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 (~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.

Nanoparticle engineered TRAIL-overexpressing adipose-derived stem cells target and eradicate glioblastoma via intracranial delivery

“…Despite extensive preclinical documentation of the antitumor potential of TRAIL, studies in patients with cancer have demonstrated little efficacy. Potential reasons for the lack of clinical efficacy may include insufficient tumor exposure (16,17) and/or weak engagement of the extrinsic pathway (10,13). We have chosen membrane display of TRAIL, which could more faithfully mimic the endogenous ligand, and markedly augment receptor clustering and apoptosis stimulation in cancer cells (30,31).…”

“…By using stem cells as drug delivery vehicles, different biological drugs have been delivered, including chemotherapeutic agents, prodrugs (10)(11)(12)(13), and genetic signals (14). One limitation of delivering chemotherapeutic agents is that they generally could not differentiate cancerous cells from normal cells.…”

Concise Review: Mesenchymal Stem Cell-Based Drug Delivery: The Good, the Bad, the Ugly, and the Promise

“…Using in vitro co-culture assays, Pessina et al demonstrated that Paclitaxel-primed MSCs needed to represent 2%-33% of the culture to reach 90% cytotoxicity against various cancer cell lines depending on the sensitivity of each line to the drug [68]. In proof-of-principle in vivo studies, we have documented that MSCs loaded with microparticles encapsulating a PSA-activated prodrug are required to reach levels of $1%-10% to achieve a significant anti-tumor effect in a prostate cancer xenograft model [69].…”

Targeting the tumour stroma to improve cancer therapy

“…A novel strategy is the use of amniotic MSCs to deliver cytotoxic drugs to the tumour site 287 . MSCs from other origins can also be used; for example, a prodrug in which the active toxin Leu12ADT is released upon cleavage by prostate-specific antigen (PSA) was bound to microparticles that were coated onto bone marrow-derived MSCs and injected into mice, resulting in tumour shrinkage 288 . These strategies might be effective in clinical settings because MSCs tend to migrate towards areas of wound healing or tumour growth 289,290 .…”