1. A prodrug-doped cellular Trojan Horse for the potential treatment of prostate cancer
- Author
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Oren Levy, Samuel R. Denmeade, Helia Safaee, Yuka Milton, Edward Han, Sachin Bhagchandani, David Marc Rosen, John T. Isaacs, Hao Wang, Sudhir H. Ranganath, W. Nathaniel Brennen, Martina Heinelt, Juliet Musabeyezu, Neil A. Bhowmick, Jeffrey M. Karp, Jessica Ngai, and Nitin Joshi
- Subjects
Male ,0301 basic medicine ,Cell ,Biophysics ,Mice, Nude ,Antineoplastic Agents ,Bioengineering ,Pharmacology ,Mesenchymal Stem Cell Transplantation ,Article ,Biomaterials ,03 medical and health sciences ,Prostate cancer ,chemistry.chemical_compound ,Drug Delivery Systems ,0302 clinical medicine ,Polylactic Acid-Polyglycolic Acid Copolymer ,Cell Line, Tumor ,LNCaP ,medicine ,Animals ,Humans ,Prodrugs ,Lactic Acid ,Cells, Cultured ,business.industry ,Mesenchymal stem cell ,Prostate ,Prostatic Neoplasms ,Mesenchymal Stem Cells ,Prostate-Specific Antigen ,Prodrug ,medicine.disease ,PLGA ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Mechanics of Materials ,030220 oncology & carcinogenesis ,Drug delivery ,Ceramics and Composites ,Stem cell ,business ,Polyglycolic Acid - Abstract
Despite considerable advances in prostate cancer research, there is a major need for a systemic delivery platform that efficiently targets anti-cancer drugs to sites of disseminated prostate cancer while minimizing host toxicity. In this proof-of-principle study, human mesenchymal stem cells (MSCs) were loaded with poly(lactic-co-glycolic acid) (PLGA) microparticles (MPs) that encapsulate the macromolecule G114, a thapsigargin-based prostate specific antigen (PSA)-activated prodrug . G114-particles (~950nm in size) were internalized by MSCs, followed by the release of G114 as an intact prodrug from loaded cells. Moreover, G114 released from G114 MP-loaded MSCs selectively induced death of the PSA-secreting PCa cell line, LNCaP. Finally, G114 MP-loaded MSCs inhibited tumor growth when used in proof-of-concept co-inoculation studies with CWR22 PCa xenografts, suggesting that cell-based delivery of G114 did not compromise the potency of this pro-drug in-vitro or in-vivo. This study demonstrates a potentially promising approach to assemble a cell-based drug delivery platform, which inhibits cancer growth in-vivo without the need of genetic engineering. We envision that upon achieving efficient homing of systemically infused MSCs to cancer sites, this MSC-based platform may be developed into an effective, systemic ‘Trojan Horse’ therapy for targeted delivery of therapeutic agents to sites of metastatic PCa.
- Published
- 2016