Nanostructure-Mediated Drug Delivery

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Nanostructure-MediatedDrug Delivery

Gareth A. Hughes, PhD

The predominant methods to deliver drugs are oral and injection, whichhas limited the progress of drug development. Most drugs have been

formulated to accommodate the oral or injection delivery routes, which

are not always the most efficient routes for a particular therapy. Newbiologic drugs such as proteins and nucleic acids require novel delivery

technologies that will minimize side effects and lead to better patientcompliance.1,2 Market forces are also driving the need for new, effective

drug delivery methods.3 It is estimated that drug delivery will account for

39% of all pharmaceutical sales by 2007.4 Meanwhile, upcoming patentexpirations are driving pharmaceutical companies to reformulate their

products. New drug delivery methods may enable pharmaceutical com-panies to develop new formulations of off-patent and soon-to-be off-

patent drugs. Reformulating old drugs can reduce side effects andincrease patient compliance, thus saving money on health care delivery.Furthermore, drug candidates that did not pass through the trials phases

may be reformulated to be used with new drug delivery systems.Innovative drug delivery systems may make it possible to use certain

chemical entities or biologics that were previously impractical because of

toxicities or because they were impossible to administer. For example,drug targeting is enabling the delivery of chemotherapy agents directly to

tumors, reducing systemic side effects. Researchers are continuallyinvestigating new ways to deliver macromolecules that will facilitate the

development of new biologic products such as bioblood proteins and

biovaccines. Similarly, the success of DNA and RNA therapies willdepend on innovative drug delivery techniques.5 Many times, the success

of a drug is dependent on the delivery method. This importance isexemplified by the presence of more than 300 companies based in the

United States involved with developing drug delivery platforms.6

Reprinted with permission from Nanomedicine: Nanotechnology, Biology, and Medicine (2005;1:23-30). 2005 Elsevier Inc.

Dis Mon 2005;51:342-3610011-5029/2005 $30.00 0doi:10.1016/j.disamonth.2005.08.004

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Drug Delivery AlternativesIn addition to the commonly used oral and injection routes, drugs can also

be administered through other means, including transdermal, transmuco-

sal, ocular, pulmonary, and implantation. The mechanisms used toachieve alternative drug delivery typically incorporate one or more of the

following materials: biologics, polymers, silicon-based materials, carbon-based materials, or metals. These materials are structured in microscale

and, more recently, nanoscale formats. Table 1 summarizes the materials

and structures currently being investigated at the nanoscale for drugdelivery applications.

Nanotechnology and Drug DeliveryThe US National Nanotechnology Initiative (NNI), initiated in October

2000, provides a federal vision for nanotechnology-based investmentthrough the coordination of 16 US departments and independent agencies.

Ten potential research and development targets by 2015 for the NNI areshown in Table 2.7

TABLE 1. Nanoscale drug delivery technologies

Drug Delivery

TechnologyMaterials Nanostructure Forms

Biologic Lipids Vesicles, nanotubes, rings

Peptides Nanoparticles

Nucleic acids

Polysaccharides

Viruses

Polymeric Poly(lactic acid) Vesicles, spheres, nanoparticles

Poly(glycolic acid) Micelles, dendrimers

Poly(alkylcyanoacrylate)

Poly(3-hydroxybutanoic acid)

Poly(organophosphazene)

Poly(ethylene glycol)Poly(caprolactone)

Poly(ethylene oxide)

Poly(amidoamine)

Poly(L-glutamic acid)

Poly(ethyleneimine)

Poly(propylene imine)

Silicon based Silicon Porous, nanoparticles

Silicon dioxide Nanoneedles

Carbon based Carbon Nanotubes, fullerness

Metallic Gold Nanoparticles, nanoshells

Silver

Palladium

Platinum

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Five of these research and development targets are relevant to drugdevelopment and delivery: no suffering and death from cancer when

treated, advanced materials and manufacturing, pharmaceutical synthesis

and delivery, converging technologies from the nanoscale, and life-cyclebiocompatible/sustainable development. This emphasis exemplifies the

importance of nanotechnology in the progress of medicine.The efficiency of drug delivery to various parts of the body is directly

