title: iRGD peptide conjugation potentiates intraperitoneal tumor delivery of paclitaxel with polymersomes.
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.
authors.affiliation: Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 14b, 50411, Tartu, Estonia. Electronic address: Lorena.Simon.Gracia@ut.ee.
authors.forename: Lorena
authors.initials: L
authors.lastname: Simón-Gracia
authors.affiliation: Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 14b, 50411, Tartu, Estonia.
authors.forename: Hedi
authors.initials: H
authors.lastname: Hunt
authors.affiliation: Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 14b, 50411, Tartu, Estonia; Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, 92037, CA, USA.
authors.forename: Pablo
authors.initials: P
authors.lastname: Scodeller
authors.affiliation: Department of Chemistry, University College London, 20 Gordon Street, WC1H OAJ, London, UK; Department of Chemistry, University of Basel, Klingelbergstrasse 80, 4056, Basel, Switzerland.
authors.forename: Jens
authors.initials: J
authors.lastname: Gaitzsch
authors.affiliation: Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, 92037, CA, USA.
authors.forename: Venkata Ramana
authors.initials: VR
authors.lastname: Kotamraju
authors.affiliation: Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, 92037, CA, USA; Department of Surgery, Columbia University College of Physicians and Surgeons, New York, NY, USA.
authors.forename: Kazuki N
authors.initials: KN
authors.lastname: Sugahara
authors.affiliation: Department of Surgical Oncology, Tartu University Hospital, Puusepa 8, 50411, Tartu, Estonia.
authors.forename: Olav
authors.initials: O
authors.lastname: Tammik
authors.affiliation: Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, 92037, CA, USA; Center for Nanomedicine, Department of Cell, Molecular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, 93106, CA, USA.
authors.forename: Erkki
authors.initials: E
authors.lastname: Ruoslahti
authors.affiliation: Department of Chemistry, University College London, 20 Gordon Street, WC1H OAJ, London, UK.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Battaglia
authors.affiliation: Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 14b, 50411, Tartu, Estonia; Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, 92037, CA, USA; Center for Nanomedicine, Department of Cell, Molecular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, 93106, CA, USA. Electronic address: tteesalu@sbpdiscovery.org.
authors.forename: Tambet
authors.initials: T
authors.lastname: Teesalu
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry; D045744:Cell Line, Tumor; D004357:Drug Synergism; D007263:Infusions, Parenteral; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry; D058726:Nanoconjugates / Q000008:administration & dosage / Q000737:chemistry; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism*; D039942:Neuropilin-1 / Q000378:metabolism*; D009842:Oligopeptides / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D016896:Treatment Outcome
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C569656:N-end cysteine peptide tumor-homing peptide; D053769:Nanocapsules; D058726:Nanoconjugates; D009842:Oligopeptides; D011108:Polymers; D039942:Neuropilin-1; D017239:Paclitaxel
keywords: NRP-1; Paclitaxel; Peritoneal carcinomatosis; Polymersomes; Tumor penetrating peptides; iRGD