Nanoparticle-mediated internal radioisotope therapy to locally increase the tumor vasculature permeability for synergistically improved cancer therapies

The limited tumor specific uptake of nanoparticles is one of major bottlenecks for clinical translation of nanoscale therapeutics. Herein, we propose a strategy using internal radioisotope therapy (RIT) delivered by liposomal nanoparticles to improve the tumor vasculature permeability, so as to increase the tumor specific uptake of the second-wave therapeutic nanoparticles for enhanced cancer therapies. Via a convenient method, a therapeutic radioisotope iodine-131 is labeled onto albumin-encapsulated liposomes with greatly improved radiolabeling stability compared to I-131-labeled albumin. The obtained I-131-liposome with long blood half-life could accumulate in the tumor and damage tumor blood endothelial cells to improve the tumor vascular permeability. As the result, the tumor retention of the second wave of liposomal nanoparticles could be greatly increased owing to the RIT-enhanced EPR effect. In three separated experiments, we then demonstrate that such strategy could be utilized for photothermal therapy (PTT), hypoxia-activated chemotherapy (HCT) and checkpoint blockade immunotherapy, all of which could be enhanced by RIT with excellent in vivo synergistic therapeutic outcomes. Our work highlights the great promises of employing nanoparticle-mediated RIT to modulate tumor vasculature for further enhanced cancer therapy, and may have potential value for clinical translation.