Nanotechnology in Therapeutics

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Nanotechnology in Therapeutics
A Focus on Nanoparticles as a Drug Delivery System
Suwussa Bamrungsap; Zilong Zhao; Tao Chen; Lin Wang; Chunmei Li; Ting Fu; Weihong Tan
Nanomedicine. 2012;7(8):12531271.
Abstract and Introduction
Abstract
Continuing improvement in the pharmacological and therapeutic properties of drugs is driving the revolution in novel drug delivery
systems. In fact, a wide spectrum of therapeutic nanocarriers has been extensively investigated to address this emerging need.
Accordingly, this article will review recent developments in the use of nanoparticles as drug delivery systems to treat a wide
variety of diseases. Finally, we will introduce challenges and future nanotechnology strategies to overcome limitations in this field.
Introduction
Nanotechnology involves the engineering of functional systems at the molecular scale. Such systems are characterized by
unique physical, optical and electronic features that are attractive for disciplines ranging from materials science to biomedicine.
One of the most active research areas of nanotechnology is nanomedicine, which applies nanotechnology to highly specific
medical interventions for the prevention, diagnosis and treatment of diseases.[1,2,401] The surge in nanomedicine research during
the past few decades is now translating into considerable commercialization efforts around the globe, with many products on the
market and a growing number in the pipeline. Currently, nanomedicine is dominated by drug delivery systems, accounting for
more than 75% of total sales.[3]
Nanomaterials fall into a size range similar to proteins and other macromolecular structures found inside living cells. As such,
nanomaterials are poised to take advantage of existing cellular machinery to facilitate the delivery of drugs. Nanoparticles (NPs)
containing encapsulated, dispersed, absorbed or conjugated drugs have unique characteristics that can lead to enhanced
performance in a variety of dosage forms. When formulated correctly, drug particles are resistant to settling and can have higher
saturation solubility, rapid dissolution and enhanced adhesion to biological surfaces, thereby providing rapid onset of therapeutic
action and improved bioavailability. In addition, the vast majority of molecules in a nanostructure reside at the particle surface,[4]
which maximizes the loading and delivery of cargos, such as therapeutic drugs, proteins and polynucleotides, to targeted cells
and tissues. Highly efficient drug delivery, based on nanomaterials, could potentially reduce the drug dose needed to achieve
therapeutic benefit, which, in turn, would lower the cost and/or reduce the side effects associated with particular drugs.
Furthermore, NP size and surface characteristics can be easily manipulated to achieve both passive and active drug targeting.
Sitespecific targeting can be achieved by attaching targeting ligands, such as antibodies or aptamers, to the surface of particles,
or by using guidance in the form of magnetic NPs. NPs can also control and sustain release of a drug during transport to, or at,
the site of localization, altering drug distribution and subsequent clearance of the drug in order to improve therapeutic efficacy
and reduce side effects.
Nanotechnology could be strategically implemented in new developing drug delivery systems that can expand drug markets.
Such a plan would be applied to drugs selected for fullscale development based on their safety and efficacy data, but which fail
to reach clinical development because of poor biopharmacological properties, for example, poor solubility or poor permeability
across the intestinal epithelium, situations that translate into poor bioavailability and undesirable pharmacokinetic properties.[5]
The new drug delivery methods are expected to enable pharmaceutical companies to reformulate existing drugs on the market,
thereby extending the lifetime of products and enhancing the performance of drugs by increasing effectiveness, safety and
patient adherence, and ultimately reducing healthcare costs.[6–8]
Commercialization of nanotechnology in pharmaceutical and medical science has made great progress. Taking the USA alone as
an example, at least 15 new pharmaceuticals approved since 1990 have utilized nanotechnology in their design and drug delivery
systems. In each case, both product development and safety data reviews were conducted on a casebycase basis, using the
best available methods and procedures, with an understanding that postmarketing vigilance for safety issues would be ongoing.
Some representative examples of therapeutic nanocarriers on the market are briefly described in .
Table 1. Representative examples of nanocarrierbased drugs on the market.
Type of nanostructure Brand name Active ingredient Indications Ref.
Rapamune® Rapamycin Immunosuppressive 193
Emend® Aprepitant Antiemetic 193

Nanocrystalline drugs
193
Tricor® Fenofibrate Hypercholesterolemia 193
Megace® Megestrol Antianorexia 193
AmBisome® Amphotericn B Fungal infections 194
Ovarian cancer, Kaposi's sarcoma and breast 195
Doxil® Doxorubicin
cancer
Liposomes Ovarian cancer, Kaposi's sarcoma and breast 196

Caelyx® Doxorubicin
cancer
Depocyt® Cytarabine Lymphomatous meningitis 197
Daunoxome® Daunorubicin Kaposi's sarcoma 198
Adenosine 199
Adagen® Adenosine deaminase enzyme deficiency
deaminase
Polymer–drug conjugates Onscaspar® Lasparaginase Acute lymphoblastic leukemia 200
PEGylated IFN 201
Pegasys® Hepatitis C
α2a
Genexol 202
Polymeric micelles Paclitaxel Cancer chemotherapy
PM®
Protein (albumin) 203
Abraxane® Paclitaxel Metastatic breast cancer
nanoparticles
Lipid colloidal dispersion Amphotec® Amphotericin B Fungal infections 204
PEG: Polyethylene glycol.
In this review, we focus mainly on the application of nanotechnology to drug delivery and highlight several areas of opportunity
where current and emerging nanotechnologies could enable novel classes of therapeutics. We look at challenges and general
trends in pharmaceutical nanotechnology, and we also explore nanotechnology strategies to overcome limitations in drug
delivery. However, this article can only serve to provide a glimpse into this rapidly evolving field, both now and what may be
expected in the future.
Nanocarriers & Their Applications
Various nanoforms have been attempted as drug delivery systems, varying from biological substances, such as albumin, gelatin
and phospholipids for liposomes, to chemical substances, such as various polymers and solid metalcontaining NPs (Figure 1).
Polymer–drug conjugates, which have high size variation, are normally not considered as NPs. However, since their size can still
be controlled within 100 nm, they are also included in these nanodelivery systems. These nanodelivery systems can be designed
to have drugs absorbed or conjugated onto the particle surface, encapsulated inside the polymer/lipid or dissolved within the
particle matrix. As a consequence, drugs can be protected from a critical environment or their unfavorable biopharmaceutical
properties can be masked and replaced with the properties of nanomaterials. In addition, nanocarriers can be accumulated
preferentially at tumor, inflammatory and infectious sites by virtue of the enhanced permeability and retention (EPR) effect. The
EPR effect involves sitespecific characteristics, not associated with normal tissues or organs, thus resulting in increased
selective targeting. Based on those properties, nanodrug delivery systems offer many advantages,[9–11] including:
Figure 1.

Some nanotechnologybased drug delivery platforms, including a nanocrystal, liposome, polymeric micelle, proteinbased
nanoparticle, dendrimer, carbon nanotube and polymer–drug conjugate.
NP: Nanoparticle.
Improving the stability of hydrophobic drugs, rendering them suitable for administration;
Improving biodistribution and pharmacokinetics, resulting in improved efficacy;
Reducing adverse effects as a consequence of favored accumulation at target sites;
Decreasing toxicity by using biocompatible nanomaterials.
By adopting nanotechnology, fundamental changes in drug production and delivery are expected to affect approximately half of
the worldwide drug production in the next decade, totaling approximately US$380 billion in revenue.[12] Next, several main
nanocarriers are briefly discussed.
Nanocrystals
One of the most obvious and important nanotechnology tools for product development is the opportunity to convert existing drugs
with poor water solubility and dissolution rate into readily watersoluble dispersions by converting them into nanosized drugs.
[13,14] In other words, the drug itself may be formulated at a nanoscale such that it can function as its own 'carrier'.[15] Many
approaches have been studied, but the most practical strategy involves reducing the drug particle size to nanometer range and
stabilizing the drug NP surface with a layer of nonionic surfactants or polymeric macromolecules.[16] By reducing the particle size
of the active pharmaceutical ingredient, the drug's surface area is increased considerably, thereby improving its solubility and
dissolution and consequently increasing both the maximum plasma concentration and area under the curve. Once the drug is
nanosized, it can be formulated into various dosage forms, such as oral, nasal and injectable. These nanocrystal drugs may have
advantages over association colloids (micelle solutions) because the level of surfactant per amount of drug can be greatly
minimized, using only the amount that is necessary to stabilize the solid–fluid interface.[15]
Furthermore, recent studies have shown that external agents, such as surfactants, for nanocrystal drug delivery can be
eliminated. For example, a method was recently developed for the delivery of a hydrophobic photosensitizing anticancer drug in
its pure form using nanocrystals.[17] Synthesized by the reprecipitation method, the resulting drug nanocrystals were stable in
aqueous dispersion, without the necessity of any additional stabilizer. These nanocrystals are uniform in size distribution with an
average diameter of 110 nm. Such nanocrystals were efficiently taken up by tumor cells in vitro, and irradiation of such cells with
visible light (665 nm) resulted in significant cell death. An in vivo study of the nanocrystal drug also showed significant efficacy
compared with the conventional surfactantbased delivery system. These results illustrate the potential of pure drug nanocrystals
for photodynamic therapy. As shown in , a number of wellknown drugs have already been commercialized using the nanocrystal
approach.

Doxil® Doxorubicin
cancer

cancer
Adenosine 199
deaminase
PEGylated IFN 201
α2a
Genexol 202
PM®
nanoparticles
Organic Nanoplatforms
Liposomes Liposomes are selfassembled artificial vesicles developed from amphiphilic phospholipids. These vesicles consist of
a spherical bilayer structure surrounding an aqueous core domain, and their size can vary from 50 nm to several micrometers.
Liposomes have attractive biological properties, including general biocompatibility, biodegradability, isolation of drugs from the
surrounding environment and the ability to entrap both hydrophilic and hydrophobic drugs. Through the addition of agents to the
lipid membrane, or the alteration of the surface chemistry, liposome properties, such as size, surface charge and functionality, can
be easily tuned.
Liposomes are the most clinically established nanosystems for drug delivery. Their efficacy has been demonstrated in reducing
systemic effects and toxicity, as well as in attenuating drug clearance.[18,19] Modified liposomes at the nanoscale have been
shown to have excellent pharmacokinetic profiles for the delivery of DNA, antisense oligonucleotide, siRNA, proteins and
chemotherapeutic agents.[20] Examples of marketed liposomal drugs with higher efficacy and lower toxicity than their
nonliposomal analogues are listed in . Doxorubicin is an anticancer drug that is widely used for the treatment of various types of
tumors. It is a highly toxic compound affecting not only tumor tissue, but also heart and kidney, a fact that limits its therapeutic
applications. However, the development of doxorubicin enclosed in liposomes culminated in an approved nanomedical drug
delivery system.[21,22] This novel liposomal formulation has resulted in reduced delivery of doxorubicin to the heart and renal
system, while elevating the accumulation in tumor tissue[23,24] by the EPR effect. Furthermore, a number of liposomal drugs are
currently being investigated, including anticancer agents, such as camptothecin[25] and paclitaxel (PTX),[26] as well as antibiotics,
such as vancomycin[27] and amikacin.[28]

