Polymer nanoparticles encapsulating siRNA for treatment of HSV-2 genital infection.
Effective, low-cost, and safe treatments for sexually transmitted viral infections are urgently needed. Here, we show for the first time that intravaginal administration with nanoparticles of poly(lactic-co-glycolic acid) (PLGA) encapsulating short interfering RNA (siRNA) molecules is effective for prevention of genital HSV-2 infections in mice. PLGA nanoparticles (NPs) were designed to interfere with HSV-2 infection by siRNA-mediated knockdown of nectin, a host cell protein. NPs were characterized in vitro to determine the optimal formulation based on siRNA loading, controlled release profile, and mRNA knockdown. Mice inoculated intravaginally with a lethal dose of HSV-2, and treated with PLGA NPs, showed increased survival from ~9 days (in untreated mice) to >28 days (in PLGA NP treated mice) - the longest survival ever observed with siRNA treatment in this mouse model. This work provides proof-of-concept that topical administration of NPs containing siRNA against a pathologically relevant host cell target can knockdown the gene in tissue and improve survival after HSV-2 infection. Furthermore, this system provides a safe delivery platform that employs materials that are already approved by the FDA and can be modified to enhance delivery of other microbicides.
Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
Jill M
JM
Steinbach
Caroline E
CE
Weller
Carmen J
CJ
Booth
W Mark
WM
Saltzman
D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics*; D004337:Drug Carriers / Q000737:chemistry; D005260:Female; D015316:Genetic Therapy; D006367:HeLa Cells; D006558:Herpes Genitalis / Q000235:genetics / Q000517:prevention & control*; D018258:Herpesvirus 2, Human / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry*; D000075983:Nectins; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use*
D015815:Cell Adhesion Molecules; D004337:Drug Carriers; D000075983:Nectins; D034741:RNA, Small Interfering; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid