Background

Around 20,000 new cases of prostate cancer (PC) are diagnosed each year in Australia with 3000 deaths from the disease.  Presently, androgen deprivation therapy is the mainstay of treatment for metastatic disease however all patients eventually become androgen resistant and overall survivals are less than 3 years. MicroRNA (miRNA) has recently emerged as therapeutic target in a number of cancer models. However, one of the major obstacles for its use in vivo is its lack of tissue-specific delivery and the poor cellular uptake. The EnGeneIC delivery vehicles (EDVs) or minicells are nano-particles, produced as a result of abnormal bacterial cell division and coated with cancer cell specific antibodies allowing targeted systemic delivery of their payloads.

 Aims

To explore the utility of microRNA delivery to treat castration resistant prostate cancer (CRPC) using minicells delivery vehicle

 Methods

Two androgen resistant human PC cell lines, DU145 and PC3, were used to create PC xenograft mouse models.

 Results

miR-15a was significantly under-expressed in PCs. Our experiments demonstrated that approximately 10,000 copies of miR-15a can be loaded per minicell. In both DU-145 and PC3 xenograft models, miRNA15a-packaged minicells were injected via tail vein over a two- week period and showed significant tumour stabilization compared with the control group. Furthermore, in the PC3 xenograft model, the expression of mRNA targets of miR-15a, BCL2 (B-cell lymphoma 2) and WNT3A (wingless-type MMTV integration site family, member 3A), was significantly decreased in the xenografts of treatment group compared with that of the control group.

 Conclusion

In summary, we have demonstrated significant tumour effect and target knockdown in murine models of CRPC utilizing miRNA replacement therapy delivered with a targeted nanoparticle system. This study offers strong prospect of developing a new treatment modality for CRPC.