Behind the buzz and beyond the hype:
Our Nanowerk-exclusive feature articles
Posted: Jul 25, 2008
The current status of nanotechnology-based therapeutics in humans
(Nanowerk Spotlight) Modern pharmaceutics is a very imprecise, wasteful and sometimes even dangerous discipline. Not only do most drug candidates fail before they make it to market (about 80% of drug candidates fail clinical trials) but even the efficacy of many drugs that are being prescribed for certain diseases is questionable. The most important challenge in drug delivery is to deliver the correct dose of a particular therapeutic (pharmaceuticals, proteins, or nuclei acids) to a specific disease or tissue site. Since this is generally unachievable, therapeutics have to be administered in excessively high doses, thereby increasing the odds of systemic toxic side effects.
Nanotechnology offers great visions of improved, personalized treatment of disease. The hope is that personalized medicine will make it possible to develop and administer the appropriate drug, at the appropriate dose, at the appropriate time to the appropriate patient. The benefits of this approach are accuracy, efficacy, safety and speed.
Large pharmaceutical companies have yet to come to terms with the emerging nanomedicine landscape (see our Spotlight "Nanotechnology patents and the future of the pharma industry"). While nanomedicine potentially offers promising new value propositions and revenue streams, it also could completely displace certain classes of drugs. For example, currently-employed chemotherapeutic agents are being substituted with novel nanoparticle reformulations. However, nanoparticle-based drugs may pose an entirely new level of development challenges: The number of potential combinatorial variations that can be developed by choosing different nanoparticle core materials, targeting moieties, and payload molecules is very large which renders the problem of selecting the candidates for biological testing much more complex (see "Mathematical engines of nanomedicine").
Today, commercial nanomedicine is at a nascent stage of development and it’s full potential years or decades away. Currently, the most advanced area of nanomedicine is the development and use of nanoparticles for drug delivery.
The last few years saw tremendous progress in the use of nanoparticles to enhance the in vivo efficacy of many drugs. Pharmaceutical nanocarriers – liposomes, micelles, nanoemulsions, polymeric nanoparticles and many others – demonstrate a broad variety of useful properties, such as increased longevity in the blood, specific targeting to certain disease sites, or enhanced intracellular penetration.
Some of these pharmaceutical carriers have already made their way into clinics, while others are at the preclinical stage of drug development. There are two types of nanoparticle-based therapeutic formulations: those where the therapeutic molecules are themselves the nanoparticles (therapeutic functions as its own carrier); and those where the therapeutic molecules are directly coupled (functionalized, entrapped or coated) to a nanoparticle carrier. Since there is no universal convention or nomenclature that classifies nanoparticles, various nanoscale structures of different shape are sometimes potentially classified as nanoparticles. In fact, some of the common shapes include spheres (hollow or solid), tubules, particles (solid or porous), and tree-like branched macromolecules.
"All nanoparticulate nanomedicines currently on the market have been approved by the FDA (the U.S. Food and Drug Administration) according to pre-existing laws," Bawa tells Nanowerk. "Although the FDA has not required any special testing of nanoparticle-based therapeutics (e.g., with respect to their pharmacokinetic profiles), there are not many marketed nanoparticle-based therapeutics. This is an obvious consequence of the extremely complex and demanding requirements of clinical trials by the FDA. There are, however, numerous nanoparticle-based therapeutics under development."
In his survey, Bawa gives several specific examples of companies and their nanoparticulate drug products. The following descriptions are quoted from Bawa's survey:
Elan Corporation – NanoCrystal Technology
Because consumers prefer oral drugs over implantables or injectables, nano-engineering traditional or shelved compounds could greatly enhance oral bioavailability in some cases, says Bawa. A classic example of improving the bioavailability of poorly water-soluble drugs is Ireland-based Elan Corporation’s NanoCrystal technology. This technology is: (a) an enabling technology for evaluating new molecular entities that exhibit poor water solubility and/or (b) a valuable tool for optimizing the performance of current drugs.
