Endothelial thermotolerance impairs nanoparticle transport in tumors

Alexander F. Bagley, Ruth Scherz-Shouval, Peter A. Galie, Angela Q. Zhang, Jeffrey Wyckoff, Luke Whitesell, Christopher S. Chen, Susan Lindquist, Sangeeta N. Bhatia

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

The delivery of diagnostic and therapeutic agents to solid tumors is limited by physical transport barriers within tumors, and such restrictions directly contribute to decreased therapeutic efficacy and the emergence of drug resistance. Nanomaterials designed to perturb the local tumor environment with precise spatiotemporal control have demonstrated potential to enhance drug delivery in preclinical models. Here, we investigated the ability of one class of heat-generating nanomaterials called plasmonic nanoantennae to enhance tumor transport in a xenograft model of ovarian cancer. We observed a temperature-dependent increase in the transport of diagnostic nanoparticles into tumors. However, a transient, reversible reduction in this enhanced transport was seen upon reexposure to heating, consistent with the development of vascular thermotolerance. Harnessing these observations, we designed an improved treatment protocol combining plasmonic nanoantennae with diffusion-limited chemotherapies. Using a microfluidic endothelialmodel and genetic tools to inhibit the heat-shock response, we found that the ability of thermal preconditioning to limit heat-induced cytoskeletal disruption is an important component of vascular thermotolerance. This work, therefore, highlights the clinical relevance of cellular adaptations to nanomaterials and identifies molecular pathways whose modulation could improve the exposure of tumors to therapeutic agents. Cancer Res; 75(16); 3255-67.

Original languageEnglish (US)
Pages (from-to)3522-3567
Number of pages46
JournalCancer Research
Volume75
Issue number16
DOIs
StatePublished - Aug 15 2015
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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