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Review Article: Pharmacology

Emerging nanopharmaceuticalsWillie E. Bawarski, Pharm D, Elena Chidlowsky, Pharm D,

Dhruba J. Bharali, PhD, Shaker A. Mousa, PhD, MBA

The Pharmaceutical Research Institute at Albany College of Pharmacy, Rensselaer, New York, USA

Abstract A budding interest in nanopharmaceuticals has generated a number of advancements throughout

recent years with a focus on engineering novel applications. Nanotechnology also offers the ability to

detect diseases at much earlier stages, such as finding hidden or overt metastatic colonies often seen

in patients diagnosed with breast, lung, colon, prostate, and ovarian cancer. Diagnostic applications

could build upon conventional procedures using nanoparticles, such as colloidal gold, iron oxidecrystals, and quantum dots. Additionally, diseases may be managed by multifunctional agents

encompassing both imaging and therapeutic capabilities, thus allowing simultaneous monitoring and

treatment. A detailed evaluation of each formulation is essential to expand our current

nanopharmaceutical repertoire. However, the safety and long-term effects of nanoformulations

must not be overlooked. This review will provide a brief discussion of the major nanopharmaceutical

formulations as well as the impact of nanotechnology into the future.

2008 Elsevier Inc. All rights reserved.

Key words: Nanoparticles; Micelles; Dendrimers; Liposomes; Quantum dots

Novel approaches to drug delivery and formulation using

nanotechnology are revolutionizing the future of medicine.

A practical definition of nanotechnology, that is uncon-

strained by an arbitrary size limitation is proposed by Bawa 1

as the design, characterization, production, and application

of structures, devices, and systems by controlled manipula-

tion of size and shape at the nanometer scale (atomic,

molecular, and macromolecular scale) that produces struc-

tures, devices, and systems with at least one novel/superior

characteristic or property. Nanomedicine, the medical

application of nanotechnology, promises an endless range

of applications from biomedical imaging to drug delivery

and therapeutics. Nanomedicine results from the manipula-

tion of atoms and molecules that can range in size from 1 to

100 nm. In perspective, a nanometer is one-billionth of a

meter, which is analogous to comparing the size of a marble

to the size of the Earth. At this size, quantum physics begins

to take over and particles begin to show entirely different

physicochemical properties.

Over recent years, advancements in drug delivery have

facilitated the targeting of specific tissues. With the advent of

nanotechnology, these targeted tissues are now becoming

specific organelles within individualized cells. Nanomedi-

cine has blossomed into a billion-dollar industry because of

these compounds inherent ability to overcome solubility

and stability issues, localize drug delivery, as well as to

diagnose via in vivo imaging. Coupled with genomic

tailoring, nanomedicine may soon spawn the much-antici-

pated individualized medicine. Upcoming innovations in

nanomedicine may even generate multifunctional entities

capable of simultaneously diagnosing, delivering therapeutic

agents, and monitoring treatment.

Several particle types and structures have been discov-

ered. Noteworthy structures include polymeric micelles,

dendrimers, quantum dots (QDs), and solid nanoparticles.

Another Food and Drug Administration (FDA)approved

nanomedicine, Abraxane (Abraxis, Los Angeles, California),

an albumin-bound nanoparticle formulation of paclitaxel, is

a prime example of the budding success offered by

conjugated polymers. Abraxane is used for metastatic breast

Available online at www.sciencedirect.com

Nanomedicine: Nanotechnology, Biology, and Medicine 4 (2008) 273282www.nanomedjournal.com

Received 2 January 2008; accepted 3 June 2008.

No conflict of interest was reported by the authors of this article.Corresponding author.

E-mail address: [email protected] (S.A. Mousa).

1549-9634/$ see front matter 2008 Elsevier Inc. All rights reserved.doi:10.1016/j.nano.2008.06.002

Please cite this article as: W.E. Bawarski, E. Chidlowsky, D.J. Bharali, S.A. Mousa, Emerging nanopharmaceuticals, Nanomedicine: NBM2008;4:273-82,

doi:10.1016/j.nano.2008.06.002
mailto:[email protected]://dx.doi.org/10.1016/j.nano.2008.06.002http://dx.doi.org/10.1016/j.nano.2008.06.002http://dx.doi.org/10.1016/j.nano.2008.06.002http://dx.doi.org/10.1016/j.nano.2008.06.002mailto:[email protected]


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cancer. Abraxane for injectable suspension evades the

hypersensitivity reaction associated with Cremophor EL

(BASF, Florham Park, New Jersey), the solvent in traditional

paclitaxel. This nanoparticle has a size of around 100 nm and

offers the ability to solubilize insoluble or poorly soluble

drugs, avoiding the need for the toxic organic solvent.

