Cabozantinib unlocks efficient in vivo targeted delivery of neutrophil-loaded nanoparticles into murine prostate tumors

Abstract

A major barrier to the successful application of nanotechnology for cancer treatment is the efficient delivery of therapeutic payloads to metastatic tumor deposits. We have previously discovered that cabozantinib, a tyrosine kinase inhibitor, triggers neutrophil-mediated anti-cancer innate immunity, resulting in tumor regression in an aggressive PTEN/p53-deficient genetically engineered murine model of advanced prostate cancer. Here, we specifically investigated the potential of cabozantinib-induced neutrophil activation and recruitment to enhance delivery of bovine serum albumin (BSA)-coated polymeric nanoparticles (NPs) into murine PTEN/p53-deficient prostate tumors. Based on the observation that BSA-coating of NPs enhanced association and internalization by activated neutrophils in vitro, relative to uncoated NPs, we systemically injected BSA-coated, dye-loaded NPs into prostate-specific PTEN/p53-deficient mice that were pre-treated with cabozantinib. Flow cytometric analysis revealed a 4-fold increase of neutrophil-associated NPs within the tumor microenvironment (TME) of mice pre-treated with cabozantinib relative to untreated controls. At steady-state, following 3 days of cabozantinib/NP administration, 1% of systemically injected dye-loaded NPs selectively accumulated within the TME of mice that were pre-treated with cabozantinib, compared to 0.11% uptake for mice that did not receive cabozantinib pre-treatment. Strikingly, neutrophil depletion with Ly6G antibody abolished NP accumulation in tumors to baseline levels, demonstrating targeted neutrophil-mediated NP delivery to the prostate TME. In summary, we have discovered a novel nano-immunotherapeutic strategy for enhanced intratumoral delivery of injected NPs, which results in significantly higher NP accumulation than reported strategies in the nanotechnology literature to-date.