Nanostructure-Mediated Drug Delivery

Gareth A. Hughes, PhD

The predominant methods to deliver drugs are oral and injection, which has 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 efcient routes for a particular therapy. New biologic drugs such as proteins and nucleic acids require novel delivery technologies that will minimize side effects and lead to better patient compliance.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 patent expirations are driving pharmaceutical companies to reformulate their products. New drug delivery methods may enable pharmaceutical companies to develop new formulations of off-patent and soon-to-be offpatent drugs. Reformulating old drugs can reduce side effects and increase 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 continually investigating 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 will depend on innovative drug delivery techniques.5 Many times, the success of a drug is dependent on the delivery method. This importance is exemplied 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;51:342-361 0011-5029/2005 $30.00 0 doi:10.1016/j.disamonth.2005.08.004 342 DM, June 2005

TABLE 1. Nanoscale drug delivery technologies Drug Delivery Technology Biologic Materials Lipids Peptides Nucleic acids Polysaccharides Viruses Poly(lactic acid) Poly(glycolic acid) 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 Silicon dioxide Carbon Gold Silver Palladium Platinum Nanostructure Forms Vesicles, nanotubes, rings Nanoparticles

Polymeric

Vesicles, spheres, nanoparticles Micelles, dendrimers

Silicon based Carbon based Metallic

Porous, nanoparticles Nanoneedles Nanotubes, fullerness Nanoparticles, nanoshells

Drug Delivery Alternatives

In addition to the commonly used oral and injection routes, drugs can also be administered through other means, including transdermal, transmucosal, ocular, pulmonary, and implantation. The mechanisms used to achieve alternative drug delivery typically incorporate one or more of the following materials: biologics, polymers, silicon-based materials, carbonbased 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 drug delivery applications.

Nanotechnology and Drug Delivery

The US National Nanotechnology Initiative (NNI), initiated in October 2000, provides a federal vision for nanotechnology-based investment through the coordination of 16 US departments and independent agencies. Ten potential research and development targets by 2015 for the NNI are shown in Table 2.7
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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 manufacturing No 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

Five of these research and development targets are relevant to drug development 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-cycle biocompatible/sustainable development. This emphasis exemplies the importance of nanotechnology in the progress of medicine. The efciency 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 to enhance drug bioavailability, improve the timed release of drug molecules, and enable precision drug targeting.8,9 Nanoscale drug delivery systems 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 benets of using targeted nanoscale drug carriers are reduced drug toxicity and more efcient drug distribution.14 Anatomic features such as the blood brain barrier, the branching pathways of the pulmonary system, and the tight epithelial junctions of the skin make it difcult for drugs to reach many desired physiologic targets. Nanostructured drug carriers will help to penetrate or overcome these barriers to drug delivery. Courrier et al.10 have shown that the greatest efciency for delivery into the pulmonary system is achieved for particle diameters of 100 nm. Greater uptake efciency has also been shown for gastrointestinal absorption15,16 and transcutaneous permeation,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 or multilayered drug carrier architectures may help with delivery to the pulmonary extremities. For instance, the outer layers of the carrier architecture may be formulated to biodegrade as the carrier travels
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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 show promise 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 x genetic mutations or alter gene expression proles. The mechanisms of cellular uptake of external particulates include clathrinand caveoli-mediated endocytosis, pinocytosis, and phagocytosis. However, 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 can be 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 prole. Three of the most common kinetic proles are zero order, rst order, and Higuchi; these are depicted in Figure 1 and expressed mathematically in Eq. (1). The delivery of most drugs is accomplished through oral administration or by injection and follows rst-order kinetics. The ideal release prole 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 model.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 : Dt D0 k0t First order : lnDt Higuchi : Dt lnD0 D0 kHt k1t
12

(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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FIG 1. Drug release proles from zero order, rst order, and Higuchi kinetics.

constant, k1 is the rst-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 methods are 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 Structures
The 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 photochemical patterning26 are examples of nonbiologic techniques used to form 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 nanoparticles,37-39 lipid emulsions,40-42 circular peptides,43,44 chitosan,45-48 viral nanoparticles,49 and nucleic acid nanostructures.50 One of the most investigated lipid forms is the liposome, which is a hollow vesicle that can
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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 for extended 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), and growth hormones.

Polymer Structures
Polymer materials exhibit several desirable properties for drug carrier use including biocompatibility, biodegradability, and functionalization capability. Through functionalization and structural manipulation of polymer materials, drug molecules can be incorporated within the polymer. 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-order kinetic prole, which establishes a more constant ow of the drug out of the carrier. This pharmacokinetic behavior maintains more appropriate steady levels of the drug at the site of delivery. In contrast, conventional oral drug delivery typically follows rst-order release kinetics where the drug release rate is proportional to the amount of drug remaining in the drug carrier. Landgraf et al.56 have compared the release kinetics of an anti-inammatory agent taken orally by use of a macroporous copolymer carrier and a microporous copolymer carrier containing nanochannels. The macroporous drug carrier releases the drug with an initial burst and follows rst-order release kinetics. The microporous carrier structured with 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 formation 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 electrospinning.62 A review of biodegradable polymeric materials that show promise for drug 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 being investigated for the delivery of proteins and genes,64,65 vaccines,66,67 anticancer drugs,68-70 ocular drugs,71,72 and cytokines.73 Other polymers being investigated for nanoscale drug carriers include polyalkylcyanoacrylate,74 poly(3-hydroxybutanoic acid) (PHB),75 poly(organophosphazene),76 poly(ethylene glycol) (PEG),77-80 poly(caprolactone) (PCL),81,82
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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 of Controlled Release.86 Copyright 2003, Elsevier Inc.