Abraxane is generally injected into a vein (intravenousinfusion) over 30 minutes. The notable side effects of

Abraxane include hair loss, infection due to low white blood

cell count, fatigue and weakness, low red blood cell count,

mouth or lip sores, joint and muscle pain, stomach upset and

diarrhea, and cardiovascular effects.

Although these structures may promise endless opportu-

nities, their safety should not be ignored. The reactivity of

these tiny particles may be due to their large surface area in

comparison to their overall mass. Semiconductor metals, such

as colloidal gold and iron oxide crystals, are commonly used

and have demonstrated toxicity. Additionally, increased

pulmonary toxicity was noted with carbon nanotubes whencompared to that of the carbon black and carbonyl iron

particles seen in mice and rats. 2,3 These tiny particles easily

permeate the skin and blood-brain barrier, leading to several

potential toxicities. Research should be carried out to fully

investigate any toxicity issuesassociated with these structures.

Nanopharmaceutical templates

Nanotechnology provides endless opportunities across a

wide array of industries. Some of these include titanium

dioxide (TiO2) nanoparticles found in sunscreen and

cosmetics, silver (Ag) nanoparticles in clothing and disin-fectants, and cerium oxide (CeO2) nanoparticles as a fuel

catalyst. The National Nanotechnology Initiative (NNI)

defines nanotechnology as the understanding and control

of matter at dimensions of roughly 1 to 100 nanometers,

where unique phenomena enable novel applications, 4

allowing fabrication of devices on the nanoscale. Nanome-

dicine is the medical application of a broad range of materials

and devices on the nanoscale so as to assess, preserve, and

restore health and well-being. It takes advantage of

nanoscale formulations to optimize drug delivery and to

facilitate noninvasive imaging. In addition to mainstream

nanomaterials like fullerenes and nanoparticles, nanomedi-cine uses biomolecules and nanoelectronic biosensors to

create therapeutic and diagnostic formulations. Despite

sharing one common name, nanomedicine signifies count-

less approaches to diagnosis and treatment; many different

nanoscale drug delivery systems can be created from

countless combinations of nanomaterials and molecules,

and these carriers can be customized for working in specific

tissues or individual patients via attachment of surface ligand

molecules. We will review some of the commonly used

nanopharmaceutical formulations. However, new advance-

ments are constantly being made that allow multifunctional

nanoformulations to deliver drugs while simultaneouslycollecting diagnostic information.

Although mainstream nanotechnology explores particles

between 1 and 100 nm in diameter, the size of the individual

particles tested for drug delivery of therapeutic and imaging

agents may range from 2 to 1000 nm. 4 However, it has been

confirmed that particles larger than 200 nm can activate the

human complement system and be cleared from the blood

by Kupffer cells. Additionally, splenic filtration captures particles that exceed slit size (200250 nm), and liver

filtration (via fenestrae in the sinus endothelium) captures

particles greater than 150 nm. Furthermore, tumor capil-

laries rarely exceed 300 nm in diameter. 5 For the

aforementioned reasons, current research on nanopharma-

ceutical formulations focuses on particles less than 200 nm.

The outer surfaces of most recently developed nanoformu-

lations are modified through incorporation of various

ligands into a membrane (i.e., specific antigens, antibodies,

and receptor ligands) to facilitate targeted delivery to

specific tissues. 6

Although some applications of nanotechnology in pharmacology may be questioned, there is an area where

the application of nanotechnology application is promising.

Specifically, nanoformulations may eliminate the need for

conditional administration of drugs, thereby promoting

patient compliance and increasing therapeutic effects.

Liposomes: progressing to nanopharmaceuticals

Liposomes are spherical vesicles composed of amphi-

philic phospholipids and cholesterol, which self-associate

into bilayers to encapsulate an aqueous interior. 7,8 The

amphiphilic phospholipid molecules form a closed bilayersphere in an attempt to shield their hydrophobic groups from

the aqueous environment, while still maintaining contact

with the aqueous phase via the hydrophilic head group.

Drugs with widely varying lipophilicities can be encapsu-

lated in liposomes, in the phospholipid bilayer, in the

entrapped aqueous volume, or at the bilayer interface.

