title: A prodrug-doped cellular Trojan Horse for the potential treatment of prostate cancer.
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.
authors.affiliation: 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.
authors.forename: Oren
authors.initials: O
authors.lastname: Levy
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, United States.
authors.forename: W Nathaniel
authors.initials: WN
authors.lastname: Brennen
authors.affiliation: 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.
authors.forename: Edward
authors.initials: E
authors.lastname: Han
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, United States.
authors.forename: David Marc
authors.initials: DM
authors.lastname: Rosen
authors.affiliation: 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.
authors.forename: Juliet
authors.initials: J
authors.lastname: Musabeyezu
authors.affiliation: 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.
authors.forename: Helia
authors.initials: H
authors.lastname: Safaee
authors.affiliation: 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.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Ranganath
authors.affiliation: 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.
authors.forename: Jessica
authors.initials: J
authors.lastname: Ngai
authors.affiliation: 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.
authors.forename: Martina
authors.initials: M
authors.lastname: Heinelt
authors.affiliation: 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.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Milton
authors.affiliation: Department of Oncology, Division of Biostatistics at the Sidney Kimmel Comprehensive Cancer Center, United States.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Sachin H
authors.initials: SH
authors.lastname: Bhagchandani
authors.affiliation: 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.
authors.forename: Nitin
authors.initials: N
authors.lastname: Joshi
authors.affiliation: The Samuel Oschin Comprehensive Cancer Institute at the Cedars-Sinai Medical Center, United States.
authors.forename: Neil
authors.initials: N
authors.lastname: Bhowmick
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, United States. Electronic address: denmesa@jhmi.edu.
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Denmeade
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, United States. Electronic address: isaacjo@jhmi.edu.
authors.forename: John T
authors.initials: JT
authors.lastname: Isaacs
authors.affiliation: 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.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Karp
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology; D008819:Mice, Nude; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011355:Prodrugs / Q000008:administration & dosage* / Q000627:therapeutic use; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D017430:Prostate-Specific Antigen
keywords: Cell-based drug delivery; Prostate cancer; Stem cells