Vascular changes in tumors resistant to a vascular disrupting nanoparticle treatment

Shweta Sharma, Aman P. Mann, Tarmo Mölder, Venkata Ramana Kotamraju, Robert Mattrey, Tambet Teesalu, Erkki Ruoslahti

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Anti-angiogenic and vascular disrupting therapies rely on the dependence of tumors on new blood vessels to sustain tumor growth. We previously reported a potent vascular disrupting agent, a theranostic nanosystem consisting of a tumor vasculature-homing peptide (CGKRK) fused to a pro-apoptotic peptide [D(KLAKLAK)2] coated on iron oxide nanoparticles. This nanosystem showed promising therapeutic efficacy in glioblastoma (GBM) and breast cancer models. However, complete control of the tumors was not achieved, and some tumors became non-responsive to the treatment. Here we examined the non-responder phenomenon in an aggressive MCF10-CA1a breast tumor model. In the treatment-resistant tumors we noted the emergence of CD31-negative patent neovessels and a concomitant loss of tumor homing of the nanosystem. In vivo phage library screening in mice bearing non-responder tumors showed that compared to untreated and treatment-sensitive tumors, treatment sensitive tumors yield a distinct landscape of vascular homing peptides characterized by over-representation of peptides that target αv integrins. Our approach may be generally applicable to the development of targeted therapies for tumors that have failed treatment.

Original languageEnglish (US)
Pages (from-to)49-56
Number of pages8
JournalJournal of Controlled Release
Volume268
DOIs
StatePublished - Dec 28 2017

Keywords

  • Drug resistance
  • Integrins
  • Phage display
  • Tumor angiogenesis
  • Tumor homing peptide

ASJC Scopus subject areas

  • Pharmaceutical Science

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