Cabozantinib unlocks efficientin vivotargeted 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.

Design and Optimization of the Circulatory Cell-Driven Drug Delivery Platform

“…There are four cargo backpack methods. As shown in Figure 2 , these include electrostatic/hydrophobic interactions [ 51 ], ligand-receptor binding via receptors on cell membranes [ 52 ], biotin-avidin binding via biotinylated cell membranes [ 53 ], and covalent conjugation via chemical groups, such as thiols or amines, on the cell membrane [ 54 ], wherein the biotin-avidin and covalent conjugation are considered the strongest binding and have specific ligand-receptor recognition that has the potential for in vivo hitchhiking use [ 55 – 57 ].…”

“…Smith et al found that carbon nanotubes were taken up by 8 μ m circulating cells once injected into the blood [ 45 ]. Recently, Chaudagar et al observed a similar phenomenon wherein NEs were in vivo activated to internalize NPs (BSA-NP-cabozantinib) to assist drug delivery to lesions [ 55 ]. Kim et al further realized that, instead of being internalized directly by tumor cells, NPs could be first engulfed by local MAs [ 93 ].…”

In vivo hitchhiking of immune cells by intracellular self-assembly of bacteria-mimetic nanomedicine for targeted therapy of melanoma

“…The inflammation tropism–mediated active targeting of immune cells was attributed to the chemoattractant difference between the systemic circulation and disease site ( 20 ). Thus, inflammation plays an essential role for immune cell–based targeted delivery, and most of previous researches also took advantage of this special feature of immune cell to construct cell-based carriers for targeted delivery of therapeutic payloads ( 21 , 22 ). Although immune cells show better tumor targeting efficiency than traditional nanomedicine, the immune-suppressive microenvironment of tumor often leads to insufficient recruitment of immune cells carriers in the tumor ( 23 ).…”