Although it is important for blood vessels to maintain barrier function under most conditions, in cancer therapy, vascular permeability enhances drug delivery to tumors. Miller et al. used intravital microscopy and computational modeling to show that a single, low dose of radiation therapy could induce transient, dynamic, and localized vascular “bursting”—increased permeability, coinciding with extravasation of fluid, cells, and nanoparticles from blood vessels in tumors. Along with vascular bursting, radiation enlarged blood vessel volume and the number of tumor-associated macrophages in mouse xenografts and patient tumor biopsies. These tumor-associated macrophages took up drug-laden nanoparticles, inducing greater drug delivery to tumors. This study demonstrates an alternative strategy for improving targeted nanotherapy delivery by modifying the local tumor microenvironment rather than the nanoparticle itself.
Efficient delivery of therapeutic nanoparticles (TNPs) to tumors is critical in improving efficacy, yet strategies that universally maximize tumoral targeting by TNP modification have been difficult to achieve in the clinic. Instead of focusing on TNP optimization, we show that the tumor microenvironment itself can be therapeutically primed to facilitate accumulation of multiple clinically relevant TNPs. Building on the recent finding that tumor-associated macrophages (TAM) can serve as nanoparticle drug depots, we demonstrate that local tumor irradiation substantially increases TAM relative to tumor cells and, thus, TNP delivery. High-resolution intravital imaging reveals that after radiation, TAM primarily accumulate adjacent to microvasculature, elicit dynamic bursts of extravasation, and subsequently enhance drug uptake in neighboring tumor cells. TAM depletion eliminates otherwise beneficial radiation effects on TNP accumulation and efficacy, and controls with unencapsulated drug show that radiation effects are more pronounced with TNPs. Priming with combined radiation and cyclophosphamide enhances vascular bursting and tumoral TNP concentration, in some cases leading to a sixfold increase of TNP accumulation in the tumor, reaching 6% of the injected dose per gram of tissue. Radiation therapy alters tumors for enhanced TNP delivery in a TAM-dependent fashion, and these observations have implications for the design of next-generation tumor-targeted nanomaterials and clinical trials for adjuvant strategies.