Hitting the target

Nanoparticulate drug delivery can target specific cells in the body, says Yates. "Engineering into the nanoparticle a strong specificity for certain types of cellular surface molecules allows for the provision of drug delivery to be specialized for a cell type," he explains. Thus, nanoparticles can be engineered to interact with specific organs, tissues, and even cells.

Nan says scientists can develop various linkers that enable nanoparticles to provide targeted drug delivery. One approach uses peptide linkers. The choice of the constituent amino acids depends on where the drug must be released. If a drug must be released inside a cell but be stable in the bloodstream, scientists can use a glycine–phenylalanine–leucine–glycine sequence. This sequence is stable in the blood, Nan says, because blood lacks the specific enzymes that lyse it.

Linkers that are susceptible to acid degradation can provide targeted delivery in certain applications. For example, the pH of the solution around a tumor is slightly more acidic than physiological pH, Nan explains. If a bond (e.g., an ester bond) is susceptible to hydrolysis, it becomes even more susceptible as the environmental acidity increases. A nanoparticle can be linked to a protein drug with such a bond. Thus a tumor can absorb a delivery mechanism, which becomes hydrolyzed in that acidic environment and releases the drug it carries. "You can get various degrees of controlled release just by changing the chemistry by which you attach your biomolecule to your macromolecular carrier," Nan says.

Because scientists can create nanoparticles that may specifically target certain cells, they also have the option of making a generic range of nanoparticle delivery systems for commonly targeted tissue types. "This method would reduce development costs significantly and provide a highly specific treatment," says Yates.

An additional benefit of a nanoparticle's ability to provide targeted drug delivery is the potential decrease in the side effects brought about by its biomolecular payload. "This decrease in side effects is of particular interest when dealing with the complex signaling problems involved with inflammation disorders and oncology diseases," Yates says.

Assuming control

Merrill Goldenberg, a scientific director at Amgen (Thousand Oaks, CA), notes that polymeric nanoparticles are also useful because scientists can change their properties to modify a drug's release profile. This technique can reduce bursts in dosage, for example.

QLT's (Vancouver, Canada) "Eligard" treatment for advanced prostate cancer is an example of this strategy. The active ingredient, leupromide (leutinizing hormone-releasing hormone) acetate, is comixed with the company's proprietary "Atrigel" copolymer. Atrigel is poly (DL-lactide-co-glycolide, PLGH), a biocompatible and biodegradable polymer that provides controlled release of leupromide. Eligard was first approved in 2002 in the United States and is also approved in seven other countries.

The protein must diffuse out of the polymer's matrix to reach its target. The polymer matrix can be tailored to release the protein over a period of days or months, says Yeh. This method of protein delivery provides more control than a bolus injection, which doesn't enable regulation of the drug release, he adds.

Sustained-release technology helps control the pharmacokinetic profiles and bioavailability of potent molecules needed in small concentrations. Cynthia Oliver, vice-president of process biochemistry and formulation sciences at MedImmune (Gaithersburg, MD), explains that polymers are used as a suspending matrix for encapsulated proteins. Biodegradable linkages allow polymers to release proteins through slow dissolution under physiological conditions. "It takes extensive experimentation to develop these technologies," she adds.

Nan describes a different way that polymeric nanoparticles can provide sustained release. Mucoadhesive polymers such as carbopol and polyacrylic acid increase the viscosity of a drug solution. Thus, when the drug is injected subcutaneously or transmitted intradermally through a patch, it forms a local depot that slowly releases the active molecule.

This method of sustained release reduces a drug's immunogenicity, Nan adds. If a drug is released at a fast rate in a local area, the body sends defense mechanisms such as macrophages or leukocytes to degrade the molecule. If the same molecule is released at a slow rate and does not exceed the minimum effective level in the blood, the body doesn't evoke that particular immune response. "It might be, over time, a lot more beneficial to release a lower concentration at a much slower rate," says Nan.

Companies that specialize in biopharmaceuticals are not the only ones that can produce polymeric nanoparticles. This delivery mechanism is produced by conventional processes typically found in most pharmaceutical companies, notes Frank Sorgi, vice-president of research and development at DPT (San Antonio, TX). "This factor allows the biologic API to be treated as if it were any other pharmaceutical," he says. Small-molecule companies and contractors routinely create nanoparticlate delivery systems, too.