title: Biodegradable Film for the Targeted Delivery of siRNA-Loaded Nanoparticles to Vaginal Immune Cells.
abstract: The goal of this study was to develop and characterize a novel intravaginal film platform for targeted delivery of small interfering RNA (siRNA)-loaded nanoparticles (NP) to dendritic cells as a potential gene therapy for the prevention of sexually transmitted human immunodeficiency virus (HIV) infection. Poly(ethylene glycol) (PEG)-functionalized poly(D, L-lactic-co-glycolic acid) (PLGA)/polyethylenimine (PEI)/siRNA NP (siRNA-NP) were fabricated using a modified emulsion-solvent evaporation method and characterized for particle size, zeta potential, encapsulation efficiency (EE), and siRNA release. siRNA-NP were decorated with anti-HLA-DR antibody (siRNA-NP-Ab) for targeting delivery to HLA-DR+ dendritic cells (DCs) and homogeneously dispersed in a biodegradable film consisting of poly vinyl alcohol (PVA) and λ-carrageenan. The siRNA-NP-Ab-loaded film (siRNA-NP-Ab-film) was transparent, displayed suitable physicomechanical properties, and was noncytotoxic. Targeting activity was evaluated in a mucosal coculture model consisting of a vaginal epithelial monolayer (VK2/E6E7 cells) and differentiated KG-1 cells (HLA-DR+ DCs). siRNA-NP-Ab were rapidly released from the film and were able to penetrate the epithelial layer to be taken up by differentiated KG-1 cells. siRNA-NP-Ab demonstrated higher targeting activity and significantly higher knockdown of synaptosome-associated 23-kDa protein (SNAP-23) mRNA and protein when compared to siRNA-NP without antibody conjugation. Overall, these data suggest that our novel siRNA-NP-Ab-film may be a promising platform for preventing HIV infection within the female genital tract.
authors.affiliation: Laboratory for Drug Delivery and Biomaterials, College of Pharmacy, Faculty of Health Sciences, University of Manitoba, 750 McDermot Avenue, Winnipeg, Manitoba Canada, R3E 0T5.
authors.forename: Jijin
authors.initials: J
authors.lastname: Gu
authors.affiliation: Laboratory for Drug Delivery and Biomaterials, College of Pharmacy, Faculty of Health Sciences, University of Manitoba, 750 McDermot Avenue, Winnipeg, Manitoba Canada, R3E 0T5.
authors.forename: Sidi
authors.initials: S
authors.lastname: Yang
authors.affiliation: Laboratory for Drug Delivery and Biomaterials, College of Pharmacy, Faculty of Health Sciences, University of Manitoba, 750 McDermot Avenue, Winnipeg, Manitoba Canada, R3E 0T5.
authors.forename: Emmanuel A
authors.initials: EA
authors.lastname: Ho
mesh_terms: D002351:Carrageenan / Q000737:chemistry; D002454:Cell Differentiation; D002470:Cell Survival; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy; D015658:HIV Infections / Q000517:prevention & control; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D011094:Polyethyleneimine / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D034741:RNA, Small Interfering / Q000235:genetics*; D050825:Synaptosomal-Associated Protein 25 / Q000037:antagonists & inhibitors* / Q000235:genetics; D014621:Vagina / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; C494208:SNAP25 protein, human; D050825:Synaptosomal-Associated Protein 25; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols; D002351:Carrageenan; D011094:Polyethyleneimine
keywords: SNAP-23; intravaginal delivery; microbicides; mucosal coculture model; polymeric film