Although liposomes vary greatly in size, most are 400 nm or

less. Depending upon their size and number of bilayers,

liposomes can be classified into three categories: multi-

lamellar vesicles, large unilamellar vesicles, and small

unilamellar vesicles. Liposomes can be classified in terms

of composition and mechanism of intracellular delivery intofive types: conventional liposomes, pH-sensitive liposomes,

cationic liposomes, immunoliposomes, and long-circulating

liposomes. Although liposome technology was discovered

over 40 years ago, liposome-based drug formulations have

not entered the market in great number. Some of the major

problems limiting the manufacture and development of

liposomes are their stability, poor batch-to-batch reproduci-

bility, difficulties in sterilization, and low drug loading. One

exceptional success story is the discovery of Doxil (ALZA,

Mountain View, California; later, Sequus Pharmaceuticals,

Menlo Park, California), a long-acting PEGylated liposomal

formulation of doxorubicin. Doxil, known for its significantimprovements over doxorubicin, has bridged the gap

274 W.E. Bawarski et al / Nanomedicine: Nanotechnology, Biology, and Medicine 4 (2008) 273282


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between pharmaceuticals and nanopharmaceuticals. Some of

the liposome-based formulations are listed in Table 1.

Polymeric micelles: enhancing solubility

Micelles are nanosized, spherical colloidal particles with

a hydrophobic interior (core) and a hydrophilic exterior

(shell). Their main utility is in the preparation of

pharmaceutical formulations, notably agents that are

regularly soluble in water. 9 Drugs or contrast agents may

be entrapped within the hydrophobic core or linked

covalently to the surface of micelles. Their individual

particle size is less than 50 nm in diameter, which provides

obvious benefits over liposomes. Polymeric micelles may

circulate for prolonged periods in the blood, evading host

defenses. With their property of continued stability in the

blood, polymeric micelles can be used to gradually releasedrugs and facilitate in vivo imaging. To support prolonged

systemic circulation, shells of polymeric micelles are

designed to be thermodynamically stable and biocom-

patible. 10,11 Many existing solvents for poorly water-

soluble pharmaceuticals, like Cremophor EL (BASF) or

ethanol, can be toxic, which limits therapeutic doses and

restricts treatment options. Polymeric micelles provide a

safer alternative for parenteral administration of poorly

water-soluble drugs like am photericin B, propofol, pacli-

taxel, and photosensitizers. 12 For the formation of micelles,

amphiphilic molecules must have both hydrophobic and

hydrophilic segments, where the hydrophilic fragments formthe micelle shell and the hydrophobic fragment forms the

core. Thus, in aqueous media, the core of the micelles can

solubilize water-insoluble drugs; the surface can adsorb

polar molecules, whereas drugs with intermediate polarity

can be distributed along with the surfactant molecules in

intermediate positions. The mechanism of solubilization andutilization of micelles has been extensively studied by

various researchers. A schematic diagram of the formation

of micelles from an amphiphilic molecule and the loading of

hydrophobic drugs are shown in Figure 1.

Similar to liposomes, polymeric micelles can be modified

using piloting ligand molecules for targeted delivery to

specific cells (i.e., cancer cells). pH-sensitive drug-binding

linkers can be added for controlled drug release. 13,14 For that

same purpose, micelles can also be formed from stimuli-

responsive amphiphilic block co-polymers. Multifunctional

polymeric micelles can be designed to facilitate simulta-

neous drug delivery and imaging.

8

A micelle formulation of an approved therapeutic agent

was evaluated in a multicenter, randomized, double-blind,

placebo-controlled trial of topical nanoparticle estradiol

emulsion (MNPEE; Estrasorb; Novavax, Inc., Malvern,

Pennsylvania). The formulation was used in postmenopau-

sal women with moderate to severe vasomotor symptoms

(hot flashes). The subjects were given 8.6 mg of estradiol

daily, and the treatment lasted 12 weeks. The treatment was

both efficacious and well tolerated. MNPEE provided rapid

symptom relief and significantly reduced hot flush

frequency and severity as compared with placebo from

week 4 to the end of the trial (Pb

0.001 for bothparameters). 15 A list of different polymers/copolymers used

Table 1

Some selected nanomedicine products currently on the market

Product Company Drug Formulation Route of administration Application

Doxil Sequus Pharmaceutical Doxorubicin Liposome Intravenous injection Kaposi sarcoma in AIDS

Amphocil Sequus Pharmaceutical Amphotericin B Lipocomplex IV infusion Serious fungal infections

Ambisome NeXstar Pharmaceutical Amphotericin B Liposome IV infusion Serious fungal infections

DaunoXome NeXstar Pharmaceutical

(Boulder, Colorado)

Daunorubicin citrate Liposome IV Kaposi sarcoma in AIDS

Abelcet The Liposome Company

(Princeton, New Jersey)

