title: Endothelial Thermotolerance Impairs Nanoparticle Transport in Tumors.
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.
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts. MD-PhD Program, Harvard Medical School, Boston, Massachusetts.
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Bagley
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Ruth
authors.initials: R
authors.lastname: Scherz-Shouval
authors.affiliation: Departments of Bioengineering and Physiology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Galie
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Angela Q
authors.initials: AQ
authors.lastname: Zhang
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Wyckoff
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Luke
authors.initials: L
authors.lastname: Whitesell
authors.affiliation: Departments of Bioengineering and Physiology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Chen
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts. Howard Hughes Medical Institute, Cambridge, Massachusetts.
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts. Howard Hughes Medical Institute, Cambridge, Massachusetts. Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts. Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts. Broad Institute, Cambridge, Massachusetts. Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. sbhatia@mit.edu.
authors.forename: Sangeeta N
authors.initials: SN
authors.lastname: Bhatia
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004317:Doxorubicin / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D006358:Hot Temperature; D006801:Humans; D006979:Hyperthermia, Induced; D053208:Kaplan-Meier Estimate; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008819:Mice, Nude; D016513:Mice, SCID; D008822:Mice, Transgenic; D053758:Nanoparticles / Q000008:administration & dosage / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin