remarkably well. Studies clearly demonstrated uptake by glioma cells, but not healthy brain cells, and the nanoprobes were readily detectable by both MRI and near-infrared fluorescence. More work remains to be done in animal studies, but Zhang and coworkers are driven by a vision that some day a surgeon will be able to use MRI to map out a surgical plan, and then have a visual guide for that plan in real time, while operating on the brain. According to Chun Li, Ph.D., at the University of Texas M. D. Anderson Cancer Center, and Eastman Kodak, near-infrared emitting nanoparticles could be a valuable tool for outlining the margins of a tumor, and helping the surgeon to avoid cutting into healthy tissue. Better cameras and detection methods will be needed before these nanoparticles are used in a real operation, but a photographic technology expert such as Eastman Kodak seems ideal to address these challenges. Kodaks engineering and chemistry teams are backed by a long history of expertise in dye chemistry. The company is supplying high-quality near-infrared emitting nanoparticles with well-controlled properties. Lis multidisciplinary approach, pooling the expertise of engineers, chemists, and biologists, is a good example of the multidisciplinary research collaborations needed to move nanotechnology research forward in the area of cancer.
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Buckyballs Pack Heat


In the 1970s, a new variety of carbon was discovered that formed hollow

nanometer-scale cage-like spheres. They were called buckminsterfullerenes or buckyballs, after the architect who built domed structures of a similar shape, and were hypothesized to have great potential for their ability to carry atoms and molecules with useful properties. Then in 1999, Virginia Tech chemists Harry Dorn, Ph.D. and Harry Gibson, Ph.D. created the first buckyballs encapsulating rare earth metals, the kind that can easily be recognized as a contrast agent for MRI. The attachment of targeting agents to the outside of the carbon cage allowed the buckyballs to accumulate in tumors. Now, Panos Fatouros, Ph.D., and neurosurgeon William Broaddus, M.D., Ph.D., both at Virginia Commonwealth University, are collaborating with Dorn and Gibson on a project using buckyballs to improve the ability of MRIs to locate brain tumors, and deliver a payload of radiation to destroy them. Experiments on rats have shown that buckyballs packed with the MRI contrast metal gadolinium can increase the sensitivity of MRI detection by at least 40-fold. This level of precision is reaching a point at which cancer cells that have spread beyond the margins of the tumor may become visible. Stray cells, left behind after surgery, are thought to be responsible for tumor relapse. Finding and removing these cells could improve a patient's chance of survival. Fatouros and colleagues have created a modified version of the buckyballs with a fluorescent metal atom called terbium. A glowing buckyball could guide surgeons to remove tumors with greater precision. Addition of yet another metal, lutetium, would deliver a lethal dose of radiation to the cancer cells, including those missed by the surgeon. The research is about three to five years away from testing in humans, but the possibilities seem remarkable.

Detect, Treat, Track


There is a growing consensus that brain cancer is a problem in need of a radically different solution, and that nanotechnology fits the bill. Functionalized nanoparticles could provide precision detection, targeted treatment, and realtime tracking that conventional technology lacks. For a disease in which only 5 percent to 32 percent of patients are likely to survive after five years, large hope is riding on the potential success of small technology.

Brain Cancer Facts

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Brain cancer is a complex disease, classified into 120 different types. So-called non-malignant (benign) brain tumors can be just as life-threatening as malignant tumors, as they squeeze out normal brain tissue and disrupt function. The glioma family of tumors comprise 44.4% of all brain tumors. Glioblastoma is the most common glioma at 51.9%, followed by astrocytoma at 21.6%. Brain tumors are the leading cause cancer death in children under the age of 20. They are the second leading cause of cancer death among 20-29 year old males. Metastatic brain tumors result from cancer that spreads from other parts of the body into the brain. About 10-15% of people with cancer will eventually develop metastatic brain tumors. The five-year survival rate following diagnosis of a primary malignant brain

tumor is about 32.7%. The five-year survival rate for some forms of cancer, such as glioblastoma, can be as low as 5%.