Doxil® Doxorubicin
cancer

cancer
Adenosine 199
deaminase
PEGylated IFN 201
α2a
Genexol 202
PM®
nanoparticles
Liposomes are also subject to some limitations, including low encapsulation efficiency, fast burst release of drugs, poor storage
stability and lack of tunable triggers for drug release.[29] Furthermore, since liposomes cannot usually permeate cells, drugs are
released into the extracellular fluid.[30] As such, many efforts have focused on improving their stability and increasing circulation
halflife for effective targeting or sustained drug action.[19,31] Surface modification is one method of conferring stability and
structural integrity against a harsh bioenvironment after oral or parenteral administration.[32] Surface modification can be
achieved by attaching polyethylene glycol (PEG) units, which form a protective layer over the liposome surface (known as stealth
liposomes) to slow down liposome recognition, or by attaching other polymers, such as poly(methacrylic acidcocholesteryl
methacrylate)[33] and poly(actylic acid),[34] to improve the circulation time of liposomes in blood. To overcome the fast burst
methacrylate)[33] and poly(actylic acid),[34] to improve the circulation time of liposomes in blood. To overcome the fast burst
release of the chemotherapeutic drugs from liposomes, drugs such as doxorubicin may be encapsulated in the liposomal
aqueous phase by an ammonium sulphate gradient.[35] This strategy enables stable drug entrapment with negligible drug
leakage during circulation, even after prolonged residence in the blood stream.[36] Further efforts to improve control over the rate
of release and drug bioavailability have been made by designing liposomes whose release is environmentally triggered.
Accordingly, the drug release from liposomeresponsive polymers, or hydrogel, is triggered by a change in pH, temperature,
radiofrequency or magnetic field.[37] Liposomes have also been conjugated with activetargeting ligands, such as antibodies[38–
40] or folate, for targetspecific drug delivery.[41]
Polymeric NPs Polymeric NPs are colloidal particles with a size range of 10–1000 nm, and they can be spherical, branched or
core–shell structures. They have been fabricated using biodegradable synthetic polymers, such as polylactide–polyglycolide
copolymers, polyacrylates and polycaprolactones, or natural polymers, such as albumin, gelatin, alginate, collagen and chitosan.
[42] Various methods, such as solvent evaporation, spontaneous emulsification, solvent diffusion, salting out/emulsification
diffusion, use of supercritical CO2 and polymerization, have been used to prepare the NPs.[43] Advances in polymer science and
engineering have resulted in the development of smart polymer (stimulisensitive polymer), which can change its physicochemical
properties in response to environmental signals. Physical (temperature, ultrasound, light, electricity and mechanical stress),
chemical (pH and ionic strength) and biological signals (enzymes and biomolecules) have been used as triggering stimuli. Various
monomers having sensitivity to specific stimuli can be tailored to a homopolymer in response to a certain signal or copolymers
answering multiple stimuli. The versatility of polymer sources and their easy combination make it possible to tune up polymer
sensitivity in response to a given stimulus within a narrow range, leading to more accurate and programmable drug delivery.
Polymeric nanocarriers can be categorized based on three drugincorporation mechanisms. The first includes polymeric carriers
that use covalent chemistry for direct drug conjugation (e.g., linear polymers). The second group includes hydrophobic
interactions between drugs and nanocarriers (e.g., polymeric micelles from amphiphilic block copolymers). Polymeric
nanocarriers in the third group include hydrogels, which offer a waterfilled depot for hydrophilic drug encapsulation.
Polymer–Drug Conjugates (Prodrugs) Many polymer–drug conjugates have been developed since the first combination
reported in the 1970s.[44,45] Conjugation of macromolecular polymers to drugs can significantly enhance the blood circulation
time of the drugs. Especially, protein or peptide drugs, which can be readily digested inside the human body, can maintain their
activity by conjugation of the watersoluble polymer PEG (PEGylation). For example, it was reported that PEGylated L
asparaginase increased its plasma halflife by up to 357 h.[46] Without PEG, the halflife of natural Lasparaginase is only 20 h. In
addition to PEGylation of proteins, small molecular anticancer drugs can also be PEGylated to improve their pharmacokinetics for
cancer therapy. For instance, PEGcamptothecin (PROTHECAN®) has entered clinical trials for cancer therapy.[47]
Increasing the otherwise poor solubility of some drugs is another important function of polymer–drug conjugation. Specifically,
conjugating watersoluble polymers to functional groups that already exist in the drug structure can significantly enhance the
water solubility of the drug. Recently, a new category of polymer–drug conjugates called brush polymer–drug conjugates were
prepared by ringopening metathesis copolymerization.[48] In this report, as PEG was employed as the brush polymer side
chains, the conjugates exhibited significant water solubility. However, polymer–drug conjugates require chemical modification of
the existing drugs; as a consequence, their production could cost more, and additional purification steps are needed. Moreover,
polymers that are chemically conjugated with drugs are often considered new chemical entities owing to a pharmacokinetic profile
distinct from that of the parent drugs. As such, additional US FDA approval is required, even though the parent drug has already
been approved. Despite the variety of novel drug targets and sophisticated chemistries available, only four drugs (doxorubicin,
camptothecin, PTX and platinate) and four polymers (N[2hydroxylpropyl]methacrylamide [HPMA] copolymer, polyLglutamic
acid [PGA], PEG and dextran) have been used to develop polymer–drug conjugates.[49–54] In addition to the commercially
available polymer drugs listed in , PGAPTX (Xyotax™, CT2103; Cell Therapeutics Inc./Chugai Pharmaceutical Co. Ltd.),[55]
PGAcamptothecin (CT2106; Cell Therapeutics Inc.)[56] and HPMA–doxorubicin (PK1/FCE28068; Pfizer Inc./Cancer Research
Campaign)[57] are now in clinical trials. As an example, PK1 has been evaluated in clinical trials as an anticancer agent, and a
Phase I evaluation has been completed in patients with several types of tumors resistant to prior therapy, such as chemotherapy
or radiation. However, although the clinical results for HPMA–doxorubicin conjugates look promising, PEGbased conjugation
remains the goldstandard in the field of polymeric drug delivery. In addition, polymer–drug conjugates are still limited by their
nonbiodegradability and the fate of polymers after in vivo administration.[58]

