Cells Loaded with Prodrug-Containing Microparticles Selectively Destroy Prostate Cancer Tumors

A novel approach to treating metastatic prostate cancer with minimal adverse side effects is based on cellular transport of a harmless prodrug that is activated and becomes toxic only in the vicinity of the tumor microenvironment.

Investigators at Brigham and Women's Hospital (Boston, MA, USA) and colleagues at Johns Hopkins University (Baltimore, MD, USA) loaded human mesenchymal stem cells (MSCs) with poly(lactic-co-glycolic acid) (PLGA) microparticles (MPs) that encapsulated the macromolecule G114, a thapsigargin-based prodrug that was specifically activated by prostate specific antigen (PSA).

Thapsigargin, a sesquiterpene lactone extracted from a plant, Thapsia garganica is a non-competitive inhibitor of the sarco/endoplasmic reticulum Ca2+ ATPase. The drug raises cytosolic (intracellular) calcium concentration by blocking the ability of the cell to pump calcium into the sarcoplasmic and endoplasmic reticula. Thapsigargin specifically inhibits the fusion of autophagosomes with lysosomes; the last step in the autophagic process. The inhibition of the autophagic process in turn induces stress on the endoplasmic reticulum, which ultimately leads to cellular death.

The investigators reported in the March 17, 2016, online edition of the journal Biomaterials that G114-particles (approximately 950 nanometers in size) were internalized by MSCs, followed by the release of G114 as an intact prodrug from the loaded cells. G114 released from G114 MP-loaded MSCs selectively induced death of the PSA-secreting prostate cancer cell line, LNCaP.

G114 MP-loaded MSCs inhibited tumor growth when used in proof-of-concept co-inoculation studies with CWR22 prostate cancer xenografts, suggesting that cell-based delivery of G114 did not compromise the potency of this pro-drug in vitro or in vivo.

"The prodrug only becomes toxic in the presence of the tumor microenvironment, which adds another layer of specificity to this targeted delivery system," said contributing author Dr. John Isaacs, professor of urology and oncology at Johns Hopkins University.

"In cancer therapeutics, one of the great challenges is finding how to specifically deliver high doses of chemotherapeutics to a tumor, but minimize the systemic toxicity," said senior author Dr. Jeffrey Karp, associate professor of medicine at Brigham and Women's Hospital.

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