Amphotericin B Lipid complex IV infusion Serious fungal infections

Rapamune Wyeth/Elan

(Madison, New Jersey)

Sirolimus Nanocrystal particles Oral Immunosuppressant in kidney

transplant patients

Emend Merck/Elan (Whitehouse

Station, New Jersey)

Aprepitant, MK869 Nanocrystal particles Oral For chemotherapy patient to

delayed nausea and vomiting

TriCor Abbott

(Abbott Park, Illinois)

Fenofibrate Nanocrystal particles oOral Primary hypercholesterolemiamixed

lipidemia, hypertriglyceridemia

Megace ES PAR Pharmaceutical

(WoodCliff Lake,

New Jersey)

Megaestrol acetate Nanocrystal particles Oral Treatment of anorexia, cachexia,

or an unexplained significant weight loss

in patients with a diagnosis of AIDS

Abraxane American Biosciences

(Blauvelt, New York)

Paclitaxel Albumin-bound

nanoparticles

IV injection Metastatic breast cancer

Elestrin BioSante

(Lincolnshire, Illinois)

Estradiol Calcium

phosphatebased

nanoparticles

Transdermal Treatment of moderate-to-severe

vasomotor symptoms (hot flashes)

in menopausal women

275W.E. Bawarski et al / Nanomedicine: Nanotechnology, Biology, and Medicine 4 (2008) 273282


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to prepare micelles loaded with various pharmaceuticals is

shown in Table 2.

Dendrimers: utilizing multivalent moieties

Dendrimers are a unique class of polymeric macromole-

cules synthesized via divergent or convergent synthesis by a

series of controlled polymerization reactions. Characteristi-

cally, the structure of these polymers is repeated branching

around the central core that results in a nearly-perfect three-

dimensional geometrical pattern. At higher generations

(greater than five) dendrimers resemble spheres with

countless cavities within their branches to hold therapeutic

and diagnostic agents. In theory, it is possible to synthesize

amphiphilic dendrimers with a hydrophobic core inside

hydrophilic branching. Dendrimers used in drug delivery and

imaging are usually 10 to 100 nm in diameter with multiplefunctional groups on their surface, rendering them ideal

carriers for targeted drug delivery. 16

The structure and function of dendrimers has been well

studied. Contemporary dendrimers can be highly specia-

lized, encapsulating functional molecules (i.e., therapeutic or

diagnostic agents) inside their core. 17 A polyamidoamine

dendrimer that can be synthesized by the repetitive addition

of branching units to an amine core (ammonia or ethylene

diamine) is an example of such an application. Polyamidoa-

mine cores can function as drug reservoirs and have been

studied as vehicles for delivery of drugs, 18 genetic

material,

19

and imaging probes.

20,21

Other pharmaceuticalapplications of dendrimers include nonsteroidal anti-inflam-

matory formulations, antimicrobial and antiviral drugs,

anticancer agents, 22 pro-drugs, and screening agents for

high-throughput drug discovery. 23 Dendrimers may be toxic

because of their ability to disrupt cell membranes as a result

of a positive charge on their surface.

24

Dendrimers are useful antiviral agents in that they allow

the presentation of multiple ligands on a single molecule as a

result of a high number of functional groups. Upon

modification with carbohydrate residues, these multivalent

molecules can inhibit viral binding. When derivatized with

peptides or anionic groups, they can inhibit infection.

Because dendrimer synthesis is controlled, they can be

made to order to fit target binding sites of specific

viruses. 25 The first investigational new drug application for

a dendrimer-based drug was submitted to the US FDA in June

2003, and the first clinical trial under this investigational new

drug application was completed in 2004. The drug, namedVivaGel (SPL7013 Gel) is a vaginal microbicide designed to

prevent the transmission of sexually transmitted infections,

including the human immunodeficiency virus (HIV) and

genital herpes. VivaGel is the first example of a dendrimer-

based product and was formulated by Starpharma (Mel-

bourne, Australia). SPL7013 is the active ingredient in

VivaGel and is a lysine-based dendrimer with naphthalene

disulfonic acid surface groups. Dendrimers such as SPL7013

are polymers that contain a central core, interior branches,

and terminal surface groups adapted to specific targets. A

polyanionic outer surface of SPL7013 is responsible for

multiple target interactions. It was demonstrated that theactive surface groups bind to gp120 proteins on HIV's

Figure 1. Micelles formation. A, Formation of micelles in aqueous media. B, Formation of micelles in aqueous media incorporating drugs.