193
193
Megace® Megestrol Antianorexia
Doxil® Doxorubicin
cancer

cancer
Adenosine 199
deaminase
PEGylated IFN 201
α2a
Genexol 202
PM®
nanoparticles
Polymeric Micelles Polymeric micelles are formed when amphiphilic surfactants or polymeric molecules spontaneously
associate in aqueous medium to form core–shell structures. The inner core of a micelle, which is hydrophobic, is surrounded by a
shell of hydrophilic polymers, such as PEG.[59] Their hydrophobic core serves as a reservoir for poorly watersoluble and
amphiphilic drugs; at the same time, their hydrophilic shell stabilizes the core, prolongs circulation time in blood and increases
accumulation in tumor tissues.[41] So far, a large variety of drug molecules have been incorporated into polymeric micelles, either
by physical encapsulation[60,61] or covalent attachment.[62] GenexolPM® (Samyang, Korea), PEGpoly(D,Llactide)PTX,
employs cremophorfree polymeric micelles loaded with PTX drugs. It was found to have a threetimes higher maximum tolerated
dose in nude mice and two to threefold higher levels of biodistribution, compared with those of pristine PTX, in various tissues,
including tumors. A Phase I clinical trial has been evaluated in patients, and the results showed that GenexolPM is superior to
conventional PTX for the delivery of higher doses without additional toxicity.[63] Recently, a series of novel dual targeting micellar
delivery systems were developed based on the selfassembled hyaluronic acidoctadecyl (HAC18) copolymer and folic acid
conjugated HAC18 (FAHAC18). PTX was successfully encapsulated by HAC18 and FAHAC18 polymeric micelles, with a
high encapsulation efficiency of 97.3%. Since these copolymers are biodegradable, biocompatible and cellspecifically targetable,
they become promising nanostructure carriers for hydrophobic anticancer drugs.[64] In addition, stimuliresponsive drugloaded
micelles[65–69] and multifunctional polymeric micelles containing imaging as well as therapeutic agents[70–72] are now under
active investigation with the potential to be the mainstream of the polymeric drug development in the near future. Furthermore,
using computer simulation, the experimental preparation of drugloaded polymeric micelles could be more efficiently guided, by
providing insight into the mechanism of mesoscopic structures and serving as a complement to experiments.[73]
Hydrogel NPs In recent years, hydrogel NPs have gained considerable attention as one of the most promising nanoparticulate
drug delivery systems owing to their unique properties. Hydrogels are crosslinked networks of hydrophilic polymers that can
absorb and retain more than 20% of their weight in water, while at the same time, maintaining the distinct 3D structure of the
polymer network. Swelling properties, network structure, permeability or mechanical stability of hydrogels can be controlled by
external stimuli or physiological parameters.[74–78] Hydrogels have been extensively studied for controlled release of
therapeutics, stimuliresponsive release and applications in biological implants.[75,79–81] However, the hydration response to
changes in stimuli in most hydrogel systems is too slow for therapeutic applications. To overcome this limitation, further
development of hydrogel structures at the micro and nanoscale is needed.[82] Recent reports showed some progress in micro
and nanogels of polyNisopropylacrylamide with ultrafast responses and attractive rheological properties.[83,84] Ding et al.
demonstrated that cisplatinloaded polyacrylic acid hydrogel NPs could be implanted and plastered on tumor tissue.[85] This
hydrogel system exhibited superior efficacy in impeding tumor growth and prolonging lifespan in mice. The in vivo biodistribution
assay also demonstrated that the hydrogel implant results in high concentration and retention of the drug. A multifunctional hybrid
hydrogel was developed by combining the magnetic properties of NPs and the typical characteristics of the hydrogel. These
hybrid hydrogels could be used to load a large number of drugs and transport them to the target site by the application of an
external magnetic field.[86] To improve the specificity of the hydrogel drug delivery systems, core–shell nanogels were developed,
which utilize aptamers as the recognition element and nearinfrared light as a triggering stimulus for drug delivery. In this system,
gold (Au)–silver nanorods, which possess intense absorption bands in the nearinfrared range, were coated with DNA cross
linked polymeric shells, so that drugs can be rapidly and controllably released upon the nearinfrared irradiation.[87] As the fate of
hydrogel NPs after in vivo administration may be a concern for clinical applications, biodegradable hydrogel NPs with diameters
of approximately 200 nm have been synthesized via inverse miniemulsion reversible addition–fragmentation chaintransfer
polymerization of 2(dimethylamino)ethyl methacrylate. A disulfide crosslinker was used to crosslink the NPs, so that the
polymer network could be degraded to its constituent primary chains by exposure to a reductive environment. It is indicated that
these biodegradable hydrogel NPs are currently being investigated for encapsulation and controlled release of siRNA.[88]
Although hydrogel NPsbased drugs are not commercially available, they have high possibility to be further developed for drug
delivery systems in the future, owing to their highly biocompatible and effective drugloading properties.
Proteinbased NPs Hydrophobic drugs, such as taxanes, are highly active and widely used in a variety of solid tumor therapies.
Both PTX and docetaxel, which are the commercially available taxanes for clinical treatments, are hydrophobic. Because of their
solubility problems, they have been formulated as suspensions with nonionic surfactants, such as Cremophor EL® (BASF Corp.)
for PTX and Tween80 (ICI Americas, Inc.) for docetaxel. However, these surfactants are associated with hypersensitivity reaction
and toxic side effects to tissues. To decrease toxicity, albumin conjugated with PTX has been formulated, yielding NPs
approximately 130 nm in size and approved by the FDA for breast cancer treatment.[89–91] In addition to reduced toxicity,
albumin–PTX has been found to bind with the albumin receptor (gp60) on endothelial cells, with further extravascular transport,
[92–94] resulting in an increase in drug concentration at tumor sites without hypersensitivity reactions. The albumin–PTX complex
is approved in 38 countries for the treatment of metastatic breast cancer. Furthermore, Abraxane® is currently in various stages
of investigation for the treatment of other cancers, such as metastatic breast cancer, nonsmallcell lung cancer, malignant
melanoma, pancreatic and gastric cancer.
Dendrimers Dendrimers are synthetic, branched macromolecules that form a treelike structure. Unlike most linear polymers, the
chemical composition and molecular weight of dendrimers can be precisely controlled; hence, it is relatively easy to predict their
biocompatibility and pharmacokinetics.[95] Dendrimers are very uniform with extremely low polydispersities, and they are
commonly created with dimensions incrementally grown in approximate nanometer steps from 1 to over 10 nm. Their globular
structures and the presence of internal cavities enable drugs to be encapsulated within the macromolecule interior and are used
to provide controlled release from the inner core.[96] Although the small size (up to 10 nm) of dendrimers limits extensive drug
incorporation, their dendritic nature and branching allows drug loading onto the outside surface of the structure[97] via covalent
binding or electrostatic interactions. Dendrimers can be synthesized by either divergent or convergent approaches. In the
divergent approach, dendrimers are synthesized from the core and further built to other layers called generations. However, this
method provides a low yield because the reactions that occur must be conducted on a single molecule processing a large
number of equivalent reaction sites.[98] In addition, a large amount of reagents is required for the latter stages of synthesis,
resulting in complication of purification. For the convergent method, synthesis begins at the periphery of the dendrimer molecules
and stops at the core. In this approach, each synthesized generation can be subsequently purified.[98]
Drug molecules associated with dendrimers can be utilized for cancer treatment,[99] the enhancement of drug solubility and
permeability (dendrimer–drug conjugates)[100] and intracellular delivery.[101] Some drugs can be physically encapsulated inside
the dendrimer network or form linkages (either covalently or noncovalently) on the dendrimer surface.[102] Furthermore,
functionalization of the dendrimer surface with specific ligands can enhance potential targeting. For example, Myc et al. reported
a polyamidoamine dendrimer conjugate containing FA as the targeting agent and methotroxate as the therapeutic agent.[103]
Cytotoxicity and specificity were tested with both FA receptorexpressing and nonexpressing cells. Both in vitro and in vivo results
showed that the dendrimer conjugate was preferentially cytotoxic to the target cells. The polyamido amine dendrimer conjugated
with an antiprostate specific membrane antigen antibody was also demonstrated.[104] The antibody–dendrimer conjugate
specifically bound to antiprostate specific membrane antigenpositive, but not negative, cell lines. However, dendrimer toxicity
and immunogenicity are the main concerns when they are applied for drug delivery. Since the clinical experience with dendrimers
has so far been limited, it is hard to tell whether the dendrimers are intrinsically 'safe' or 'toxic'.
Inorganic Platforms
Au NPs Noble metal NPs, such as Au NPs, have emerged as a promising scaffold for drug and gene delivery in that they provide
a useful complement to more traditional delivery vehicles. The combination of inertness and low toxicity,[105] easy synthesis, very
