A prodrug-doped cellular Trojan Horse for the potential treatment of prostate cancer

• Published in: Biomaterials 2016-06, Vol.91, p.140-150
• Main Authors: Levy, Oren, Brennen, W. Nathaniel, Han, Edward, Rosen, David Marc, Musabeyezu, Juliet, Safaee, Helia, Ranganath, Sudhir, Ngai, Jessica, Heinelt, Martina, Milton, Yuka, Wang, Hao, Bhagchandani, Sachin H, Joshi, Nitin, Bhowmick, Neil, Denmeade, Samuel R, Isaacs, John T, Karp, Jeffrey M
• Format: Article
• Language: English
• Subjects: Advanced Basic Science; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - therapeutic use; Cancer; Cell Line, Tumor; Cell-based drug delivery; Cells, Cultured; Chemical compounds; Dentistry; Drug delivery systems; Drug Delivery Systems - methods; Drugs; Humans; Lactic Acid - chemistry; Macromolecules; Male; Malware; Mesenchymal Stem Cell Transplantation; Mesenchymal Stromal Cells - cytology; Mice, Nude; Platforms; Polyglycolic Acid - chemistry; Prodrugs - administration & dosage; Prodrugs - therapeutic use; Prostate; Prostate - drug effects; Prostate - metabolism; Prostate - pathology; Prostate cancer; Prostate-Specific Antigen - metabolism; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Stem cells
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2016.03.023

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 (∼950 nm 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.