iRGD peptide conjugation potentiates intraperitoneal tumor delivery of paclitaxel with polymersomes

  • Biomaterials. 2016 Oct:104:247-57. doi: 10.1016/j.biomaterials.2016.07.023.
Lorena Simón-Gracia  1 ,  Hedi Hunt  2 ,  Pablo Scodeller  3 ,  Jens Gaitzsch  4 ,  Venkata Ramana Kotamraju  5 ,  Kazuki N Sugahara  6 ,  Olav Tammik  7 ,  Erkki Ruoslahti  8 ,  Giuseppe Battaglia  9 ,  Tambet Teesalu  10
Affiliations
  • 1. Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 14b, 50411, Tartu, Estonia. Electronic address: [email protected].
  • 2. Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 14b, 50411, Tartu, Estonia.
  • 3. 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.
  • 4. Department of Chemistry, University College London, 20 Gordon Street, WC1H OAJ, London, UK; Department of Chemistry, University of Basel, Klingelbergstrasse 80, 4056, Basel, Switzerland.
  • 5. Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, 92037, CA, USA.
  • 6. 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.
  • 7. Department of Surgical Oncology, Tartu University Hospital, Puusepa 8, 50411, Tartu, Estonia.
  • 8. 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.
  • 9. Department of Chemistry, University College London, 20 Gordon Street, WC1H OAJ, London, UK.
  • 10. 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: [email protected].
PMID: 27472162 DOI: 10.1016/j.biomaterials.2016.07.023
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.

Keywords
NRP-1; Paclitaxel; Peritoneal carcinomatosis; Polymersomes; Tumor penetrating peptides; iRGD.
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