Abraxis BioScience, Inc. – Paclitaxel-Albumin Nanoparticles
The company's Abraxane is an albumin-bound nanoparticle formulation of the widely used anticancer drug, Paclitaxel (Taxol). Bawa describes it as the only albumin-bound solvent-free taxane nanoparticulate formulation (∼130 nm) that takes advantage of albumin to transport Paclitaxel into tumor cells. It was approved by the FDA in 2005 for use in patients with metastatic breast cancer who have failed combination therapy. Because Abraxane is free of toxic solvents typically associated with other approved Paclitaxel preparations, there is no need for pre-medication with steroids or antihistamines often needed to prevent these side effects. Another advantage is that it is administered in 30 minutes, as compared to three hours for solvent-based Paclitaxel.
Nanospectra Biosciences – AuroShell Particles
AuroShell particles (previously known as Nanoshells) were developed by Drs. Naomi Halas and Jennifer West of Rice University in the 1990s. This eventually led to the formation of Nanospectra Biosciences. Formal operations began in 2002 to commercialize applications using AuroShell particles. Nanospectra has obtained FDA approval to commence human trial for the treatment of head and neck cancers. According to Nanospectra, AuroShell particles are a new type of optically tunable particles composed of a dielectric core coated with an ultra-thin metallic layer. For their oncology applications a silica core is surrounded by an ultra-thin gold shell (gold-coated glass nanoparticles).
Calando Pharmaceuticals, Inc. – RONDEL Technology
Calando Pharmaceuticals, Inc. is a privately held biopharmaceutical company funded by Arrowhead Research Corporation. The company has developed proprietary therapeutic cyclodextrin-containing polymer RNA interference (RNAi) delivery technology and demonstrated the first clear in vivo sequence-specific gene inhibition in tumors. Calando’s technology for RNAi is called RONDEL. Specifically, it employs small interfering RNA (siRNA) as the therapeutic RNA. Calando’s nanoparticle delivery system is designed for IV injection. According to the company, upon delivery of the RNA-containing nanoparticles, the targeting ligand binds to membrane receptors on the targeted cell surface enabling the nanoparticles to be taken up into the cell via endocytosis.
Starpharma Holdings Limited, a leader in the development of dendrimer nanotechnology products, is principally composed of two operating companies, Starpharma Pty. Ltd. and Dendritic Nanotechnologies, Inc. Products based on Starpharma’s dendrimer technology are already on the market in the form of diagnostic elements and laboratory reagents. Starpharma’s lead nanopharmaceutical development product is VivaGel (SPL7013 Gel) ,a dendrimer-based gel currently in phase 2 trials.
Mersana—Fleximer – Camptothecin Conjugate
Mersana Therapeutics, Inc. (formerly Nanopharma Corp.) is a privately held, venture backed company that utilizes its proprietary nanotechnology platform to transform existing and experimental anti-cancer agents into new, patentable drugs with superior pharmaceutical properties. Mersana’s key component of this platform is a “stealth” material derived from dextran called Fleximer. Fleximer is a biodegradable, hydrophilic and multivalent polymer that can be chemically linked to small molecules and biologics to enhance their pharmacokinetics and safety.
"So far, the process of converting basic research in nanomedicine into commercially viable products has been difficult," Bawa sums up the current status. "In the future, several variables will determine whether advances in the laboratory will translate into commercial products available in the clinic. Presently, multiple challenges and risks beset the commercialization of nanoparticle-based therapeutics." Among the risks that he lists are:
nanoparticle separation from undesired nanostructures like byproducts, catalysts, and starting materials;
scalability issues and enhancing the production rate;
reproducibility from batch to batch with respect to particle size distribution, charge, porosity, and mass;
high fabrication costs;
lack of knowledge regarding the interaction between therapeutic nanoparticles and living cells (the issue of biocompatibility and toxicity); and
big pharma’s reluctance to seriously invest in nanomedicine.
Nevertheless, it appears to be just a question of time when nanoparticle-based therapeutics will become an integral part of mainstream medicine and a standard in the drug industry.