iRGD peptide conjugation potentiates intraperitoneal tumor delivery of paclitaxel with polymersomes

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• 作者：Lorena Sim&oacute ; n-Gracia^a ; ^{Lorena.Simon.Gracia@ut.ee" class="auth_mail" title="E-mail the corresponding author} ; Hedi Hunt^a ; Pablo Scodeller^a ; ^b ; Jens Gaitzsch^c ; ^d ; Venkata Ramana Kotamraju^b ; Kazuki N. Sugahara^b ; ^e ; Olav Tammik^f ; Erkki Ruoslahti^b ; ^g ; Giuseppe Battaglia^c ; Tambet Teesalu^a ; ^b ; ^g ; ^{tteesalu@sbpdiscovery.org" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Polymersomes ; Tumor penetrating peptides ; Peritoneal carcinomatosis ; Paclitaxel ; iRGD ; NRP-1
• 刊名：Biomaterials
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：104
• 期：Complete
• 页码：247-257
• 全文大小：3213 K

文摘

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.