Biodegradable Nanoparticles for Safe Delivery of siRNA-Based Drugs

A team of biomedical engineers has developed a safe, biodegradable antiviral agent based on PLGA nanoparticles loaded with specific small interfering RNA (siRNA).

PLGA or poly(lactic-co-glycolic acid) has been successfully adapted as a biodegradable polymer because it undergoes hydrolysis in the body to produce the original monomers, lactic acid and glycolic acid. These two monomers are by-products of various metabolic pathways in the body, and since the body effectively deals with the two monomers, there is very minimal systemic toxicity associated with using PLGA for drug delivery or biomaterial applications. Due to these qualities of biodegradability and biocompatibility, the copolymer is now being used in many [U.S.] Food and Drug Administration (FDA) approved therapeutic devices, including grafts, sutures, implants, prosthetic devices, and in micro and nanoparticles.

Investigators from Yale University (New Haven, CT, USA) were hoping to capitalize on new developments in siRNA technology to develop a topical treatment for viral sexually transmitted diseases (STDs) such as AIDS, herpes, and HPV (human papillomavirus). While the use of liposomes to transport siRNA had been well documented, the inherent toxicity of the liposomes severely limited their use as therapeutic agents. To replace liposomes the investigators created PLGA nanoparticles that could be loaded with siRNA and would then slowly release the siRNA as the particles decomposed.

The investigators described in the May 3, 2009, online edition of the journal Nature Materials, a "proof-of-principle" study conducted on a mouse STD model. The siRNA was directed at a gene expressed widely in the lining of the female mouse reproductive tract. Results showed that a single dose of siRNA-loaded nanoparticles to the mouse female reproductive tract caused efficient and sustained gene silencing. The nanoparticles penetrated the surface mucosa to reach underlying cells and were disseminated throughout the vaginal, cervical, and uterine regions. The siRNAs remained in the tissues for at least a week, and knockdown of gene activity lasted up to 14 days.

While this study demonstrated that biodegradable polymer nanoparticles could be effective delivery vehicles for siRNA to the vaginal mucosa, a tremendous amount of work remains. Senior author Dr. W. Mark Saltzman, professor of biomedical and chemical engineering at Yale University, said, "Before human clinical testing can begin, our next step in research will be to test this approach directly in disease models--for example in the HIV model mice that have an immune system genetically identical to humans."

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