title: Bioresorbable polymersomes for targeted delivery of cisplatin.
abstract: Nontoxic bioresorbable polymersomes have been developed that efficiently and site-selectively tether targeting peptides under mild conditions with no toxic catalysts. The binding and release properties of these polymersomes have been evaluated when targeting DLD-1 human colon cancer cells overexpressing the α(5)β(1) integrin. The delivery efficacy to these cells is markedly improved over commonly used RGD targeting peptides by use of an α(5)β(1)-specific targeting peptide, PR_b. Release profiles in buffered solution from pH 7.4 to 4.5 were evaluated and compared to release after binding to cells, and enzymatic degradation was identified as a major cause of rapid payload release in the cell. Intracellular trafficking and release were imaged via confocal microscopy in live cells and colocalization with organelles was evaluated quantitatively over time. Finally, the anticancer drug cisplatin was encapsulated in the PR_b functionalized polymersomes and the presence of PR_b greatly improved delivery efficacy, with increased cisplatin-induced losses to targeted DLD-1 colon cancer cell viability. When delivered to CACO-2 model human epithelial cells expressing low levels of α(5)β(1) integrin, low toxicity was maintained, suggesting that targeting was specific to α(5)β(1) overexpressing cells. These results demonstrate that PR_b-functionalized bioresorbable polymersomes may be an attractive route to minimizing the dose-limiting side effects associated with existing approaches to cisplatin chemotherapy.
authors.affiliation: Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Petersen
authors.forename: Marc A
authors.initials: MA
authors.lastname: Hillmyer
authors.forename: Efrosini
authors.initials: E
authors.lastname: Kokkoli
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D039081:Integrin alpha5beta1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011108:Polymers / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D039081:Integrin alpha5beta1; D011108:Polymers; D002945:Cisplatin