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 re-exposure 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 (HSR), 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.

Tumour-on-a-chip: microfluidic models of tumour morphology, growth and microenvironment

“…Bagley et al demonstrated the use of plasmonic nanoantennae to enhance transport into a model of ovarian cancer via heat generation. They also used temperaturecontrolled microfluidic devices to measure diffusion of the nanoparticles in vitro [192]. The use of microfluidic devices to aid in the rapid development of translatable nanoparticles for TME studies is a very active and promising area of research.…”

Imaging the pharmacology of nanomaterials by intravital microscopy: Toward understanding their biological behavior

“…Vascular structure, perfusion, and permeability continue to be key features captured by IVM, and IVM studies have been useful in parsing the influence of various cell populations including perivascular VEGF+ macrophages [64]; therapeutic adjuvants such as anti-VEGF treatment [226], radiation [227], ultrasound [228], and hyperthermia [47,229,230]; and NP physicochemical features such as size [50,219] and shape [231] impact transport from vasculature to the target tissue. Reporter GEMMs enable clear and simultaneous visualization of vascularity, for instance using Tie2-GFP GEMMs [230], and neighboring cell populations.…”

“…Reporter GEMMs enable clear and simultaneous visualization of vascularity, for instance using Tie2-GFP GEMMs [230], and neighboring cell populations. As an example, a two-color GEMM that ubiquitously expresses membrane-anchored RFP, including in the endothelium, and GFP in CX3CR1+ phagocytes, was used to visualize NP transport from tumor vasculature to adjacent perivascular phagocytic cells [54].…”

“…As an example, a two-color GEMM that ubiquitously expresses membrane-anchored RFP, including in the endothelium, and GFP in CX3CR1+ phagocytes, was used to visualize NP transport from tumor vasculature to adjacent perivascular phagocytic cells [54]. Fluorescent dextran conjugates of various molecular weight are often used to measure vessel permeability in both cancer and inflammation, as was recently done in study of local tissue heating [230], local macrophage accumulation [64], allergan-induced permeability from IgE release [232], and interferon-gamma induced permeability in a model of colitis [233]. Increasing IVM resolution and stability have enabled much greater mechanistic insight into the causes of macromolecular or NP extravasation, with recent insight into the role of subcellular tumor-cell protrusions into vascular space [64] and highly dynamic bursts of NP extravasation that last under 30 min for smaller NPs [30].…”

Chemotaxis-driven assembly of endothelial barrier in a tumor-on-a-chip platform

“…Such microfluidic devices have been used to study various aspects of cancer progression such as tumor growth, presence of high interstitial fluid pressure, and cancer cell extravasation 18–24 . Such technological platforms have also been used to understand drug-tumor interactions such as drug specificity, penetration into cancer spheroids, and efficacy towards repressing cancer growth 20, 24–27 . Many of these platforms employ multi-layered or multi-channel devices to create a perfused tumor-a-on-chip system 18, 21, 25, 26 .…”