Endothelial Thermotolerance Impairs Nanoparticle Transport in Tumors
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; ... Show more Show less
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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.
Date issued
2015-08Department
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 MITJournal
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
ISSN
0008-5472
1538-7445