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 suboptimal delivery of therapeutic payloads to metastatic tumor deposits. We previously discovered that cabozantinib, a tyrosine kinase inhibitor, triggers neutrophil-mediated anticancer 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 BSA-coated polymeric nanoparticles (BSA-NPs) into murine PTEN/p53-deficient prostate tumors. On the basis of the observation that BSA coating of NPs enhanced association and internalization by activated neutrophils by approximately 6-fold in vitro, relative to uncoated NPs, we systemically injected BSA-coated, dye-loaded NPs into prostate-specific PTEN/p53-deficient mice that were pretreated with cabozantinib. Flow cytometric analysis revealed an approximately 4-fold increase of neutrophil-associated BSA-NPs and an approximately 32-fold increase in mean fluorescent dye uptake following 3 days of cabozantinib/BSA-NP administration, relative to BSA-NP alone. Strikingly, neutrophil depletion with Ly6G antibody abolished dye-loaded BSA-NP accumulation within tumors to baseline levels, demonstrating targeted neutrophil-mediated intratumoral NP delivery. Furthermore, we observed an approximately 13-fold decrease in accumulation of BSA-NPs in the liver, relative to uncoated NPs, post-cabozantinib treatment, suggesting that BSA coating of NPs can significantly enhance cabozantinib-induced, neutrophil-mediated targeted intratumoral drug delivery, while mitigating off-target toxicity. Collectively, we demonstrate a novel targeted nano-immunotherapeutic strategy for enhanced intratumoral delivery of BSA-NPs, with translational potential to significantly augment therapeutic indices of cancer medicines, thereby overcoming current pharmacologic barriers commonly encountered in preclinical/early-phase drug development.

Versatile Design of Organic Polymeric Nanoparticles for Photodynamic Therapy of Prostate Cancer

“…(e) Concentration of DiO-OPNP was determined by the fluorescence method, and percentage of OPNP uptake was calculated according to the dose of OPNPs administered ( n = 3). Reproduced with permission from ref . Copyright 2021 American Association for Cancer Research.…”

“…91,92 Building on these findings, Chaudagar and colleagues conducted a study to enhance the targeted delivery of BSA-coated organic polymeric nanoparticles (BSA-OPNPs) to the prostate tumor region by inducing neutrophil activation and aggregation using cabozantinib. 93 To ensure that the internalization of OPNPs by neutrophils does not adversely affect their activation, researchers conducted an experiment in which neutrophils were incubated with varying amounts of DiR-loaded BSA-OPNP (10, 100, and 1000 μg) in 1.4 mL of conditioned medium. The results demonstrated that the binding of BSA-OPNPs did not alter neutrophil activation or function across a range of doses.…”

Targeting the innate immune system with nanoparticles for cancer immunotherapy

“…Therefore, a study also showed that bovine serum albumin (BSA)-coated polymeric nanoparticles (BSA-NPs) can significantly enhance cabozantinibinduced, neutrophil-mediated targeted intratumoral drug delivery. 214 Because inflammatory factors released after tumor resection guide the movement of the neutrophils into the inflamed brain, neutrophils carrying cationic liposomes that contain PTX (PTX-CL) have been shown to penetrate the brain and suppress the recurrence of glioma in mice whose tumors have been resected surgically. 215 The receptors for monomer of poly(sialic acid) (PSA) are expressed on peripheral blood neutrophils, and PSA-modified liposomes provide greater uptake to neutrophils than plain liposomes and PEGmodified liposomes; therefore, pro-PSA-octadecylamine conjugate anchored on the surface of liposomal pixantrone provided an increased accumulation of liposomes in peripheral blood neutrophils and enhance neutrophil-mediated pixantrone delivery for eradication of tumors.…”

Improving Outcomes of Tyrosine Kinase Inhibitors in Hepatocellular Carcinoma: New Data and Ongoing Trials

“…BSA-coated, dye-loaded nanoparticles were injected into prostate-specific PTEN/p53-deficient mice pretreated with cabozantinib. Their findings indicate that coating nanoparticles with BSA can improve cabozantinibinduced, neutrophil-mediated targeted intratumoral drug delivery while reducing off-target effects (55). The deliveries of apatinib and cediranib using polymeric nanoparticles were tested for osteosarcoma and glioblastoma, respectively.…”