References
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Kreuter J, Shamenkov D, Petrov V, Ramge P, Cychutek K, Koch-Brandt C, Alyautdin R. Apolipoprotein-mediated transport of nanoparticle-bound drugs across the blood-brain barrier. J Drug Target 10(4):317-25 (2002) Costantino L , Gandolfi F, Tosi G, Rivasi F, Vandelli MA, Forni F. Peptidederivatized biodegradable nanoparticles able to cross the blood-brain barrier. J Control Release 108(1):84-96 (2005) Kopelman R, Philbert M, Koo YEL, Moffat BA, Reddy GR, P. McConville, Hall DE, Chenevert TL, Bhojani MS, Buck SM, Rehemtulla A, Ross BD. Multifunctional Nanoparticle Platforms for In Vivo MRI Enhancement and Photodynamic Therapy of a Rat Brain Cancer. J. of Magnetism and Magnetic Materials 293:404-410 (2005) Veiseh O, Sun C, Gunn J, Kohler N, Gabikian P, Lee D, Bhattarai N, Ellenbogen R, Sze R, Hallahan A, Olson J, Zhang M. Optical and MRI multifunctional nanoprobe for targeting gliomas. Nano Lett. 5(6):1003-8 (2005) Jemal A, Murray T, Samuels A, Cancer Statistics, 2003. CA: A Cancer Journal for Clinicians 53(1):5-26 (2003) Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L, Edwards BK (eds.) Seer Cancer Statistics Review, 1973-1999: National Cancer Institute, Bethesda, MD (2002) Primary Brain Tumors in the United States Statistical Report 2002-2003. Central Brain Tumor Registry of the United States (CBTRUS)

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Nanotechnology advances brain cancer detection and therapy Brain cancer is one of the most aggressive and lethal of malignancies, made even more difficult to treat by the fact that most anticancer drugs have a hard time even getting to the tumours. Now, studies by three different groups of researchers show that targeted nanoparticles hold

promise for solving this delivery problem. In a report published in the journal Small, a team of investigators led by Miqin Zhang, Ph.D., principal investigator (PI) of the Nanotechnology Platform for Paediatric Brain Cancer Imaging and Therapy at the University of Washington, and Jim Olson, M.D., of the Fred Hutchinson Cancer Research Centre, describes its development of an iron oxide nanoparticle targeted to glioblastoma cells and shows that brain tumours in animal models take up these nanoparticles. The researchers start with iron oxide nanoparticles coated with PEG and add a targeting molecule known as chlorotoxin. Chlorotoxin is a peptide isolated from scorpions and has been shown to have high selectivity for binding strongly to gliomas and other malignancies, including prostate cancer, sarcoma, and intestinal cancer. The investigators first tested this nanoparticle construct in glioma cells growing in culture, showing that the nanoparticle was internalised rapidly. More importantly, the nanoparticles ended up in the cells' cytoplasm rather than remaining confined

within uptake vesicles known as endosomes. In contrast, nanoparticles lacking chlorotoxin showed almost no uptake by glioma cells. The researchers also showed in these experiments that they could detect the internalized nanoparticles using magnetic resonance imaging (MRI). Tumours soon apparent Based on these results, the investigators examined whether these nanoparticles would target gliomas implanted in mice. By three hours after injection, tumours were readily apparent in MRI scans and were easily distinguished from surrounding healthy tissue. The researchers also found that maximal signal enhancement occurred approximately 12 hours after injection. A thorough examination of tissues from kidney, liver, and spleen showed no signs of acute toxicity from the nanoparticles. In a second paper, published in the journal Biomaterials, Victor Yang, Ph.D., and colleagues at the University of Michigan showed that they could use a magnetic field to target iron oxide nanoparticles to gliomas implanted in the brains of mice. In this study, the investigators used