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surface, preventing CD4 receptor binding by healthy cells,

thus preventing transmission of HIV to healthy cells. Because

of its size and polyvalent nature, a dendrimer can activatemany receptors simultaneously as compared with a small

molecule, which can interact with only a single receptor;

therefore, these polyvalence dendrimers can lead to new or

enhanced biological effects (Figure 2).

Quantum dots: enhancing in vivo imaging

QDs are colloidal semiconductor nanocrystals ranging

from 2 to 10 nm in diameter. QDs can be synthesized from

various types of semiconductor materials via colloidal

synthesis or electrochemistry. The most commonly used

QDs are cadmium selenide (CdSe), cadmium telluride(CdTe), indium phosphide (InP), and indium arsenide

(InAs). In bioimaging these particles serve as contrast

agents, providing much greater resolution than existing

fluorescent dyes. These particles can absorb white light and

re-emit it within nanoseconds with different bulk band gap

energies corresponding to different combinations of parti-

cles. Thus, different QDs can emit different fluorescent light

(in wavelength from 400 to 1350 nm). For example, 2-nm

QDs will emit green light, whereas 5-nm particles will emit

red light. 26,27 QD libraries can be assembled to include

particles of various size and composition to support

derivation of multicolored images for bimolecular studies,

26

gene expression, 28 cell labeling and tracking, 29 Fluores-

cence resonance energy transfer (FRET), in vivo imaging,

and related applications. 30 Similar to other nanoparticles,

QDs can be modified via conjugation of various surface

molecules for targeted delivery. 31,32 QDs also provide

enough surface area to attach therapeutic agents for

simultaneous drug delivery and in vivo imaging, 26,33 as

well as for tissue engineering. 34 In vivo cancer targeting and

imaging in living animals by QDs was first demonstrated by

Gao et al., 35 wherein both subcutaneous injection of QD-

tagged cancer cells (prostate cancer) and systemic injection

of multifunctional QD probes were used to achieve sensitiveand multicolor fluorescence imaging of cancer cells. In a

Table 2

Some block co-polymers used to prepare micelles loaded with various

pharmaceuticals

Pharmaceuticals

incorporated

Polymers/block polymer used

for micelles formation

Doxorubicin Pluronics

Poly(aspartic acid)-b-PEGPoly(aspartic acid)-b-PEG

Poly(hydroxyl-ethylene oxide)

Poly(benzyl-L-aspartate)-b-PEG

Poly(2-ethyl-2-oxazoline)-b-poly( L-lactide)

Poly(N-isopropylacrylamide)-b-poly

(alkyl(meth)acrylate) (pH-sensitive)

Poly(L-histidine)-b-PEG (folate-targeted)

Poly(L-lactic acid)-b-PEG (folate-targeted)

Carboplatin Pluronics

Cisplatin Pluronics

Polycaprolactone-b-methoxy-PEG

Poly(aspartic acid)-b-PEG

Poly(glutamic acid)-b-PEG

Paclitaxel Poly(delta-valerolactone)-b-methoxy-PEG

Polycaprolactone-b-methoxy-PEG

Poly(D,L-lactide)-b-methoxy-PEG

Poly(2-ethyl-2-oxazoline)-b-poly

(-caprolactone)

PEG-lipid

PEG-PE/egg phosphatidylcholine

(mixed micelles)

Indomethacin Polycaprolactone-b-methoxy-PEG



Poly(N-vinyl-2-pyrrolidone)-b-poly

(d,L-lactide)

Cyclosporine A Polycaprolactone-b-PEG

Amphotericin B Poly(benzyl-L-aspartate)-b-PEG

PEG-lipid

Adriamycin Poly(aspartic acid)-b-PEG

Poly(hydroxyl-ethylene oxide)

Ibuprofen Chitosan grafted with palmitoylKetorolac Poly(N-isopropylacrylamide)-poly

(vinylpyrrolidone)-poly(acrylic acid)

Camptothecin Poly(aspartic acid)-b-PEG


PEG-lipid

PEG-PE/egg phosphatidylcholine

(mixed micelles)

Phtalocyanine Poly(N-isopropylacrylamide)-b-poly

(d,L-lactide) (thermosensitive)

Poly(N-isopropylacrylamide)-based

(continued on next page)

Table 2 (continued)

Pharmaceuticals

incorporated

Polymers/block polymer used

for micelles formation

micelles (pH-sensitive)

Poly(N-isopropylacrylamide)-b-poly

(alkyl(meth)acrylate) (pH-sensitive)

PEG-lipid

Testosterone Poly(D,l-lactide)-b-methoxy-PEG

Iodine-125 Poly(L-lysine)-b-PEG

Indium-111

(via DTPA-PE, diagnostic)

PEG-lipid

Gd

(via DTPA-PE, diagnostic)

PEG-lipid

DTPA-PE = Diethylenetriaminepentaacetic acid phosphatidylethanolamine.