affected by particle size. Nanostructure-mediated drug delivery, a key

technology for the realization of nanomedicine, has the potential toenhance drug bioavailability, improve the timed release of drug mole-

cules, and enable precision drug targeting.8,9 Nanoscale drug deliverysystems can be implemented within pulmonary therapies,10 as gene

delivery vectors,11 and in stabilization of drug molecules that would

otherwise degrade too rapidly.12,13 Additional benefits of using targetednanoscale drug carriers are reduced drug toxicity and more efficient drug

distribution.14

Anatomic features such as the blood brain barrier, the branchingpathways of the pulmonary system, and the tight epithelial junctions of

the skin make it difficult for drugs to reach many desired physiologictargets. Nanostructured drug carriers will help to penetrate or overcome

these barriers to drug delivery. Courrier et al.10 have shown that the

greatest efficiency for delivery into the pulmonary system is achieved forparticle diameters of100 nm. Greater uptake efficiency has also been

shown for gastrointestinal absorption15,16 and transcutaneous perme-

ation,17 with particles around 100 nm and 50 nm in size, respectively.However, such small particles traveling in the pulmonary tract may also

have a greater chance of being exhaled. Larger, compartmental ormultilayered drug carrier architectures may help with delivery to the

pulmonary extremities. For instance, the outer layers of the carrierarchitecture may be formulated to biodegrade as the carrier travels

TABLE 2. Potential R&D targets by 2015 for U.S. National Nanotechnology Initiative

Nanoscale visualization and simulation of 3-dimensional domains

Transistor beyond/integrated CMOS 10 nm

New catalysts for chemical manufacturingNo suffering and death from cancer when treated

Control of nanoparticles in air, soils, and waters

Advanced materials and manufacturing: one-half from molecular level

Pharmaceuticals synthesis and delivery: one-half on nanoscale level

Converging technologies from nanoscale

Life-cycle biocompatible/sustainable development

Education: nanoscale instead of microscale based

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through the pulmonary tract. As the drug carrier penetrates further into the

lung, additional shedding will allow the encapsulated drug to be released.

Biodegradable nanoparticles of gelatin and human serum albumin showpromise as pulmonary drug carriers.18

Advantages of nanostructure-mediated drug delivery include the ability

to deliver drug molecules directly into cells19 and the capacity to target

tumors within healthy tissue.20 For example, DNA and RNA that is

packaged within a nanoscale delivery system can be transported into the

cell to fix genetic mutations or alter gene expression profiles. The

mechanisms of cellular uptake of external particulates include clathrin-

and caveoli-mediated endocytosis, pinocytosis, and phagocytosis. How-ever, phagocytosis may not play a role in the uptake of nanoscale particles

because of the small size of such particles.21

Nanoscale drug delivery architectures are able to penetrate tumors due

to the discontinuous, or leaky, nature of the tumor microvasculature,

which typically contains pores ranging from 100 to 1000 nm in diameter.

The microvasculature of healthy tissue varies by tissue type, but in most

tissues including the heart, brain, and lung, there are tight intercellular

junctions less than 10 nm. Therefore, tumors within these tissue types canbe selectively targeted by creating drug delivery nanostructures greater

than the intercellular gap of the healthy tissue but smaller than the pores

found within the tumor vasculature.

Through precise control of the drug carrier architecture, the release of

the drug can be tuned to achieve a desired kinetic profile. Three of the

most common kinetic profiles are zero order, first order, and Higuchi;

these are depicted in Figure 1 and expressed mathematically in Eq. (1).

The delivery of most drugs is accomplished through oral administrationor by injection and follows first-order kinetics. The ideal release profile

for most drugs would follow a steady release rate so that the drug levels

in the body remain constant while the drug is being administered. More

recent transdermal drug delivery mechanisms follow the Higuchi mod-

el.22 As will be shown in subsequent sections, nanostructured polymeric

and silica nanoparticles are being developed as drug carriers which

achieve near zero-order kinetics:

