Nanoparticles for Drug Delivery

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Nanoparticle-based delivery vehicles improve drug efficacy by modulating drug pharmocokinetics and biodistribution. Small-molecule drugs are rapidly eliminated from the circulation by the kidneys. Injectable nanoparticledelivery vehicles, typically ranging from 5nm to 200nm in size, substantially increase circulation (particles >5nm avoid kidney clearance) while minimizing removal by cells that police the blood for foreign particles (macrophages have less propensity for particles <200nm in size). Oral delivery is currently the most preferred method of drug administration because of its cost effectiveness and ease of use.

The market for oral drug-delivery systems has been growing at a rate of 8.6 percent per year since 2000. A major area of research in oral delivery is in delivery materials for protein drugs. Because particle permeability across the intestinal wall is inversely proportional to size, nanoparticles used for oral delivery offer obvious advantages. The interest in nanoparticle-based drug delivery for other administration routes is also growing. The following sections focus on polymer, lipid, and inorganic or metallic nanoparticles that are <500nm in size.

Polymer Conjugates (Polymer-Drug Chemical Linkage)

Polymer-drug conjugates (520nm) represent the smallest nanoparticulate delivery vehicles. The polymers used for such purposes are usually highly water-soluble and include synthetic polymers (for example, poly(ethylene glycol) (PEG)) and natural polymers (such as dextran). When hydrophobic small molecules are attached to these polymers, their solubilities in water can be substantially improved. For example, a cyclodextrin-based polymer developed at Insert Therapeutics increases the solubility of camptothecin, an insoluble chemotherapy drug, by three orders of magnitude.

Small molecules or proteins conjugated to these polymer delivery vehicles can achieve extended retention in circulation because of reduced kidney clearance. PEG-L-asparaginase (ONCASPAR; Enzon), an FDA-approved PEGylated protein drug as a treatment for acute lymphoblastic leukemia, can be administered every two weeks, instead of the two to three times per week required for the non-PEGylated enzyme. Other PEGylated systems approved by the FDA include PEGadenosine deaminase (ADAGEN; Enzon) as a treatment for X-linked severe combined immunogenicity syndrome and PEGinterferon (PEGASYS; Roche and PEGINTRON; Schering-Plough) as treatments for hepatitis CJ1 Many polymer-small molecule and polymer-protein conjugates are currently in clinical trials. A promising nanoparticle drug-delivery systema proprietary, albumin-bound paclitaxel conjugate codeveloped by American Pharmaceutical Partners and American BioSciencehas shown excellent antitumor efficacy in Phase III clinical trial for the treatment of metastatic breast cancer.

One group of polymers that has attracted enthusiasm recently are dendrimers (Figure 16-2). They are monodispersed, symmetric, globular-shaped macromolecules comprising a series of branches around an inner core. Dendrimers are potential nanometer-sized systems for drug delivery, and their sizes can be controlled simply by adjusting the generation of dendritic branches.

Figure 16-2. Schematic drawing of dendrimer for application in drug delivery and targeting. (Reprinted with permission from, Thiagarajan Sakthivel, Ph.D., and Alexander T. Florence, Ph.D., D.Sc., "Dendrimers & Dendrons: Facets of Pharmaceutical Nanotechnology.")

Figure 16-2. Schematic drawing of dendrimer for application in drug delivery and targeting. (Reprinted with permission from, Thiagarajan Sakthivel, Ph.D., and Alexander T. Florence, Ph.D., D.Sc., "Dendrimers & Dendrons: Facets of Pharmaceutical Nanotechnology.")

Dendrimers Nanoparticles

Y Attached Drug • Solubtlizing group

H/> Encapsulated Drug * Targeting moiely

Polymer Micelles (Polymer Surfactant-Drug Self-Assembly)

Amphiphilic block copolymerspolymers that contain both hydrophilic and hydrophobic regionstend to self-assemble in aqueous solution into spherical structures called micelles. Polymeric micelles typically have a hydrophilic corona and a hydrophobic shell. When used as drug-delivery agents, polymeric micelles are most commonly formulated to include hydrophobic drugs (for example, doxorubicin, cisplatin, amphotericin B) in the core, leaving the outer hydrophilic layer to form a stable dispersion in aqueous media.