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recent a study, Bagalkot et al. 33 has used QD-apatmer-

doxorubicin (Dox) conjugate for targeted cancer therapy,

imaging, and sensing. It was shown that this multifunctional

nanoparticle system can deliver Dox to the targeted prostate

cancer cells and sense the delivery of Dox by activating

the fluorescence of QDs, which concurrently images the

cancer cells.

Under some conditions QDs can become cytotoxic.

36

Itwas discovered that CdSe particles may leak cytotoxic

cadmium ions after long-term exposure to ultraviolet light,

whereas CdTe particles produce reactive oxygen species as

a result of the loss of their protective coating after long-

term circulation. In both cases, cytotoxicity and cell death

were recorded. 37-40

Research is continuing to find biocompatible and stable

QD coatings. One recently proposed option was to cover

CdSe-ZnS QDs with silica spheres. Resulting CdSe-ZnS-

SiO2particles demonstrated consistent fluorescence intensity

and predictable behavior. 41

Solid nanoparticles: constructing versatile drug carriers

Most commonly used solid nanoparticles (SNPs) are

spherical objects made of biodegradable materials, such as

proteins (i.e., albumin or collagen), fats, or polymers.42

First SNPs were constructed to deliver drugs. Ranging in

size from 10 to 1000 nm, current SNPs can multitask,

providing simultaneous imaging and drug delivery. Analo-

gous to other nanoparticles, SNPs can be modified with

surface molecules for guided drug delivery. A major

advantage of this formulation is that SNPs can be prepared

to provide controlled drug release.

43

SNPs are among themost common current nanoformulations.

In August 2000, the US FDA approved the first

nanoparticle-mediated medicine known as Rapamune

(sirolimus), an immunosuppressant to prevent organ trans-

plant rejection, developed by Elan (King of Prussia,

Pennsylvania). 44 Rapamune was previously available only

as an oral solution that requires refrigeration, and must be

mixed with water or orange juice before administration. A

new tablet developed by using NanoCrystal technology(Elan) is more convenient in terms of storage and adminis-

trations. NanoCrystal particles are typically in the size range

of 80 to 400 nm and are made by wet-milling a drug

substance, water, and a stabilizer. For compounds with

negligible water solubility, Elan's proprietary NanoCrystal

technology can facilitate formulation development, as well as

improving compound activity and final product character-

istics. The NanoCrystal technology can be incorporated into

all dosage forms, both parenteral and solid, liquid, fast-melt,

pulsed release, and controlled-release oral dosage forms.

Several years ago an albumin-stabilized nanoparticle

formulation of paclitaxel, ABI-007, was designed toovercome insolubility of this agent. 45 The formulation

was designed to eliminate the use of its toxic solvent,

Cremophor EL (BASF), which allowed increasing adminis-

tered doses, thus increasing overall drug efficacy. ABI-007,

unlike conventional paclitaxel, did not require pre-medica-

tion, and showed acceptable toxicities and considerable

antitumor activity (80.9% of patients had a complete or

partial response). The recommended phase II ABI-007 dose

was 230 mg/m 2 every 3 weeks. A phase III trial of that

same formulation for metastatic breast cancer was com-

pleted, and fast-track status for application was granted by

the US FDA in January 2003. In another study the pharmacokinetics of Cremophor-free ABI-007 was

Figure 2. Dendrimers work more effectively than a small molecule. A, Small molecules have the ability to interact with only one receptor in a biological system.

B, Dendrimers can interact with multiple receptors simultaneously and thus have the potential to increase the biological effect.



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compared to traditional Cremophor-ethanol paclitaxel for-

mulation (Taxol; Bristol-Meyers Squibb, New York, New

York) in animals and humans. 46 Both formulations were

administered intravenously. The study found fecal excretion

to be the main elimination pathway for both formulations.

Scientists also reported higher paclitaxel clearance and

volume of distribution for ABI-007 as compared with paclitaxel in humans (21.13 versus 14.76 L/hr/m2 (P =

.048) and 663.8 versus 433.4 L/hr/m 2 (P = .040),

respectively). Some of the selective SNP formulations

available in the market are shown in Table 1. A SNP

formulation of another cancer agent, Dox, was also

evaluated. 47 Dox was incorporated into biodegradable

acrylate nanoparticles of polyisohexylcyanoacrylate. The

nanoformulation of Dox reported an increase in cytotoxicity

and a reduction in cardiotoxicity in preclinical studies. This

formulation was tested in human subjects with refractory

solid tumors at six dosing regimens (15, 30, 45, 60, 75, and

90 mg/m

2

). The drug was infused intravenously over 60minutes in 250 mL of 5% dextrose in water. No

cardiotoxicity was reported, and dose-limiting toxicity was

neutropenia; hematologic toxicity appeared at 75 and

90 mg/m 2. Cautiously, the recommended phase II dose

was 75 mg/m 2.

