Cabozantinib Unlocks Efficient In Vivo Targeted Delivery of Neutrophil-Loaded Nanoparticles into Murine Prostate Tumors
| العنوان: | Cabozantinib Unlocks Efficient In Vivo Targeted Delivery of Neutrophil-Loaded Nanoparticles into Murine Prostate Tumors |
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| المؤلفون: | Akash Patnaik, Wen Li, Natalie Landon-Brace, John G. Clohessy, Soumya Ullas, Aniruddh Solanki, Yue Shao, Devan J. Wilkins, Hanna M. Hieromnimon, Xiang-Ling Li, Kaela Bynoe, Jeffrey M. Karp, Emma Hegermiller, Kiranj K. Chaudagar, John Joseph |
| المصدر: | Molecular Cancer Therapeutics. 20:438-449 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Cabozantinib, medicine.drug_class, media_common.quotation_subject, Tyrosine-kinase inhibitor, 03 medical and health sciences, chemistry.chemical_compound, Prostate cancer, 0302 clinical medicine, In vivo, medicine, PTEN, Internalization, media_common, biology, technology, industry, and agriculture, Cancer, medicine.disease, 030104 developmental biology, Oncology, chemistry, 030220 oncology & carcinogenesis, Drug delivery, Cancer research, biology.protein |
| الوصف: | 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. |
| تدمد: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.mct-20-0167 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::3397fcbd9d98a44f6ab412ec2d1fce31 https://doi.org/10.1158/1535-7163.mct-20-0167 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi...........3397fcbd9d98a44f6ab412ec2d1fce31 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15388514 15357163 |
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| DOI: | 10.1158/1535-7163.mct-20-0167 |