March 15, 2005 (Vol. 25, No. 6)
Nanomaterials are More Than the Sum of Tiny Parts
Of the 2004 global investment of $8.6 billion in nanotechnology, the earliest real payoffs may come from the biotechnology and pharmaceutical industries.
Materials that exist in nanospace (generally defined as in the range of 100 nanometers to 0.1 nanometers) are not only smaller, but have entirely different physical and chemical properties than their more macro versions.
Nanotechnologies have enabled the development of entirely new drugs and altered the properties of already marketed drugs to create potentially safer, more directed, and effective pharmaceuticals. And pharmaceutical companies are pursuing collaborations with biotech and technology companies with nanotechnologies that can revitalize drug pipelines.
At the Center for Business Intelligence’s recent conference on “Nanoparticles for Biotechnology and Medical Applications,” participating companies described technologies for the creation of novel nanomaterials.
Five Star Technologies (Cleveland, OH) uses its proprietary Controlled Flow Cavitation to create nanoparticles and nano-scale dispersions, encapsulations, and emulsions. Five Star’s technology exploits and controls hydrodynamic cavitation, the formation, growth, and implosive collapse of vapor bubbles in a liquid created by fluid pressure changes.
Cavitation: Beyond Submarines
When this process occurs on a massive, uncontrolled scale (for example, close to rotating propeller blades on a submarine), it unleashes potentially destructive forces. Once under control, it can be used to create nano-sized crystals of pharmaceutically active compounds.
“Working with the Illinois Institute of Technology, we have to date created a model drug compound,” says Tim Fahey, Five Star’s vp of business development. “We expect that our controlled cavitation device should enable the development of novel drug dosages or controlled release forms of drugs.”
In addition, the technology also allows the introduction of encapsulants that surround the tiny drug crystals so they don’t reaggregate into bigger crystals.
Thus far, Five Star’s technology has been applied to the manufacture of a sprayable gel to treat sore throats in children and adults. The company is currently seeking partnerships with pharmaceutical manufacturers looking for unique delivery systems or drug excipient manufacturers with a product that could serve as part of a drug delivery platform.
Less Drug Toxicity
American Pharmaceutical Partners (APP; Schaumburg, IL) launched Abraxanean injectable suspension of paclitaxel-albumin nanoparticles for the treatment of advanced breast cancer.
Indicated for the treatment of this cancer after failure of combination chemotherapy for metastatic disease or relapse within six months of adjuvant chemotherapy, Abraxane was approved by the U.S. FDA in January.
The technology that allowed formulation of Abraxane, NAB (nanoparticle albumin-bound) was developed by American Bioscience (ABI; Santa Monica, CA), the majority shareholder in American Pharmaceutical Partners.
ABP, with the only commercial-scale manufacturing facility in the U.S. for NAB technology, exclusively licensed the manufacturing and marketing rights for Abraxane from ABI.
Because of its poor solubility, paclitaxel is currently combined with solvents for administration to patients. The solvents, detergent-like substances used to make hydrophobic substances more soluble, may themselves cause severe allergic reactions in patients and add to the toxicity of the active chemotherapeutic drug.
ABI’s technology combines paclitaxel with albumin formulated as a nanoparticle, about 1/100th the size of a red blood cell. This solvent-free formulation of a toxic drug may also take advantage of the albumin receptor-mediated drug transport system to more efficiently transport the active drug across the endothelial cell membranes of tumor blood vessels.
APP’s nanoparticle formulation is expected to allow delivery of a higher dose of paclitaxel over 30 minutes without steroid premedication and the toxicities associated with solvents usually administered with paclitaxel.
Small Sugar
Nanopharma (Boston) is an oncology company developing new therapeutics incorporating sugar-derived nano compounds.
Based on technology developed at the Massachusetts General Hospital by Misha Papisov, Ph.D., the company’s core technology, named Fleximer, is based on a proprietary biodegradable polymer that mimics the carbohydrates the body uses to shuttle materials such as proteins and small molecule drugs through the bloodstream to different organs.
According to Peter B. Leone, Nanopharma’s COO and former senior principal in PureTech Ventures, “Our scientific founder was looking for PEG replacements that could shield proteins and small molecules from rapid breakdown and that also breakdown into safe metabolic products.
“By combining our proprietary linker technology with our ability to produce nano-sized carbohydrate-like materials, we hope to considerably improve upon anticancer drugs.” Formulation using Fleximer is also expected to increase compound solubility and direct drugs to tumors instead of healthy tissues.
