Topsalysin

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.

Endoscopic surgical treatment represents the gold standard in patients with lower urinary tract symptoms (LUTS) when medical treatment fails. In the past years there has been a growing interest in intraprostatic injections which represent a minimally invasive alternative for those patients not suitable for surgery. Aim of our study is to systematically review all the available data on intraprostatic injections for the treatment of LUTS patients with benign prostatic enlargement (BPE).

A systematic review of the literature using the Medline, Scopus and Web of Science databases for relevant articles published until June 2018 was performed using both the Medical Subjects Heading and free test protocols. The MeSH search was conducted by combining the following terms: "Intraprostatic Injections," "Botulinum Toxin A," "Onabotulinum," "Ethanol," "Lower Urinary tract Symptoms," "Benign prostatic enlargement," "Benign Prostatic Hyperplasia," "NX1207," "PRX302." Each article's title and abstract were reviewed for their appropriateness and their relevance with regards to the relationship to intraprostatic injections.

Intraprostatic injections for the treatment of LUTS/BPE patients may be performed using different products as: ethanol, onabotulinum toxin A, NX1207 and PRX 302. Ethanol, the first agent for intraprostatic use, showed promising results in prospective trials, however, the rare but serious adverse events associated with extraprostatic diffusion of ethanol stopped its use. Many studies on onabotulinum toxin A (BotoxR) have been performed, however, two large randomized clinical trials showed no differences in terms of symptoms improvements and flow improvements when compared to placebo. Two new promising drugs NX 1207 and PRX 302 have been developped in the past years. NX 1207 showed lack of efficacy in the two large European phase III RCT. PRX 302 showed promising results in phase I and II studies, however, definitive results from a large phase III randomized controlled trial (RCT) are awaited before drawing any definitive conclusions.

Intraprostatic injections are still to be considered investigational for the minimally invasive management of LUTS/BPE patients. Emerging data suggest a possible role of new agents in the near future when definitive data of ongoing RCTs will be available.