Endothelial Thermotolerance Impairs Nanoparticle Transport in Tumors
Name
Lindquist_Endothelial thermotolerance.pdf
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1.14 MB
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Author(s)
Scherz-Shouval, R.
Galie, P. A.
Whitesell, L.
Chen, C. S.
Bagley, Alexander F
Zhang, Angela Q.
Wyckoff, Jeffrey
Lindquist, Susan
Bhatia, Sangeeta N
Date Issued
August 2015
Journal
Cancer Research
Publisher
American Association for Cancer Research
Citation
Bagley, A. F. et al. “Endothelial Thermotolerance Impairs Nanoparticle Transport in Tumors.” Cancer Research 75.16 (2015): 3255–3267.
Version
Author's final manuscript
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 endothelial model 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.
MIT Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Harvard University--MIT Division of Health Sciences and Technology
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1158/0008-5472.CAN-15-0325