Zero order : DtD0 k0tFirst order : lnDt lnD0 k1t

Higuchi : DtD0 kHt12

(1)

where Dt

is the amount of drug released at time t, D0 is the initial amount

of drug released, result of initial rapid release, k0 is the zero-order release

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constant, k1 is the first-order release constant, and kH is the Higuchi

release constant.Various nanoscale architectures can be realized including solid spheres,

hollow spheres, tubes, porous particles, solid particles, and branched

structures. To achieve such nanostructures, different fabrication methodsare used depending on the type of material. The methods used for

nanoscale assembly include molecular self-assembly,23 bioaggregation,24

nanomanipulation,25 photochemical patterning,26 molecular imprinting,26

layer-by-layer electrostatic deposition,27,28 and vapor deposition.29

Biologic StructuresThe biologic world is full of nanostructures. Researchers are now

devising ways to mimic, enhance, and harness the functionality of these

biologic nanostructures.30,31 Scanning probe manipulation25 and photo-

chemical patterning26 are examples of nonbiologic techniques used toform nanostructures out of biologic materials. Furthermore, techniques

mimicking biologic actions such as molecular self-assembly23,32 and

biologic aggregation24 are used to create nanostructures.Biologic nanostructures that have been developed for drug delivery

purposes include lipid nanotubes,33 lipid nanospheres,34-36 lipid nanopar-ticles,37-39 lipid emulsions,40-42 circular peptides,43,44 chitosan,45-48 viral

nanoparticles,49 and nucleic acid nanostructures.50 One of the mostinvestigated lipid forms is the liposome, which is a hollow vesicle that can

FIG 1. Drug release profiles from zero order, first order, and Higuchi kinetics.

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be used to entrap and release drug molecules.51-55 Multicompartment

liposomes have also been fabricated54 that may provide a means forextended drug release. Biologics that have been developed or are being

investigated by use of delivery systems that are based on biologic

nanostructures include genes, small interfering RNA (siRNA), andgrowth hormones.

Polymer StructuresPolymer materials exhibit several desirable properties for drug carrier

use including biocompatibility, biodegradability, and functionalizationcapability. Through functionalization and structural manipulation of

polymer materials, drug molecules can be incorporated within thepolymer. Entrapping or encapsulating the drug within a polymer allows

for greater control of the pharmacokinetic behavior of the active drug

molecule. The drug can be released with a more ideal, near zero-orderkinetic profile, which establishes a more constant flow of the drug out of

the carrier. This pharmacokinetic behavior maintains more appropriatesteady levels of the drug at the site of delivery. In contrast, conventional

oral drug delivery typically follows first-order release kinetics where the

drug release rate is proportional to the amount of drug remaining in thedrug carrier. Landgraf et al.56 have compared the release kinetics of an

anti-inflammatory agent taken orally by use of a macroporous copolymercarrier and a microporous copolymer carrier containing nanochannels.

The macroporous drug carrier releases the drug with an initial burst and

follows first-order release kinetics. The microporous carrier structuredwith nanochannels steadily releases the drug in near zero-order fashion.

Techniques that are used to couple the drug with the polymer include

sequestering, conjugation, and micelle formation.57 Nanostructure forma-tion of polymers has been accomplished through mold replication,58

colloidal lithography,59 interfacial polymerization,60 nanoprecipitation,60

multiple solvent emulsion evaporation,60 nanoimprinting,61 and electro-

spinning.62

A review of biodegradable polymeric materials that show promise fordrug delivery applications is compiled in Ulrich et al.63 Biodegradable

polymer nanoparticles, typically consisting of polylactic acid (PLA),

polyglycolic acid (PGA), or a copolymer of PLA and PGA, are beinginvestigated for the delivery of proteins and genes,64,65 vaccines,66,67

anticancer drugs,68-70 ocular drugs,71,72 and cytokines.73 Other polymersbeing investigated for nanoscale drug carriers include polyalkylcyanoac-

rylate,74 poly(3-hydroxybutanoic acid) (PHB),75 poly(organophospha-zene),76 poly(ethylene glycol) (PEG),77-80 poly(caprolactone) (PCL),81,82

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poly(ethylene oxide) (PEO),83 and copolymers such as PLA-PEG.84,85

Synthetic polymers, such as PEG, can be used to encapsulate biologic

materials to create a more stable drug carrier. One example of a hybrid

drug carrier is a liposome coated with PEG, called a stealth liposome.Conventional liposomes are typically cleared rapidly from the blood.

