Delivering the Results in Drug-Based Nanotechnology

Drug delivery dominates the use of nanotechnology in pharmaceuticals. Applications include organic nanoplatforms such as polymers, lipids (e.g., liposomes, nanoemulsions, and solid–lipid nanoparticles), self-assembling structures, and dendrimers as well as certain inorganic nanoplatforms including metal (e.g., gold and silver), and silica-based nanostructures (1).

Patricia Van Arnum

Setting the framework

The US Food and Drug Administration has not established its own formal definition of nanotechnology, although the agency participated in a definition of nanotechnology set by the National Nanotechnology Initiative (NNI). The NNI is a federal research and development (R&D) program established to coordinate the multiagency efforts in nanoscale science, engineering, and technology. FDA and 22 other federal agencies participate. The NNI defines nanotechnology to involve all of the following criteria:

• Research and technology development at the atomic, molecular, or macromolecular levels, in the length scale of approximately 1–100 nm range
• Creating and using structures, devices, and systems that have novel properties and functions because of their small and/or intermediate size
• Ability to control or manipulate on the atomic scale (1).

Using that definition, nanotechnology relevant to FDA may include R&D that would satisfy the NNI definition and relate to a product regulated by FDA (2). The specific regulatory requirments, including safety and related issues, are still under consideration. To gain input on these matters, FDA held a public meeting in September 2008. Earlier this year, FDA launched a public–private partnership with the Alliance for NanoHealth and eight academic institutions for purposes of expanding knowledge of how nanoparticles behave and affect biologic systems. The alliance hopes to facilitate the development of tests and processes that might mitigate the risks associated with nanoengineered products.

ROBERT KOHLHUBER, SOUTHERN STOCK/GETTY IMAGES

Nanodrugs in action

Although the regulatory framework for nanotechnology in pharmaceutical applications and its exact definition are under consideration, in the context of technology platforms, a broader term of nanodrugs may be used. These nanomedicines are drugs that use platforms based on nanotechnology and related approaches. The technology evolution of nanodrugs can be seen when evaluating commercial products and clinical and preclinical candidates.

"In the current nanotechnology drug market, the strategy is largely on product-life extension by formulating existing drugs to enhance their half-lives, improve their oral bioavailability, or efficacy," says Lee Jia, senior project officer of the Developmental Therapeutics Program for the National Cancer Institute at the National Institutes of Health, who spoke at the 2008 American Association of Pharmaceutical Scientists annual meeting. Advanced nanotechnology systems such as dendrimers and carbon nanotubes are not yet represented in the list of approved nanodrugs. Unlike the majority of clinical and preclinical nanodrugs, only 25% of currently marketed nanodrugs are directed toward cancer treatment (3).

There are approximately 28 approved nanodrugs on the market. These drugs primarily use liposomes, polymers, and nanocrystallines as the basis of formulations. Twelve of these drugs use a liposomal drug-delivery system, 10 a polymeric-based system (such as pegylation), and 5 nanocrystalline systems. Other systems include albumin-bound platforms (3).

Nanoparticles as vaccine adjuvants.

When examining the nanodrugs in clinical development, more advanced systems are used, and there is a greater emphasis on anticancer therapeutics (2). Although liposomal and polymeric-based platforms are still represented, more complex systems such as nanocrystals, nanoemulsions, drugs formulated with gold nanoparticles, and dendrimers are used. Gold nanoparticles, for example, use the leaky vasculatures of tumors to target delivery of pharmaceutically active compounds to the tumor. Dendrimers, which have high loading power and specific targeting units, can deliver more active compounds to specific organs and tissues. There are at least 27 nanodrugs in clinical trials, and approximately 60% of them are for cancer treatment (3).

The value-added focus on nanotechnology in drug development is pushed further in preclinical drug candidates. There are at least 23 nanodrugs in preclinical development, and 78% of them are anticancer agents. New formulations involve the use of dendrimers and metallic, ceramic, and virus-based nanoparticles (3).

Looking at the technologies

Pegylation, or the attachment of a polyethylene glycol moiety, is one example of a commercialized drug-delivery approach that can employ nanocarriers (3). Pegylation is used as a means of modifying naturally occurring proteins to improve the pharmacodynamics of the protein (4). Several commercial products using pegylated-based systems, and which are broadly classified as nanocarriers, are pegylated interferon and peglyated granulocyte colony-stimulating factor (3–6). Pegasys (peginterferon alfa-2a) by Roche (Basel, Switzerland) and Nektar Therapeutics (San Carlos, CA) and Peg- Intron (pegylated-alfa interferon 2b) by Schering-Plough (Kenilworth, NJ) and Enzon Pharmaceuticals (Bridgewater, NJ) are two examples of pegylated interferons, and Neulasta by Amgen (Thousand Oaks, CA) is an example of a peglyated granulocyte colony-stimulating factor. Pegylated-based formulations address pharmacologic limitations such as toxicity, poor solubility, or a limited half-life.

Several commercial products use nanocrystallines as a drug-delivery platform. Elan Drug Technologies, a business unit of Elan (Dublin, Ireland), for example, uses its NanoCrystal technology to improve the delivery of poorly water-soluble drugs by transforming them into nanometer-sized particles, typically less than 2000 nm in diameter. These particles are produced by milling the drug substance using a proprietary wet-milling technique, according to company information. The NanoCrystal particles of the drug are stabilized against agglomeration by surface adsorption of select stabilizers. The result is an aqueous dispersion of the drug substance that behaves like a solution, a nanocrystal colloidal dispersion, which can be processed into finished-dosage forms.