large surface area, wellestablished surface functionalization (generally through thiol linkages) and tunable stability provide Au
NPs with unique attributes to enable new delivery strategies. Moreover, excess loading of pharmaceuticals on NPs allows 'drug
reservoirs' to accumulate for controlled and sustained release, thereby maintaining the drug level within the therapeutic window.
An Au NP with 2nm core diameter could, in principle, be conjugated with 100 molecules to available ligands (n = 108) in the
monolayer.[106] Zubarev et al. have recently succeeded in coupling 70 PTX molecules, a chemotherapeutic drug, to an Au NP
with a 2nm core diameter.[107] Efficient release of these therapeutic agents could be triggered by internal (e.g., glutathione[108]
or pH[109]) or external (e.g., light[110,111]) stimuli. In addition to serving as the carrier for drug delivery, Au NPs can also be
imaged using contrast imaging techniques. Once the Au NPs are targeted to the diseased site, such as a tumor, hyperthermia
treatment can be used for tumor destruction. For example, a recent study demonstrated that PEGylated Au NPs were employed
for highly efficient drug delivery and in vivo photodynamic therapy of cancer.[112] Compared with conventional photodynamic
therapy drug delivery in vivo, PEGylated Au NPs accelerated the silicon phthalocyanine 4 administration by approximately two
orders of magnitude without side effects in treated mice. The key issue that needs to be addressed with Au NPs is the
engineering of the particle surface for optimized properties, such as bioavailability and nonimmunogenicity.
Superparamagnetic NPs Magnetic NPs have been proposed as drug carriers with a push towards clinical trials.[113] The
superparamagnetic properties of iron (II) oxide particles can be used to guide microcapsules in place for delivery by external
magnetic fields. Another advantage of using magnetic NPs is the ability to heat the particles after internalization, which is known
as the hyperthermia effect. For example, Brazel et al. developed a grafted thermosensitive polymeric system by embedding FePt
NPs in poly(Nisopropylacrylamide)based hydrogels, which can be triggered to release the loaded drug by inducing an increase
in temperature based on a magnetic thermal heating event.[114] The grafted hydrogel system is also shown to exhibit a desirable
positive thermal response with an increased drug diffusion coefficient for temperatures higher than physiological temperature.[115]
Besides being utilized for targeting and raising temperature, magnetic NPs can also affect the permeability of microcapsules by
applying external oscillating magnetic fields and releasing encapsulated materials.[116] For example, ferromagnetic Aucoated
cobalt NPs (3 nm in diameter) were incorporated into the polymer walls of microcapsules. Subsequently, application of external
alternating magnetic fields of 100–300 Hz and 1200 Oe strength disturbed the capsule wall structures and dramatically increased
their permeability to macromolecules. This work supports the hypothesis that magnetic NPs embedded in polyelectrolyte
capsules can be used for the controlled release of substances by applying an external magnetic field.
The main benefits of superparamagnetic NPs over classical cancer therapies are minimal invasiveness, accessibility of hidden
tumors and minimal side effects. Conventional heating of a tissue by, for example, microwaves or laser light results in the
destruction of healthy tissue surrounding the tumor. However, targeted paramagnetic particles provide a powerful strategy for
localized heating of cancerous cells.
Ceramic NPs Ceramic NPs are particles fabricated from inorganic compounds with porous characteristics, such as silica,
alumina and titania.[117–119] Among these, silica NPs have attracted much research attention as a result of their biocompatibility
and ease of synthesis, as well as surface modification.[120–122,301] Furthermore, the wellestablished silane chemistry facilitates
the crosslinking of drugs to silica particles.[123,124] For example, recent breakthroughs in mesoporous silica NPs (MSNs) have
brought new possibilities to this burgeoning area of research. MSNs contain hundreds of empty channels (mesopores) arranged
in a 2D network of a honeycomblike porous structure. In contrast to the low biocompatibility of other amorphous silica materials,
recent studies have shown that MSNs exhibit superior biocompatibility at concentrations adequate for pharmacological
applications.[125,126] Once the vehicle is localized in the cytoplasm, it is desirable to have effective control over the release of
drug molecules in order to reach pharmacologically effective levels. The ability to selectively functionalize the external particle
and/or the interior nanochannel surface of MSNs is advantageous in achieving this goal.[127,128] Different functional groups can
be added by using this methodology, including, for example, functionalization with stimuliresponsive tethers that could be further
attached to NPs (Au and iron [II] oxide). These NPs could work as gatekeepers and be removed by either intracellular or external
triggers, such as changes in pH, reducing environment, enzymatic activity, light, electromagnetic field or ultrasound.[128] The
surface of MSNs can be engineered with cellspecific moieties, such as organic molecules, peptides, aptamers and antibodies, to
achieve cell type or tissue specificity. Moreover, optical and magnetic contrast agents can be introduced to develop multipurpose
drug delivery systems.
These strategies demonstrated that the application of targetspecific MSN vehicles in vitro is promising; however, the application
in vivo has not yet been reported. These particles are not biodegradable; consequently, there is a concern that they may
accumulate in the human body and cause harmful effects.[117] For further in vivo applications, the biocompatibility, biodistribution,
retention, degradation and clearance of MSNs must be systematically investigated.
Carbonbased Nanomaterials Carbonbased nanomaterials have attracted particular interest because they can be surface
functionalized for the grafting of nucleic acids, peptides and proteins. Carbon nanotubes (CNTs), fullerene, and
nanodiamonds[129] have been extensively studied for drug delivery applications.[130] The size, geometry and surface
characteristics of singlewall nanotubes (SWNTs), multiwall nanotubes and C60 fullerenes make them appealing for drug carrier
usage. For example, PTXconjugated SWNTs have shown promise for in vivo cancer treatment. SWNT delivery of PTX affords
markedly improved treatment efficacy over clinical Taxol (BristolMyers Squibb Co.), as evidenced by its ability to slow down
tumor growth at a low PTX dose.[131]
However, the primary drawback of carbonbased nanomaterials appears to be their toxicity. Experiments have shown that CNTs
can lead to cell proliferation inhibition and apoptosis. Although they are less toxic than carbon fibers and NPs, the toxicity of CNTs
increases significantly when carbonyl, carboxyl and/or hydroxyl functional groups are present on their surface.[132] Because of
the reported toxicity of CNTs,[133–137] studies involving their application for drug delivery are still being conducted.[138–140] In
order to promote the application of CNTs for drug delivery, researchers have functionalized their surface, rendering them benign.
[136] Unfortunately, concerns that functionalized CNTs may revert back to a toxic state if the functional group detaches has limited
[136] Unfortunately, concerns that functionalized CNTs may revert back to a toxic state if the functional group detaches has limited
the pursuit of using these modified CNTs for biomedical applications.
The toxicity of other forms of nanocarbons has also been reported.[132,140,141] One study of human lung tumor cells showed that
carbon NPs are even more toxic than multiwall nanotubes and carbon nanofibers.[132] Given the mounting evidence
demonstrating the toxicity of carbon NPs, the enthusiasm to develop carbon NPs for drug delivery has decreased significantly in
recent years.
Integrated Nanocomposite Particles
A variety of nanoplatforms have been developed for a wide spectrum of applications, and each of these applications has unique
advantages and limitations. By combining the specific function of each material, new hybrid nanocomposite materials can be
fabricated. For instance, liposomes and polymeric NPs are the two most widely studied drug delivery platforms, and attempts
have been made to combine the advantages of both systems. A recent study reported the use of nanocells consisting of nuclear
poly(lacticcoglycolic acid) NPs within an extranuclear PEGylated phospholipid envelope for temporal targeting of tumor cells
and neovasculature.[142] Moreover, liposomes are routinely coated with a hydrophilic polymer, such as PEG or poly(ethylene
oxide), to improve the circulation time in vivo, which is another example of a liposome–polymer composite.[143] Similarly,
liposomal lockedin dendrimers, the combination of liposomes and dendrimers in one formulation, has resulted in higher drug
loading and slower drug release from the composite, as compared with pure liposomes.[144] Another LipoMag formulation, which
consists of an oleic acidcoated magnetic nanocrystal core and a cationic lipid shell, was magnetically guided to deliver and
silence genes in cells and tumors in mice.[145]
Targeting Strategies
Two basic requirements should be realized in the design of nanocarriers to achieve effective drug delivery (Figure 2). First, drugs
should be able to reach the desired tumor sites after administration with minimal loss to their volume and activity in blood
circulation. Second, drugs should only kill tumor cells without harmful effects to healthy tissue.[146] These requirements may be
enabled using two strategies: passive and active targeting of drugs.[147]
Figure 2.

