Open AccessMicroparticle Encapsulation of a Prostate-targeted Biologic for the Treatment of Liver Metastases in a Preclinical Model of Castration-resistant Prostate Cancer
Author(s) -
Oliver C. Rogers,
Lizamma Antony,
Oren Levy,
Nitin Joshi,
Brian W. Simons,
Susan L. Dalrymple,
David Rosen,
Andrew Pickering,
Haoyue Lan,
Heidi Kuang,
Sudhir H. Ranganath,
Lei Zheng,
Jeffrey M. Karp,
S. Peter Howard,
Samuel R. Denmeade,
John T. Isaacs,
W. Nathaniel Brennen
Publication year - 2020
Publication title -
molecular cancer therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.717
H-Index - 173
eISSN - 1538-8514
pISSN - 1535-7163
DOI - 10.1158/1535-7163.mct-20-0227
Subject(s) - prostate cancer , du145 , cancer research , microparticle , metastasis , prostate , plga , in vivo , cancer , medicine , chemistry , pharmacology , in vitro , biology , lncap , biochemistry , microbiology and biotechnology , astrobiology
PRX302 is a highly potent, mutant bacterial pore-forming biologic protoxin engineered for selective activation by PSA, a serine protease expressed by benign and malignant prostate epithelial cells. Although being developed as a local therapy for benign prostatic hyperplasia and localized prostate cancer, PRX302 cannot be administered systemically as a treatment for metastatic disease due to binding to ubiquitously expressed glycosylphosphatidylinositol (GPI)-anchored proteins, which leads to poor accumulation within the tumor microenvironment. To overcome this limitation, poly-lactic-co-glycolic acid (PLGA) microparticles encapsulating the protoxin were developed, which are known to accumulate in the liver, a major site of metastasis for prostate cancer and other solid tumors. A highly sensitive and reproducible sandwich ELISA to quantify PRX302 released from microparticles was developed. Utilizing this assay, PRX302 release from different microparticle formulations was assessed over multiple days. Hemolysis assays documented PSA-dependent pore formation and lytic potential (i.e., function) of the released protoxin. MTT assays demonstrated that conditioned supernatant from PRX302-loaded, but not blank (i.e., unloaded), PLGA microparticles was highly cytotoxic to PC3 and DU145 human prostate cancer cells in the presence of exogenous PSA. Microparticle encapsulation prevented PRX302 from immediately interacting with GPI-anchored proteins as demonstrated in a competition assay, which resulted in an increased therapeutic index and significant antitumor efficacy following a single dose of PRX302-loaded microparticles in a preclinical model of prostate cancer liver metastasis with no obvious toxicity. These results document that PRX302 released from PLGA microparticles demonstrate in vivo antitumor efficacy in a clinically relevant preclinical model of metastatic prostate cancer.