Nanopharma’s pipeline includes proprietary compounds with demonstrated human clinical efficacy in oncology. By applying its Fleximer technology to these drugs, the company believes it can improve drug bioavailability, metabolic stability, and therapeutic index as well as minimize liabilities associated with these drugs, such as toxicity.
“We are working with drugs in three areas and collaborating with the National Cancer Institute to develop other anticancer drugs,” Leone continued. NanoPharma expects to enter clinical trials late this year or early next year.
Improving Drug Solubility
According to Elan (Dublin, Ireland), its NanoCrystal technology provides an enabling method to develop new drug entities with poor solubility characteristics and improve the formulations and performance of existing drugs.
Elan’s NanoCrystal technology has been successfully used to develop two approved drugs and a third drug currently in Phase III clinical trials. Wyeth’s Rapamune (sirolimus), a nanocrystallized form of the immunosuppressant drug, received marketing approval in 2000.
Previously available only as a solution or sachet, the oral solution required refrigeration or mixture with water or orange juice prior to administration. Reformulation through nanocrystallization provided a more convenient solid-dose tablet formulation.
While Rapamune was a reformulation of an already existing drug, Merck & Co.’s (Whitehouse Station, NJ) Emend (aprepitant), a drug to control nausea and vomiting resulting from chemotherapy, was approved by the FDA in March 2003 and originally formulated as NanoCrystal drug particles.
NanoCrystal technology is also being used by Johnson & Johnson Research & Development (New Brunswick, NJ) in a Phase III clinical trial of a long-acting injectable formulation of its paliperidone palmitate in patients with schizophrenia.
Elan claims that its technology can be incorporated into all parenteral and oral dosage forms, including solid, liquid, fast-melt, pulsed release and controlled release.
NanoCrystallization works by increasing drug compound solubility. Poor water solubility slows drug dissolution in the body. By decreasing drug particle size, the surface area of the drug in contact with the solvent increases tremendously, thereby leading to an increase in dissolution.
NanoCrystal technology produces particles that are typically less than 1,000 nanometers in diameter, produced by what the company describes as a proprietary technique. NanoCrystal particles are stabilized against agglomeration into larger particles through surface adsorption of stabilizers, and then finished into final dosage forms.
Elan claims that nearly one half of the 150,000 new chemical entities synthesized annually by pharma companies are poorly soluble in water, and more than 10% of the Top 200 marketed drugs could be improved by increasing their solubility.
Unnatural Killer Cells
IMedd (Foster City, CA) is an early-stage biomedical company developing improved drug delivery and medical products based on bioMEMS, microfabrication, and nanotechnology.
The company developed NanoGATE, a small cylindrical implant inserted under the skin providing a continuous alpha interferon release for 36 months.
The implant is designed to maintain drug plasma levels consistently above 50 pg/mL to maintain an antiviral effect but at levels that do not cause acute side effects. Critical to the fabrication of NanoGate implants are NanoPORE membranes, silicon films with parallel rectangular channels arrays from 450 nm in diameter.
Fitted around the implants, 400 microliter reservoirs 12 cm long and 35 cm in diameter capped at both ends, the membranes control diffusion of drugs from the capsule, providing a continuous release of drug for from three to six months.
Frank Martin, Ph.D., IMedd’s principal scientist, described NK-Medds (microengineered drug delivery systems), microfabricated porous particles that combine features including targeting, detection, and drug transport and delivery.
IMedd describes these particles as synthetic mini cancer-cell-killing machines that bind to their targets via a specific ligand-receptor interaction, and then release a potent cytolysin into the target cell. NK-Medds consisted of silicon dioxide particles made in the 0.75 m range with pores in the nanometer range.
According to Charles Grove, IMedd president, “These particles are made porous so they are able to act like sponges. We can attach antibodies to them for targeting and fill them with a tumor-cell lytic agent. Currently we use Melittin (bee venom). This substance is released by the particle only upon contact with the target cell.”
IMedd has tested NK-Medds particles’ ability to specifically kill target cells in vitro. Particles coated with epidermal growth factor (EGF) and loaded with melittin were incubated with either target cells expressing EGF receptors or control cells without the receptor.
Over 95% of the targeted cells were killed, while less than 5% of the control cells were eradicated. “We are at a fairly early stage and need to show antitumor cytolytic activity in animals,” Grove notes.
Acute safety studies performed by the company in mice showed that solid, micro-fabricated 5-m disk-shaped particles did not produce acute toxicity at doses of up to one million particles per mouse.