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 circulation times.52 The mechanisms behind prolonged circulation are still being investigated. Additionally, polymers are being used to enhance the release characteristics 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 migration towards zero-order release kinetics as the particle size is decreased, as shown in Figure 2.

Dendrimers
Dendrimers, a unique class of polymers, are highly branched macromolecules whose size and shape can be precisely controlled.87,88 Dendrimers are
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FIG 3. Example chemical structure of a polyamidoamine dendrimer (left). Stick model representation 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).

fabricated from monomers using either convergent or divergent step-growth polymerization. Two representations of polyamidoamine-based dendrimers are shown in Figure 3. The well-dened 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 as shown 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 therapy.92,93 Dendrimers used in drug delivery studies typically incorporate one or more of the following polymers: polyamidoamine (PAMAM),94,95 melamine,96 poly(L-glutamic acid) (PG),97 polyethyleneimine (PEI),97 poly(proDM, June 2005 349

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 Structures
Silicon-based structures can be fabricated by photolithography, etching, and deposition techniques commonly used in the manufacture of semiconductors and microelectromechanical systems (MEMS). The most commonly investigated silicon-based materials for drug delivery are porous silicon and silica, or silicon dioxide. Architectures include calcied nanopores, platinum-containing nanopores, porous nanoparticles, and nanoneedles.101 Figure 5 shows a nanoporous membrane fabricated 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 suspension containing sacricial nanoscale templates such as calcium carbonate.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 material is then dissolved in a wet etch bath, leaving behind the porous silica shell. Creation of drug carriers involves the mixing of the PHSNPs with the drug 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 release kinetics 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 nanoparticles exhibit a much more desirable gradual release.104 Examples of therapies being investigated for use with silicon-based delivery systems include porous silicon embedded with platinum as an antitumor agent,105 calcied porous silicon designed as an articial growth factor,106 silicon nanopores for antibody delivery,102,107 and porous silica nanoparticles containing antibiotics,108 enzymes,109 and DNA.110

Carbon Structures
Two nanostructures, shown in Figure 8, that have received much attention in recent years are hollow, carbon-based, cage-like architectures: nanotubes and fullerenes, also known as buckyballs because of their spherical 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 Advances in 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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FIG 7. Comparison of release proles of conventional silica nanoparticles and porous hollow silica nanoparticles. Chemical released was BB (brilliant blue F). Reprinted with permission from Journal of Controlled Release.104 Copyright 2004, Elsevier Inc.

Single-wall nanotubes (SWNTs), multiwall nanotubes (MWNTs), and C60 fullerenes are common congurations. The size, geometry, and surface characteristics of these structures make them appealing for drug carrier 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 depending 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 ow of water molecules through CNTs has been modeled,116-118 and implies their potential use as small molecule transporters. 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 ow through single-wall CNTs.117
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FIG 8. Ball-and-stick model of a single-wall carbon nanotube (left). Reprinted with permission from 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 States of America.112 Copyright 2000, National Academy of Sciences, USA.

Much work with CNTs has involved composite materials. For example, temperature-stabilized hydrogels for drug delivery applications incorporate CNTs.120 Fullerenes have also shown drug targeting capability. Tissue-selective targeting121 and intracellular targeting of mitochondria122 have been shown with use of fullerene structures. Furthermore, experiments with fullerenes have also shown that they exhibit antioxidant123,124 and antimicrobial behavior.125

Metal Structures
Hollow 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 nanoparticles can be used as thermal release triggers when irradiated with infrared light or excited by an alternating magnetic eld.127 Biomolecular conjugation methods of metals include bifunctional linkages, lipophilic interaction,
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FIG 9. Simulation snapshot of water molecule ow through single-wall carbon nanotubes. Inset at 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 Academy of Sciences, USA.

silanization, electrostatic attraction, and nanobead interactions.128 Figure 10 shows examples of silanization and electrostatic attraction methods of metal nanoparticle conjugation.

Conclusions
As we gain more knowledge with respect to disease pathophysiology and cellular mechanisms, more specic drugs are being developed. To use the specicity and potency of these drugs, new drug delivery systems must be implemented. Nanostructured delivery architectures are promising candidates that will enable efcient and targeted delivery of novel
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FIG 10. Nanoparticle bioconjugation methods: (1) silanization, and (2) electrostatic attraction.

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 disease rather than the symptoms of the disease.

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