Stealth liposomes, with PEG coatings, can have prolonged circulationtimes.52 The mechanisms behind prolonged circulation are still being

investigated. Additionally, polymers are being used to enhance the releasecharacteristics of another drug carrier as in the coating of tablets with

hydroxypropyl methylcellulose phthalate (HPMCP) nanoparticles.86 The

nanoparticle-coated tablets show a decrease in release rate and a migra-

tion towards zero-order release kinetics as the particle size is decreased,as shown in Figure 2.

DendrimersDendrimers, a unique class of polymers, are highly branched macromole-

cules whose size and shape can be precisely controlled.87,88 Dendrimers are

FIG 2. Effect of HPMCP nanoparticle size on release behavior of coated diclofenac tablets.Particle diameters: closed circles, 810 nm; open squares, 590 nm; closed triangles, 335 nm;inverted open triangles, 220 nm; plus sign, 171 nm. Reprinted with permission from Journal ofControlled Release.86 Copyright 2003, Elsevier Inc.

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fabricated from monomers using either convergent or divergent step-growth

polymerization. Two representations of polyamidoamine-based dendrimers

are shown in Figure 3. The well-defined structure, monodispersity of size,surface functionalization capability, and stability are properties of dendrimers

that make them attractive drug carrier candidates. Drug molecules can be

incorporated into dendrimers via either complexation or encapsulation asshown in Figure 4. Dendrimers are being investigated for both drug and gene

delivery,89,90 as carriers for penicillin,91 and for use in anticancer ther-apy.92,93 Dendrimers used in drug delivery studies typically incorporate one

or more of the following polymers: polyamidoamine (PAMAM),94,95 mel-amine,96 poly(L-glutamic acid) (PG),97 polyethyleneimine (PEI),97 poly(pro-

FIG 3. Example chemical structure of a polyamidoamine dendrimer (left). Stick modelrepresentation of a polyamidoamine dendrimer (right).

FIG 4. Schematic of incorporation of drug within a dendrimer structure. Complexation

covalent attachment to end groups (left).

Encapsulationtrapment inside dendrimer core (right).

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pylene imine),98 and poly(ethylene glycol) (PEG).98 Chitin and chitosan have

also been incorporated with dendrimers.99 For further review on dendrimers,see Aulenta et al.100

Silicon-Based StructuresSilicon-based structures can be fabricated by photolithography, etching,

and deposition techniques commonly used in the manufacture of semi-conductors and microelectromechanical systems (MEMS). The most

commonly investigated silicon-based materials for drug delivery are

porous silicon and silica, or silicon dioxide. Architectures includecalcified nanopores, platinum-containing nanopores, porous nanopar-

ticles, and nanoneedles.101 Figure 5 shows a nanoporous membranefabricated on a silicon substrate.102 The density and diameter of the

nanopores can be accurately controlled to achieve a constant drug

delivery rate through the pores.Porous hollow silica nanoparticles (PHSNP) are fabricated in a suspen-

sion containing sacrificial nanoscale templates such as calcium carbon-ate.103 Silica precursors, such as sodium silicate, are added into the

suspension, which is then dried and calcinated creating a core of the

template material coated with a porous silica shell. The template materialis then dissolved in a wet etch bath, leaving behind the porous silica shell.

Creation of drug carriers involves the mixing of the PHSNPs with thedrug molecule and subsequently drying the mixture to coalesce the drug

molecules to the surface of the silica nanoparticles as shown in Figure 6.

Through controlling the pore size and the particle diameter, the releasekinetics approach near zero-order as shown in Figure 7, where the release

behavior of conventional silica nanoparticles is compared with that of

porous hollow silica nanoparticles. As shown, the porous hollow nano-particles exhibit a much more desirable gradual release.104

Examples of therapies being investigated for use with silicon-baseddelivery systems include porous silicon embedded with platinum as an

antitumor agent,105 calcified porous silicon designed as an artificial

growth factor,106 silicon nanopores for antibody delivery,102,107 andporous silica nanoparticles containing antibiotics,108 enzymes,109 and

DNA.110

Carbon StructuresTwo nanostructures, shown in Figure 8, that have received much

attention in recent years are hollow, carbon-based, cage-like architec-

tures: nanotubes and fullerenes, also known as buckyballs because of theirspherical structure resembling the geodesic domes of Buckminster Fuller.