Elan's NanoCrystal technology is used in five US-approved products. These products include Wyeth's (Madison, NJ) Rapamune (sirolimus), Merck & Co.'s (Whitehouse Station, NJ) Emend (aprepitant), Abbott Laboratories' (Abbott Park, IL) Tricor (fenofibrate), and Par Pharmaceutical's (Woodcliff Lake, NJ) Megace ES (megestrol). In August 2009, a fifth product was approved, Invega Sustenna (Johnson & Johnson, New Brunswick, NJ), a long-acting injectable form of paliperidone palmitate. Elan says it is the first approval of a long-acting injectable formulation using its technology.

Albumin-bound paclitaxel is another example of a commercialized nanoparticle drug-delivery platform. Abraxis BioScience's (Los Angeles) Abraxane for injectable suspension (paclitaxel protein- bound particles for injectable suspension, albumin-bound) is an anticancer drug that uses the company's "nab" technology platform. The drug is an albumin-bound taxane particle of approximately 130 nm. Albumin is a protein that acts as the body's key transporter of nutrients and other water-insoluble molecules and selectively accumulates in tumor tissues. In the case of Abraxane, by wrapping the albumin around the active drug, the drug can be administered to patients at higher doses, thereby delivering higher concentrations of paclitaxel to the tumor site than solvent-based paclitaxel. Abraxane is approved for treating metastatic breast cancer. It is currently in various stages of investigation for treating expanded applications for metastatic breast, non small-cell lung, melanoma, pancreatic, and gastric cancers.

Advances from the pipeline

Nanodrugs under clinical development include candidates using liposomal and polymeric platforms such as pegylation as well as composition polymers (3). For example, Supratek Pharma (Montreal) is developing an anticancer drug using its Biotransport nanocomposition of block copolymers for a pluronic block–copolymer formulation of doxorubicin. The drug is in preclinical and clinical development for various cancers. The Biotransport compositions consist of an active pharmaceutical ingredient with specific polymer combinations to achieve improved biological response and targeted drug delivery. The resulting nanosystems range from 10–100 nm in size, according to the company. Cell Therapeutics (Seattle) is developing Opoxio (formerly Xyotax) (paclitaxel poliglumex, CT-2103), a chemotherapeutic that links paclitaxel to a biodegradable polyglutamate polymer.

Dendrimers and nanogold particles are examples of other nano-based delivery systems. Starpharma (Melbourne, Australia), for example, has several products and platforms under development using dendrimer technology. The synthesis of dendrimers involves a core molecule with branching groups to which other branching molecules are added in layers; each new layer is called a generation. The final generation can incorporate additional active groups that give the particular functionality to the dendrimer. The linkage of the active to the dendrimer nanoparticle is designed to extend half-life, reduce toxicity, improve drug solublization, and target delivery, according to the company.

Cytimmune Sciences (Rockville, MD) is developing colloidal gold-based nanomedicines. CytImmune's lead drug candidate, Aurimune (CYT-6091), consists of recombinant human tumor necrosis factor-alpha (TNF) bound to the surface of pegylated colloidal gold nanoparticles. The company says by simultaneously binding TNF and pegylated-thiol to the surface of colloidal gold nanoparticles, the therapeutic payload can travel safely through the bloodstream and avoid immune detection and is preferentially delivered to the site of disease. At 27 nm, Aurimune primarily and preferentially exits the circulation through leaky, newly formed vasculature at tumor sites, thereby selectively passing through gaps in blood-vessel walls. In addition to Aurimune, the company is developing other pegylated collodial gold-bound TNF systems of other anticancer drugs, including paclitaxel, doxorubicin, interleukin-12, and interleukin-2.

Patricia Van Arnum is a senior editor at Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, pvanarnum@advanstar.com

References

1. Mansoor M. Amiji, "Nanodelivery of Molecular Therapies," Pharm. Technol. online exclusive, Dec. 2007, pharmtech.findpharma.com/pharmtech/Special+Report/Whats-Next-In-Drug-Delivery/ArticleStandard/Article/ detail/477141, accessed Sept. 7, 2009.

2. FDA, "Frequently Asked Questions on Nanotechnology," (Rockville, MD), www.fda.gov/ScienceResearch/SpecialTopics/Nanotechnology/FrequentlyAskedQuestions/default.htm, accessed Sept. 7, 2009.

3. L. Jia, "Global Investment in Nanotechnology," presented at the American Association of Pharmaceutical Scientists Annual Meeting, Atlanta, GA, November 2008.

4. M.D. Howard et al., "PEGylation of Nanocarrier Drug Delivery Systems: State of the Art," J. Biomedical Nanotechnol. 4 (2), 133–148 (2008).

5. T. Thomas and G. Foster, "Nanomedicines in The Treatment of Chronic Hepatitis C—Focus on Pegylated Interferon alpha-2a," Int. J. Nanomedicine.2 (1), 19–24 (2007).

6. D. Peer et al., "Nanocarriers as an Emerging Platform for Cancer Therapy," Nat. Nanotechnol. 2 (12), 751–760 (2007).