IRGD peptide conjugation potentiates intraperitoneal tumor delivery of paclitaxel with polymersomes. (October 2016)

• Record Type: Journal Article
• Authors: Simón-Gracia, Lorena; Hunt, Hedi; Scodeller, Pablo; Gaitzsch, Jens; Kotamraju, Venkata Ramana; Sugahara, Kazuki N.; Tammik, Olav; Ruoslahti, Erkki; Battaglia, Giuseppe; Teesalu, Tambet
• Is Part Of: Biomaterials. Volume 104(2016)
• Page Start: 247
• Page End: 257
• Publication Date: 2016-10
• Subjects: Polymersomes -- Tumor penetrating peptides -- Peritoneal carcinomatosis -- Paclitaxel -- iRGD -- NRP-1; Biomedical materials -- Periodicals; Biocompatible Materials -- Periodicals; Biomatériaux -- Périodiques; 610.28
• DOI: 10.1016/j.biomaterials.2016.07.023
• Languages: English
• ISSNs: 0142-9612

Abstract

Abstract: Polymersomes are versatile nanoscale vesicles that can be used for cytoplasmic delivery of payloads. Recently, we demonstrated that pH-sensitive polymersomes exhibit an intrinsic selectivity towards intraperitoneal tumor lesions. A tumor homing peptide, iRGD, harbors a cryptic C-end Rule (CendR) motif that is responsible for neuropilin-1 (NRP-1) binding and for triggering extravasation and tumor penetration of the peptide. iRGD functionalization increases tumor selectivity and therapeutic efficacy of systemic drug-loaded nanoparticles in many tumor models. Here we studied whether intraperitoneally administered paclitaxel-loaded iRGD-polymersomes show improved efficacy in the treatment of peritoneal carcinomatosis. First, we demonstrated that the pH-sensitive polymersomes functionalized with RPARPAR (a prototypic CendR peptide) or iRGD internalize in the cells that express NRP-1, and that internalized polymersomes release their cargo inside the cytosol. CendR-targeted polymersomes loaded with paclitaxel were more cytotoxic on NRP-1-positive cells than on NRP-1-negative cells. In mice bearing peritoneal tumors of gastric (MKN-45P) or colon (CT26) origin, intraperitoneally administered RPARPAR and iRGD-polymersomes showed higher tumor-selective accumulation and penetration than untargeted polymersomes. Finally, iRGD-polymersomes loaded with paclitaxel showed improved efficacy in peritoneal tumor growth inhibition and in suppression of local dissemination compared to the pristine paclitaxel-polymersomes or Abraxane. Our study demonstrates that iRGD-functionalization improves efficacy of paclitaxel-polymersomes for intraperitoneal treatment of peritoneal carcinomatosis. Graphical abstract: