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Biomaterials. 2016 Jun;91:140-150. doi: 10.1016/j.biomaterials.2016.03.023. Epub 2016 Mar 17.

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

Author information

1
Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women's Hospital, United States; Harvard Medical School, United States; Harvard Stem Cell Institute, United States; Harvard - MIT Division of Health Sciences and Technology, United States.
2
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, United States.
3
Department of Oncology, Division of Biostatistics at the Sidney Kimmel Comprehensive Cancer Center, United States.
4
The Samuel Oschin Comprehensive Cancer Institute at the Cedars-Sinai Medical Center, United States.
5
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, United States. Electronic address: denmesa@jhmi.edu.
6
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, United States. Electronic address: isaacjo@jhmi.edu.
7
Division of Biomedical Engineering, Department of Medicine, Center for Regenerative Therapeutics, Brigham and Women's Hospital, United States; Harvard Medical School, United States; Harvard Stem Cell Institute, United States; Harvard - MIT Division of Health Sciences and Technology, United States. Electronic address: jeffkarp.bwh@gmail.com.

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.

KEYWORDS:

Cell-based drug delivery; Prostate cancer; Stem cells

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