期刊
CANCER RESEARCH
卷 75, 期 16, 页码 3255-3267出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-15-0325
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资金
- Koch Institute Support Grant from the National Cancer Institute (Swanson Biotechnology Center) [P30-CA14051]
- Core Center from the National Institute of Environmental Health Sciences [P30-ES002109]
- Marie-D. & Pierre Casimir-Lambert Fund
- US National Institutes of Health [UH3 EB017103, R01 EB000262, U54CA151884]
- MIT-Harvard Center of Cancer Nanotechnology Excellence
- Harvard-MIT MD-PhD Program at Harvard Medical School
- MSTP grant from the National Institute of General Medical Sciences [T32GM007753]
- Human Frontiers Science Program
- Fulbright Program
- Israel National Postdoctoral Award Program for Women in Science
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. (C) 2015 AACR.
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