Passive and active targeting.
By the enhanced permeability and retention effect, nanoparticles (NPs) can be passively extravasated through leaky
vascularization, allowing their accumulation at the tumor region (A). In this case, drugs may be released in the extracellular matrix
and then diffuse through the tissue. Active targeting (B) can enhance the therapeutic efficacy of drugs by the increased
accumulation and cellular uptake of NPs through receptormediated endocytosis. NPs can be engineered to incorporate ligands
that bind to endothelial cell surface receptors. In this case, the enhanced permeability and retention effect does not pertain, and
the presence of leaky vasculature is not required.
Passive Targeting
Passive targeting takes advantage of the unique pathophysiological characteristics of tumor vessels, enabling nanodrugs to
accumulate in tumor tissues. Typically, tumor vessels are highly disorganized and dilated with a high number of pores, resulting in
enlarged gap junctions between endothelial cells and compromised lymphatic drainage. The 'leaky' vascularization, which refers
to the EPR effect, allows migration of macromolecules up to 400 nm in diameter into the surrounding tumor region.[147–149] One
of the earliest nanoscale technologies for passive targeting of drugs was based on the use of liposomes. More advanced
liposomes are coated with a synthetic polymer that protects the agents from immune destruction.[150]
Moreover, the EPR effect, the microenvironment surrounding tumor tissue, is different from that of healthy cells, a physiological
phenomenon that also supports passive targeting. Based on the high metabolic rate of fastgrowing tumor cells, they require
more oxygen and nutrients. Consequently, glycolysis is stimulated to obtain extra energy, resulting in an acidic environment.[151]
Taking advantage of this, pHsensitive liposomes have been designed to be stable at physiological pH 7.4, but degraded to
release drug molecules at the acidic pH.[152]
Although passive targeting approaches form the basis of clinical therapy, they suffer from several limitations. Ubiquitously
targeting cells within a tumor is not always feasible because some drugs cannot diffuse efficiently, and the random nature of the
approach makes it difficult to control the process. The passive strategy is further limited because certain tumors do not exhibit an
EPR effect, and the permeability of vessels may not be the same throughout a single tumor.[153]
Active Targeting
One way to overcome the limitations of passive targeting is to attach affinity ligands (antibodies,[154] peptides,[155] aptamers[156]
or small molecules[157] that only bind to specific receptors on the cell surface) to the surface of the nanocarriers by a variety of
conjugation chemistries. Nanocarriers will recognize and bind to target cells through ligand–receptor interactions by the
expression of receptors or epitopes on the cell surface. In order to achieve high specificity, those receptors should be highly
expressed on tumor cells, but not on normal cells. Furthermore, the receptors should homogeneously express and should not be
shed into the blood circulation. Internalization of targeting conjugates can also occur by receptormediated endocytosis after
binding to target cells, facilitating drug release inside the cells. Based on the receptormediated endocytosis mechanism,
targeting conjugates bind with their receptors first, followed by plasma membrane enclosure around the ligand–receptor complex
to form an endosome. The newly formed endosome is transferred to specific organelles, and drugs could be released by acidic
pH or enzymes. Although the active targeting strategy looks intriguing, nanodrugs currently approved for clinical use are relatively
simple and generally lack active targeting or triggered drug release components. Moreover, nanodrugs currently under clinical
development lack specific targeting. To fully explore the application of targeted drug delivery, we need to investigate whether the
specific diseases are the correct application for targeting, whether the properties of the therapeutic drugs, as well as their site and
mode of action, are suited for targeting and whether the delivery vehicles are optimal for product development.[158]
Key Factors Impacting Drug Delivery
In order to achieve effective drug delivery, nanocarriers must have suitable circulation time to prevent the elimination of drugs
before reaching their target. Based on previous investigations, size, shape and surface characteristics are key factors that impact
the efficiency of drug delivery systems.
Size & Shape
Particle size plays a key role in particle functions, such as degradation, vascular dynamics, targeting, clearance and uptake
mechanisms.[159] Particles have been shown to have different velocities, diffusion characteristics and adhesion properties,
depending on their size,[160] resulting in different uptake efficiencies.[161–164] The size of nanodrugs should be large enough to
prevent rapid leakage in blood capillaries, but, at the same time, small enough to escape the capture of macrophages in the
reticuloendothelial system, such as the liver and spleen. Some of the main outcomes reported in these studies are that the size
limits for internalization of NPs through endocytosis are clearly cell dependent; particles less than 200 nm in size will mainly
follow endocytic pathways; particles above this size can be either engulfed through endocytosis or not internalized at all and
microsized particles have to be internalized by phagocytic pathways.[165] Interestingly, in the case of spherical Au NPs, it was
found that the maximum uptake occurred with Au NPs 50 nm in diameter.[166,167] Coincidently, in a separate study, it was
reported that a diameter of 50 nm is the optimal size to achieve the most efficient endocytosis of MNSs.[168]
Apart from size, recent studies have shown that the shape of particles can also have an intriguing effect on particle functions,
especially in biological processes, including internalization, transport through the blood vessels and targeting diseased sites.[169–
171] Varying toxicities of materials having identical chemical composition (silica), but different shape (nanowire vs NP), was also
reported.[172] Recent advances with particular focus on the importance of particle shape, as well as the challenges yet to be
reported.[172] Recent advances with particular focus on the importance of particle shape, as well as the challenges yet to be
overcome, are reviewed elsewhere.[173]
Surface Characteristics
Besides size and shape, surface characteristics of NPs can also determine their lifespan during circulation in the blood stream.
One of the major breakthroughs in this area was the finding that particles coated with hydrophilic polymer molecules, such as
PEG, can resist serum protein adsorption, prolonging the systemic circulation of the particle.[174] Since then, numerous variations
of PEG and other hydrophilic polymers have been tested for improved circulation.[175]
The surface charge on the particle also affects other functions, such as internalization by macrophages. Positively charged
particles have been shown to exhibit higher internalization by macrophages and dendritic cells compared with neutral or
negatively charged particles,[176] although surface charge effect could also be celltype dependent.[177] The effects of particle
size and surface chemistry on particle function have been reviewed elsewhere.[174,175,178]
Challenges of Nanotechnology for Drug Delivery
Although progress in the application of nanotechnology to drug delivery has been dramatic and successful, as evidenced by
some nanodrugs now on the market, several main challenges remain in this field (Figure 3).
Figure 3.

Remaining challenges in the field of nanomedicine.
Biological Understanding
In order for bionanotechnologies to progress toward human applications, a better understanding of the mechanisms underlying
intracellular uptake, trafficking and the fate of nanomaterials in complex biological networks is needed. Current delivery systems
suffer from some major hindrances (e.g., rapid clearance by the immune system, low targeting efficiency and difficulty in crossing
biological barriers).[179] In view of these obstacles, a full understanding of the basic science of NP transport will result in
achieving the ability to control and manipulate drug delivery.
Safety Concern
Paralleling the development of nanomedicine, a field known as nanotoxicology has also emerged. Nanotoxicology refers to the
study of the potential negative impact of the interactions between nanomaterials and biological systems.[180] Some preliminary
nanotoxicity investigations have led to the speculation that nanomaterials may contribute to the formation of free radicals,[181]
damage of brain cells[182] and undesirable penetration through the epidermis or other physiological barriers into areas of the
body that are more susceptible to toxic effects.[183] Several mechanisms have been proposed to affect the toxicity of
nanomaterials, depending on multiple factors derived from physiochemical properties, physical characteristics and environmental
conditions. For example, naked quantum dots show cytotoxicity by induction of reactive oxygen species, resulting in damage to
the nucleus, mitochondria and plasma membranes.[184] Also, cadmium (Cd)containing quantum dots have been reported to be
toxic by the release of free Cd2+ ions.[185] However, their toxicity was reduced after surface modification, such as attaching N
acetylcystein.[186] Au solution has not been considered to present a hazard, and Au NPs have been taken up by cells without
cytotoxic effects. By contrast, Au nanorod cytotoxicity could be attributed to the presence of the stabilizer cetyltrimethylammonium
bromide.[187] For silica NPs, only concentrations above 0.1 mg/ml were found to be toxic, as shown in a reduction of cell
availability and proliferation.[188] CNTs also cause reactive oxygen species generation, mytochondria dysfunction, lipid
peroxidation and changes in cell morphology,[189] while graphite and fullerene produce no significant adverse effects.[190] In
addition, it was reported that most cationic NPs can cause hemolysis and blood clotting, while neutral and anionic NPs are quite
nontoxic.[191]
NPs can be inhaled, ingested or absorbed through the skin, and they can penetrate cells, even into the cell nucleus, where, if
sufficiently small, they can come into close contact with genetic material. Thus, nanomaterial toxicity should be considered
relative to the patient population, as well as the entire manufacturing and disposal processes. Based on safety concerns, the
establishment of standards or reference materials and consensus testing protocols that can provide benchmarks for the
development of novel classes of materials are needed.
Manufacturing Issue
Another challenge facing nanodrug delivery is the largescale production of nanomaterials in terms of scaling up laboratory or
pilot technologies for consistent and reproducible production and commercialization. A number of nanodrug delivery technologies
may not be compatible with largescale production owing to the nature of the preparation method and high cost of materials
employed. The challenges of scaling up include a low concentration of nanomaterials, agglomeration and the chemistry process.
It is much easier to modify or maintain the size or composition of nanomaterials at the laboratory scale for improved performance
than at a large scale. The biomedical community should rethink the level of control needed when working with nanomaterials.
Rather than requiring perfect control of the physical dimensions of nanomaterials, a statistical approach may be adopted in order
to establish a metric for classifying nanomaterials by material type, average size, aspect ratio and standard deviation. This would
fit well with the formation of a toxicology database, since it is unrealistic to establish the toxicology of every size or aspect ratio of
a nanomaterial.
Economic & Financial Barriers
Economic and financial barriers can also stand in the way of implementing nanomedicine. The limited availability of
reimbursement by public and private health insurers for relatively expensive new diagnostic tests has emerged as a major
impediment to the deployment of personalized medicine in general, and nanoproducts are likely to encounter even greater
hurdles because of their costs and complexity.[192]
Despite the number of patents for nanodrug delivery technologies, commercialization is still in its early stage. Because of the high
development costs of nanodrugs and medical devices, startup companies have little chance of bringing products to the market
without support from 'Big Pharma', which is able to provide the financial resources and expertise needed to achieve regulatory
and commercial success.
Future Perspective
The marriage of nanotechnology and medicine has yielded an offspring that is set to bring momentous advances in the fight
against a range of diseases. Nanomedicine is actually a child well past its infancy, with two families of therapeutic nanocarriers –
liposomes and albumin NPs – already firmly in clinical practice worldwide, and still more in the preclinical phases of development.
In order to transform nanotechnologies from basic research into clinical products, it is important to understand how the
biodistribution of NPs, which is primarily governed by their ability to negotiate biological barriers, affects the body's complex
biological network, as well as mass transport across compartmental boundaries in the body. Moreover, the healthy growth of this
field depends on establishing a toxicology database to support safety determinations and risk assessments. The database should
include toxicity as a function of material, size, shape, cell type or animal, duration of exposure and the methods used to assay
toxicity. In addition, the ability to scale up the production of drug particles is required. The manufacturing complexity of nanodrug
delivery may be an obstacle confronting generic drug companies. Lastly, storage and handling protocols must be considered.
With such a database, the translation of biomedical nanotechnology from the laboratory to the general public will be significantly
accelerated.
Realizing such a goal requires harmonized efforts among scientists in various disciplines, including medicine, materials science,
engineering, physics and biotechnology. Better cross training would produce better proposals with a greater likelihood of success.
Experts from different disciplines need to work together to translate novel laboratory innovation into commercially viable medical
products. In addition, continuous cooperation between federal agencies and the pharmaceutical industry is necessary.
The ultimate goal of nanodrug delivery systems is to develop clinically useful formulations for treating diseases. As nanomedical
applications for personalized medicine become more advanced and multifunctional, they may increasingly challenge, and
perhaps eventually invalidate, traditional regulatory categories and criteria. Therefore, it will be critical for regulatory systems to
provide oversight and welldefined evaluation pathways for nanomedicine products, while remaining adaptive to rapidly emerging
nanomedical technologies and products.
Summary
Nanotechnology is an emerging field with the potential to revolutionize drug delivery. Advances in this area have allowed some
nanomedicines in the market to achieve desirable pharmacokinetic properties, reduce toxicity and improve patient compliance, as
well as clinical outcomes. Integration of nanoparticulate drug delivery technologies in preformulation work not only accelerates
the development of new therapeutic moieties, but also helps in the reduction of attrition of new molecular entities caused by
undesirable biopharmaceutical and pharmacokinetic properties.
Optimizing the integration of nanomaterials into drug delivery systems will require standardized metrics for their classification, as
well as protocols for their handling. This will, in turn, result in a better understanding of the interactions of nanomaterials with
biological systems, which will facilitate better engineering of their properties specific to biomedical applications. The development
of such drug carriers will require a greater understanding of both the surface chemistry of nanomaterials and the interaction
chemistry of these nanomaterials with biological systems. This can only be achieved through collaborative efforts among
scientists in different disciplines. Those who work in this emerging field should have uptodate information on related toxicology
issues, potential health and safety risks and the regulatory environment that will impact patient use. Understanding both the
benefits and the risks of these new nanotechnology applications will be essential to good decisionmaking for drug developers,
regulators and ultimately the consumers and patients who will be the beneficiaries of new drug delivery technologies.
Sidebar
Executive Summary
The emergence of nanotechnology is revolutionizing drug delivery with considerable commercialization efforts around the
world.
A multitude of nanoforms have been attempted as drug delivery systems with the ultimate goal of synthesizing a
multifunctional vehicle optimized to perform desired tasks in a defined order.
Several challenges remain in the field of nanodrug delivery.
Addressing the challenges of nanomedicine with harmonized efforts among scientists in different disciplines will accelerate
the commercialization of this field.
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Type of nanostructure Brand name Active ingredient Indications Ref.