The stable structure of the polymeric micelles prevents rapid dissociation (release of drug) in vivo. Polymer micelles typically range from 60 to 100nm, with fairly narrow size distributions. The micellar corona can be further modified with targeting moieties (for example, antibodies) to deliver drugs to desired sites. Development of micellar drug-delivery vehicles is in an early stage, with most formulations still in preclinical studies. I31

Polymer Nanoparticles (Drug Dispersion or Encapsulation in Polymer Aggregates)

Nanoparticles are solid, small colloidal particles made of polymers having diameters from 50nm to several hundred nanometers. Depending on the method of preparation, two types of drug-containing nanoparticles exist: nanospheres (a matrix system in which drugs are uniformly distributed) or nanocapsules (a reservoir system in which drugs are confined to the core of the particles and are surrounded by polymer membranes). Many of these systems are made of biodegradable polymers, such as poly(ortho ester) (Figure 16-3). Poly(ortho ester) nanoparticles release drugs with tunable release rates, depending on solution pH. Drugs encapsulated in nanoparticles have increased stability against enzymatic and chemical degradation, an important advantage for unstable drugs such as proteins and nucleic acids.-41

Figure 16-3. Scanning electron microscopy image of poly(ortho ester) nano- and microspheres. Scale bars: 5mm. (Reprinted with permission from Chun Wang, Qing Ge, David Ting, David Nguyen, Hui-Rong Shen, Jianzhu Chen, Herman N. Eisen, Jorge Heller, Robert Langer, and David Putnam, "Molecularly engineered poly(ortho ester) microspheres for enhanced delivery of DNA vaccines," Nature Materials 3 (2004): 190196.)

Nanoparticles have been tested for the delivery of all types of drugs (small molecules, proteins, and nucleic acids) in almost all types of administration routes (such as inhalation, oral, and injection). Although many of these approaches are still in an early stage of their development, some of them have already shown great potential. An example is Dr. Edith Mathiowitz's (Brown University) poly(fumaric-co-sebacic) anhydride nanoparticles for the oral delivery of insulin, a promising way to achieve oral protein delivery.-5!

Polyplexes (Polymer-Nucleic Acids Complex through Charge Interaction)

In nonviral gene therapy, plasmid DNA is introduced into cells to express therapeutic proteins, whereas in oligonucleotide therapy, oligonucleotides (such as ribozymes and DNAzymes) and small, interfering RNA (siRNA) are used to suppress disease-associated expression. However, the cell membrane is a natural barrier for these genetic materials. For therapeutic nucleic acids to be successfully delivered into the cell, they must be complexed with materials that facilitate cellular uptake.

Polyplexes, a group of nanoparticulates formed by charge interaction between positively charged polymers and negatively charged nucleic acids, are developed for such purposes. Polyplexes range in size from 40nm to 200nm (Figure 16-4). RNA interference (RNAi) is an emerging and promising approach for oligonucleotide therapy, and there is currently active research in developing materials for siRNA delivery.

Figure 16-4. Cyclodextrin polycation-based polyplexes developed by Davis and coworkers (California Institute of Technology).!6! These materials are being investigated for gene therapy applications at Insert Therapeutics. Bar is 100nm. (Reprinted with permission from S. J. Hwang, N. C. Bellocq, and M. E. Davis, "Effects of Structure of beta-cyclodextrin-containing Polymers on Gene Delivery," Bioconjugate Chemistry 12(2) (2001):



Liposomesnano-sized particles (25 to several hundred nanometers) made from phospholipids and cholesterolsare sometimes referred to as "fat bubbles." Liposomes consist of bilayers of lipids that can encapsulate drugs. Their properties for use as delivery vehicles are closely associated with lipid composition, liposomal size, and fabrication methods. For example, saturated phospholipids with long hydrophobic chains usually form a rigid, impermeable bilayer structure, whereas the unsaturated phosphatidylcholine-based lipid layers are much more permeable and less stable.

Liposomal drug delivery has achieved great success in the past decade. Several liposome-based drug-delivery systems have been approved for clinical use. AmBisome (lipid-based delivery of amphotericin B, Fujisawa Healthcare, Inc., and Gilead Science) was approved for the treatment of cryptococcal meningitis in HIV-infected patients. The sales of AmBisome were nearly $200 million in 2003 (an increase of 7 percent from 2002). Doxil (Alza) was approved in 1999 for the treatment of refractory ovarian cancer and is the first and only liposomal cytotoxic agent approved to treat a solid tumor. The sales of Doxil reached $80 million in 2000.

Inorganic and Metallic Nanoparticles

Delivery of drugs using new inorganic and metallic nano-sized vectors are still in the proof-of-concept of stage. One unique approach originates from C-60, a soccer ballshaped fullerene.-t7 Another interesting approach is to use magnetic nanoparticles to carry chemotherapeutic drugs to cancer sites directed by an external magnetic field.

Very recently, other metal nanoparticles have been investigated as therapeutics and drug-delivery systems. An example from Dr. Naomi Halas's research group (Rice University) is the nanoshell, a new type of nanoparticle composed of a dielectric silica core coated with an ultrathin gold layer.!8 Once the nanoshells penetrate tumor tissues, they can be activated for thermal therapy by taking advantage of their ability to convert absorbed energy from the near-infrared region to heat.

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