title: Targeted polymersome delivery of siRNA induces cell death of breast cancer cells dependent upon Orai3 protein expression.
abstract: Polymersomes, polymeric vesicles that self-assemble in aqueous solutions from block copolymers, have been avidly investigated in recent years as potential drug delivery agents. Past work has highlighted peptide-functionalized polymersomes as a highly promising targeted delivery system. However, few reports have investigated the ability of polymersomes to operate as gene delivery agents. In this study, we report on the encapsulation and delivery of siRNA inside of peptide-functionalized polymersomes composed of poly(1,2-butadiene)-b-poly(ethylene oxide). In particular, PR_b peptide-functionalized polymer vesicles are shown to be a promising system for siRNA delivery. PR_b is a fibronectin mimetic peptide targeting specifically the α(5)β(1) integrin. The Orai3 gene was targeted for siRNA knockdown, and PR_b-functionalized polymer vesicles encapsulating siRNA were found to specifically decrease cell viability of T47D breast cancer cells to a certain extent, while preserving viability of noncancerous MCF10A breast cells. siRNA delivery by PR_b-functionalized polymer vesicles was compared to that of a current commercial siRNA transfection agent, and produced less dramatic decreases in cancer cell viability, but compared favorably in regards to the relative toxicity of the delivery systems. Finally, delivery and vesicle release of a fluorescent encapsulate by PR_b-functionalized polymer vesicles was visualized by confocal microscopy, and colocalization with cellular endosomes and lysosomes was assessed by organelle staining. Polymersomes were observed to primarily release their encapsulate in the early endosomal intracellular compartments, and data may suggest some escape to the cytosol. These results represent a promising first generation model system for targeted delivery of siRNA.
authors: Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, Minnesota 55455, United States.
authors: Todd O
authors: TO
authors: Pangburn
authors: Katerina
authors: K
authors: Georgiou
authors: Frank S
authors: FS
authors: Bates
authors: Efrosini
authors: E
authors: Kokkoli
mesh_terms: D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015220:Calcium Channels / Q000235:genetics* / Q000378:metabolism; D002214:Capsules; D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008081:Liposomes; D010455:Peptides / Q000737:chemistry; D011108:Polymers / Q000737:chemistry* / Q000378:metabolism; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics* / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D015220:Calcium Channels; D002214:Capsules; D008081:Liposomes; C522867:Orai3 protein, human; D010455:Peptides; D011108:Polymers; D034741:RNA, Small Interfering