Solid lipid nanoparticles (SLNs) (made from solid lipids)

has attracted significant interest by various researchers since

the mid 1990s as an innovative drug delivery carrier system,

because of their physical stability, protection of incorporated

labile drugs from degradation, controlled release, and

excellent tolerability. These versatile SLN formulations can

be administered by various routes like parenteral, oral,dermal, ocular, pulmonary, and rectal. Depending on the

drugs to be incorporated and the route of administration,

SLNs can be synthesized by various techniques, which includes

high-pressure homogenization, 48-50 microemulsions, 51-55 sol-

vent emulsificationevaporation or diffusion, 56-58 water-in-

oil-in-water (w/o/w) double-emulsion method, high speed

stirring, and/or ultrasonication. 59,60 Literature describes that

SLNs can be used for all parental applications, right from intra-

articular to intravenous administration. Many researchers

suggest that SLNs have the capability to cross the blood-brain

barrier; in support of this theory, a higher amountof drug was

found in the brain after intravenous injection.

61-64

Thus, SLNshave the potential tobe used as delivery vehicles to the brain for

drugs like Dox, 61,62 paclitaxel,61 camptothecin,65 and others

that cannot cross the blood-brain barrier. Significant efforts have

been made by various research groups to study the efficacy of

various drugs incorporated in SLNs after oral administration.

Successful in vi vo st udies include oral delivery of

tobramycin,63 clozapine,64 camptothecin,65 rifampicin,66

and isoniazid.66 Furthermore, the utility of SLNs has been

demonstrated through ocular,67buccal, 68 and rectal delivery. 69

Several research groups reported successful trials of SLNs

in the topical application of all-trans retinoic acid, 70

clobetasol propionate,

71

cosmetics,

72

and in transdermaldrug delivery of isotretinoin. 73 All nanoformulations

improved the stability and efficacy over traditional formula-

tions. One study evaluated the transdermal formulation of

naproxen, which utilized increased particle permeability at

the nanoscale. 74 In this study, naproxen-loaded nanoparti-

cles were formed into unilaminar films using Eudragit E-100

Rhm GmbH & Co. KG, Darmstadt, Germant. The

nanoformulation was similar to films prepared by conven-tional methods from naproxen-methanol solutions. No

organic solvents were used in the novel formulation. The

study reported that there was no statistical difference

between the amounts of naproxen that penetrated across

the stratum corneum for either formulation.

Surface modifications: targeting drug delivery

Currently, the major struggle surrounding administration

of anticancer agents is differentiating between cancerous and

normal cells, thereby avoiding systemic toxicity and adverse

events associated with conventional therapies. Targetednanomedicines may aid in evading the adverse effects

(such as immunosuppression, cardiomyopathy, and neuro-

toxicity) of traditional therapies, while also providing

improved therapeutic efficacy. Throughout recent years,

targeting nanomedicines have rapidly evolved.

Passive targeting of tumors by nanoparticles takes

advantage of their hyperpermeable cells. The rapid vascular-

ization of tumors results in leaky, defective cells and

impaired lymphatic drainage. Nanoparticles ranging from

10 to 100 nm in size then begin to accumulate within tumors

because of their ineffective lymphatic drainage. This results

in a phenomenon known as the enhanced permeability andretention effect.75 Consideration of the size and surface

properties of nanomedicines is vital. As previously noted,

particles must be smaller than 100 nm to avoid uptake by the

reticuloendothelial system and their surfaces should be

hydrophilic to avoid clearance by macrophages. 76

Recent advances have led to the transformation from

passive to active targeting. Active targeting has revolutionized

nanomedicine, and this can now be achieved by a number of

scientific interactions. Namely, lectin-carbohydrate, ligand-

receptor, and antibody-antigen binding have provided the

framework for such advancements. 77 These various interac-

tions all generally result in preferential accumulation withinthe tumor-bearing organ or tumor cancer cells.