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FIG 5. Nanoporous membrane with 24.5-nm pores. Reprinted with permission from Advancesin Drug Delivery Reviews.102 Copyright 2003, Elsevier Inc.

FIG 6. Preparation of hollow silica nanoparticle-based drug carriers. A, Silica nanoparticle. B,Suspend drug molecule with silica nanoparticle. C, Dry mixture to entrap drug molecule.Reprinted with permission from Biomaterials.103 Copyright 2004, Elsevier Inc.

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Single-wall nanotubes (SWNTs), multiwall nanotubes (MWNTs), and

C60 fullerenes are common configurations. The size, geometry, and

surface characteristics of these structures make them appealing for drugcarrier usage. SWNTs and C60 fullerenes have diameters on the order of

1 nm, about half the diameter of the average DNA helix. MWNTs have

diameters ranging from several nanometers to tens of nanometers depend-ing on the number of walls in the structure. Fullerenes and carbon

nanotubes are typically fabricated using electric arc discharge (EAD),laser ablation (LA), chemical vapor deposition (CVD), or combustion

processes.29,111,112

Surface-functionalized carbon nanotubes (CNTs) can be internalized

within mammalian cells,113 and when linked to peptides may be used as

vaccine delivery structures.114,115 With use of molecular dynamics (MD)

simulations, the flow of water molecules through CNTs has beenmodeled,116-118 and implies their potential use as small molecule trans-porters. Other simulations have involved the transport of DNA through

CNTs, indicating potential use as a gene delivery tool.119 Figure 9 shows

a snapshot from an MD simulation of molecular water flow throughsingle-wall CNTs.117

FIG 7. Comparison of release profiles of conventional silica nanoparticles and porous hollowsilica nanoparticles. Chemical released was BB (brilliant blue F). Reprinted with permission from

Journal of Controlled Release.104 Copyright 2004, Elsevier Inc.

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Much work with CNTs has involved composite materials. For example,

temperature-stabilized hydrogels for drug delivery applications incorpo-

rate CNTs.120 Fullerenes have also shown drug targeting capability.

Tissue-selective targeting121 and intracellular targeting of mitochon-dria122 have been shown with use of fullerene structures. Furthermore,experiments with fullerenes have also shown that they exhibit antioxi-

dant123,124 and antimicrobial behavior.125

Metal StructuresHollow metal nanoshells are being investigated for drug delivery

applications.126 Typical fabrication methods involve templating of the

thin metal shell around a core material such as a silica nanoparticle.Typical metals include gold, silver, platinum, and palladium. When

linked to or embedded within polymeric drug carriers, metal nanoparticlescan be used as thermal release triggers when irradiated with infrared light

or excited by an alternating magnetic field.127 Biomolecular conjugationmethods of metals include bifunctional linkages, lipophilic interaction,

FIG 8. Ball-and-stick model of a single-wall carbon nanotube (left).

Reprinted with permissionfrom Precision Engineering.29 Copyright 2004, Elsevier Inc. Model of a fullerene molecule(right). Reprinted from Proceedings of the National Academy of Sciences of the United Statesof America.112 Copyright 2000, National Academy of Sciences, USA.

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silanization, electrostatic attraction, and nanobead interactions.128 Figure

10 shows examples of silanization and electrostatic attraction methods of

metal nanoparticle conjugation.

ConclusionsAs we gain more knowledge with respect to disease pathophysiology

and cellular mechanisms, more specific drugs are being developed. To usethe specificity and potency of these drugs, new drug delivery systems

must be implemented. Nanostructured delivery architectures are promis-ing candidates that will enable efficient and targeted delivery of novel

FIG 9. Simulation snapshot of water molecule flow through single-wall carbon nanotubes. Insetat top right: Close-up view within a single nanotube. Reprinted from Proceedings of the National

Academy of Sciences of the United States of America.117

Copyright 2003, National Academyof Sciences, USA.

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drug compounds. Sustained drug release and intracellular entry capability

are properties of nanoscale drug delivery mechanisms that will minimize

side effects and allow for the direct treatment of the cause of the diseaserather than the symptoms of the disease.

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