commercially available iron oxide nanoparticles coated with starch. After placing tumour-bearing animals so that their heads rested between the poles of an electromagnet, the researchers injected nanoparticles into the animals' tail veins. After 30 minutes, the researchers then placed the animals into a small-bore MRI system. MRI scans obtained 1 and 3 hours after injection showed significant accumulation of the nanoparticles within the tumours. Shin-Ichi Miyatake, M.D., Ph.D., of Osaka Medical College in Japan led another team of investigators that developed a tumour-targeted liposome that was able to deliver high concentrations of boron to brain tumours for boron-neutron capture therapy, which in turn enhanced the survival of animals with implanted human brain tumours. They created the delivery vehicle first by forming PEG-coated liposomes loaded with sodium borocaptate and then attaching transferrin, a well-studied tumourtargeting agent, to the PEG coating. Researchers then loaded boron into liposomes coated with PEG. Lethal to the cells Studies using glioma cells growing in culture showed

that liposomes were internalised within 12 hours, concentrating in the cell nucleus. Neutron irradiation was lethal to the cells. In contrast, little effect was seen when cells were treated with an untargeted liposome or a targeted liposome lacking boron prior to neutron irradiation. The researchers then injected the targeted liposomes into mice with tumours growing on one side of their brains. Boron accumulated in the tumours within 6 hours and remained there for at least 72 hours after administration, whereas very little boron accumulated in the opposite brain hemisphere. Neutron irradiation produced a marked effect on the treated animals, significantly increasing the time of survival. The work from Drs. Zhang and Olson and their colleagues is detailed in the paper In vivo MRI detection of gliomas by chlorotoxinconjugated superparamagnetic nanoprobes. This work was funded by the NCI's Alliance for Nanotechnology in Cancer. An investigator from the Children's National Medical Center in Washington, DC, also participated in this study. An abstract of this

paper is available through PubMed. View abstract The work from Dr. Yang and collaborators is described in the paper Iron oxide nanoparticles as a drug delivery vehicle for MRI monitored magnetic targeting of brain tumours. This research was funded by the NCI. Investigators from chemicell GmbH in Berlin, Germany and from Tianjin University in China also participated in this study. An abstract of this paper is available through PubMed. View abstract The work from Dr. Miyatake and colleagues appears in the paper "Tumour-specific targeting of sodium borocaptate (BSH) to malignant glioma by transferrin-PEG liposomes: a modality for boron neutron capture therapy." Investigators from Hiroshima International University, Teikyo University, the Japan Atomic Energy Research Institute, and Kyoto University, all in Japan, also participated in this study. An abstract of this paper is available through PubMed. View abstract http://nano.cancer.gov

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To overcome the limited access of the drug 5-fluoro-2'-deoxyuridine (FUdR) to the brain, 3',5'-dioctanoyl-5-fluoro-2'-deoxyuridine (DO-FUdR) was synthesized and incorporated into solid lipid nanoparticles (DO-FUdR-SLN). DO-FUdR-SLN were prepared by a thin-layer ultrasonication technique and a central composite design (CCD) was applied to optimize the formulation. The median particle size of DO-FUdRSLN was 76 nm with drug loading of 29.02% and entrapment efficiency of 96.62%. The in vitro drug release was studied by a bulk-equilibrium reverse dialysis bag technique in phosphate-buffered saline (pH 7.4) containing 0.3% pancreatic enzyme at 37 degrees C. The concentrations of FUdR in various organs were determined by reversed-phase high-performance liquid chromatography after intravenous administration of DO-FUdR-SLN, DO-FUdR or FUdR. The brain area under the concentration-time curve of DO-FUdR-SLN and DO-FUdR were 10.97- and 5.32-fold higher than that of FUdR, respectively. These results indicated that DO-FUdR-SLN had a good brain targeting efficiency in vivo. SLN can improve the ability of the drug to penetrate through the blood-brain barrier and is a promising drug targeting system for the treatment of central nervous system disorders.