Toxicity

Although there is a tremendous increase in applications of

nanoparticles in industrial materials, medical imaging,

disease diagnoses, drug delivery, cancer treatment, gene

therapy, and other areas, the possible toxic health effects of

these nanoparticles associated with human exposure have

not been studied properly. There is a good chance that these

tiny particles may acquire unique surface properties in their

nanosized form and may be toxic, causing adverse healtheffects. Although the use of nanotechnology in drug delivery,



8/10

imaging, diagnosis, and cancer therapy may be beneficial, it

may cause unintentional human exposure with unknown

health effects that can only be imagined at present. Shvedova

et al. 78 concluded the possibility of cancer and dermatolo-

gical disorders associated with an excess in iron, alteration of

pigmentation, inflammation, porphyria, and other conse-

quences. In another study the same group observed thatexposure to the unrefined single-walled carbon nanotubes

can lead to increased pulmonary toxicity due to oxidative

stress. 79 Further, it was shown by two other groups that these

carbon nanotubes caused granulomas in rats and mice after

acute exposure. 2,80

In two separate studies done by Lam et al. 81 and Poon

and Burd, 82 the possibility of cytotoxicity was found in

lesioned skin, growing human fibroblasts, and keratinocytes

after the utilization of crystalline silver nanoparticles. There

are also a few reports of toxicity of different inorganic

nanoparticles like CdCl2, TiO2, gold nanoparticles, and iron

oxide, at different levels. Although there are insufficient datafor nanoparticles, a few nanomaterials and their relative

cytotoxicity index on murine macrophage cells were

described by Soto et al. in 2005. 83

Prospective applications

Researchers at Rice University have constructed the

world's smallest carthe nanocar. Composed of four C60molecules (the wheels), connected by organic molecules

(the chassis), the nanocar measures just 3-by-4 nm. 84 This

provides support that materials can be moved around in a

controlled manner at the nanoscale level using fullerene- based technology. Nanocars can be applied to targets and

further enhance drug delivery systems. Nanomedicine may

be the key to unlocking the innovation of oral delivery of

peptides, such as oral insulin. Other examples include

hormones, growth factors, clotting factors, and anticoagu-

lants. The major obstacle to delivering peptides and protein

medications is their limited bioavailability, inadequate

stability, immunogenicity, and limited permeability across

biological membranes. Nanotechnology can assist in over-

coming these setbacks, allowing increased gastrointestinal

absorption of these peptides. More than 200 proteins and

peptides have been approved within the United States, andthe bulk of these medications are delivered through

injection. Nanotechnology will soon permit the fusion of

peptides with implantable, oral, topical, and transdermal

drug delivery systems.

Implantable devices using pulsatile delivery systems

capable of controlling drug administration may soon become

prevalent. Implantable devices, or nanochips, promise

improved disease management and may potentially be

applied as antitumor therapy, gene therapy, or vaccines.

Nanochips may even be used to assist in repairing

damaged tissue, detecting mutated genes, or detecting high

hormone levels indicative of certain malignancies.

85

Nanochips may be capable of triggering immediate

responses to inflamed, ischemic, or neoplastic tissues and

simultaneously provide therapy to these tissues. Surpris-

ingly, a silicon-based nanochannel has already been used

to deliver antitumor compounds locally to unresectable

tumors with zero-order kinetics. This implantable device

circumvented the inconvenience of frequent local injec-

tions using novel nanotechnology applications.86

Prospec-tive delivery systems include biosensing functionalities

with in vivo feed back, which will soon permit qsmartq

drug delivery. 87,88

Nanotechnology is beginning to shape the way diseases

are diagnosed, treated, and prevented; visions from the

recent past will soon become a reality. Throughout recent

years the nanotechnology field has grown exponentially

and is predicted to be in full swing within the next 25

years. Multifunctional entities capable of detecting dis-

eases, delivering medications, and monitoring will soon be

within reach. New advancements in nanotechnology

promise desired therapeutic effects while amelioratingside effects associated with many traditional medications.

Nanomedicines propose solutions to the age-old problems

associated with the solubility, bioavailability, immunocom-

patibility, cellular uptake, and cytotoxicity of many of these

traditional medications. 34

Nanotechnology promises anything but minuscule

effects, but most of these visions are hypothetical at this

point. Accordingly, most pitfalls of molecular manufacturing

have not yet been explored, because the benefits remain the

dominant focus of researchers. Many questions surround

nanotechnologynamely safety, cost, and ethical considera-

tions. Regarding safety, little attention has been paid toenvironmental effects and the potential effects on the health

of those manufacturing these particles. Of the US $1.2 billion

spent on nanotechnology research, only 1% was spent on

occupational health and safety research. 89 Granted, the

applications of nanotechnology are limitless, but the

development of safety guidelines by the government should

strongly be considered.

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