Rapamune® Rapamycin Immunosuppressive 193

Emend® Aprepitant Anti­emetic 193

Megace® Megestrol Anti­anorexia 193

AmBisome® Amphotericn B Fungal infections 194

Liposomes Ovarian cancer, Kaposi's sarcoma and breast 196

Depocyt® Cytarabine Lymphomatous meningitis 197

Daunoxome® Daunorubicin Kaposi's sarcoma 198

Polymer–drug conjugates Onscaspar® L­asparaginase Acute lymphoblastic leukemia 200

Lipid colloidal dispersion Amphotec® Amphotericin B Fungal infections 204

Type of nanostructure Brand name Active ingredient Indications Ref.

Rapamune® Rapamycin Immunosuppressive 193

Emend® Aprepitant Anti­emetic 193

Megace® Megestrol Anti­anorexia 193

AmBisome® Amphotericn B Fungal infections 194

Liposomes Ovarian cancer, Kaposi's sarcoma and breast 196

Depocyt® Cytarabine Lymphomatous meningitis 197

Daunoxome® Daunorubicin Kaposi's sarcoma 198

Polymer–drug conjugates Onscaspar® L­asparaginase Acute lymphoblastic leukemia 200

Lipid colloidal dispersion Amphotec® Amphotericin B Fungal infections 204

Type of nanostructure Brand name Active ingredient Indications Ref.

Rapamune® Rapamycin Immunosuppressive 193

Emend® Aprepitant Anti­emetic 193

Megace® Megestrol Anti­anorexia 193

AmBisome® Amphotericn B Fungal infections 194

Liposomes Ovarian cancer, Kaposi's sarcoma and breast 196

Depocyt® Cytarabine Lymphomatous meningitis 197

Daunoxome® Daunorubicin Kaposi's sarcoma 198

Polymer–drug conjugates Onscaspar® L­asparaginase Acute lymphoblastic leukemia 200

Lipid colloidal dispersion Amphotec® Amphotericin B Fungal infections 204

Type of nanostructure Brand name Active ingredient Indications Ref.

Rapamune® Rapamycin Immunosuppressive 193

Emend® Aprepitant Anti­emetic 193

AmBisome® Amphotericn B Fungal infections 194

Liposomes Ovarian cancer, Kaposi's sarcoma and breast 196

Depocyt® Cytarabine Lymphomatous meningitis 197

Daunoxome® Daunorubicin Kaposi's sarcoma 198

Polymer–drug conjugates Onscaspar® L­asparaginase Acute lymphoblastic leukemia 200

Lipid colloidal dispersion Amphotec® Amphotericin B Fungal infections 204

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Emend® Aprepitant Antiemetic 193

Megace® Megestrol Antianorexia 193

Polymer–drug conjugates Onscaspar® Lasparaginase Acute lymphoblastic leukemia 200

Emend® Aprepitant Antiemetic 193

Megace® Megestrol Antianorexia 193

Polymer–drug conjugates Onscaspar® Lasparaginase Acute lymphoblastic leukemia 200

Emend® Aprepitant Antiemetic 193

Polymer–drug conjugates Onscaspar® Lasparaginase Acute lymphoblastic leukemia 200