PSMA-specific theranostic nanoplex for combination of TRAIL gene and 5-FC prodrug therapy of prostate cancer

Abstract

Metastatic prostate cancer causes significant morbidity and mortality and there is a critical unmet need for effective treatments. We have developed a theranostic nanoplex platform for combined imaging and therapy of prostate cancer. Our prostate-specific membrane antigen (PSMA) targeted nanoplex is designed to deliver plasmid DNA encoding tumor necrosis factor related apoptosis-inducing ligand (TRAIL), together with bacterial cytosine deaminase (bCD) as a prodrug enzyme. Nanoplex specificity was tested using two variants of human PC3 prostate cancer cells in culture and in tumor xenografts, one with high PSMA expression and the other with negligible expression levels. The expression of EGFP-TRAIL was demonstrated by fluorescence optical imaging and real-time PCR. Noninvasive 19F MR spectroscopy detected the conversion of the nontoxic prodrug 5-fluorocytosine (5-FC) to cytotoxic 5-fluorouracil (5-FU) by bCD. The combination strategy of TRAIL gene and 5-FC/bCD therapy showed significant inhibition of the growth of prostate cancer cells and tumors. These data demonstrate that the PSMA-specific theranostic nanoplex can deliver gene therapy and prodrug enzyme therapy concurrently for precision medicine in metastatic prostate cancer.

Magnetic Resonance Imaging and Spectroscopy in Cancer Theranostic Imaging

“…17 Higher uptake of PSMA targeted particle was detected in PSMA overexpressing PC3-PIP human prostate cancer xenografts compared to isogenic low PSMA expressing PC3-Flu human prostate cancer xenografts, while there was no difference observed with non-targeted particle. 17 The PSMA targeting moiety has been used in separate studies in combination with the bCD-siRNA nanoplex described earlier to achieve PSMA specific delivery of siRNA or cDNA in combination with a prodrug enzyme in vivo 18 for theranostic imaging of prostate cancer. 18a …”

“…17 The PSMA targeting moiety has been used in separate studies in combination with the bCD-siRNA nanoplex described earlier to achieve PSMA specific delivery of siRNA or cDNA in combination with a prodrug enzyme in vivo 18 for theranostic imaging of prostate cancer. 18a …”

“…For instance, 19 F MRS was used to assess the activity of the prodrug enzyme bCD in the tumor after injection of the prodrug 5-FC, by following the conversion of 5-FC to cytotoxic 5-FU non invasively (Figure 6A-B). 13-14,18a 1 H MRS and MRSI can also be applied to assess treatment efficacy if the therapeutic target affects metabolites that can be measured by 1 H MRS. For example, total choline concentration can be measured in vivo , and by targeting the enzyme choline kinase with siRNA, the efficacy of siRNA-mediated downregulation of choline kinase can be assessed through its effect on decreasing total choline as shown in Figures 6C-D. 14, 18a …”

Delayed Progression of Lung Metastases Following Delivery of a Prodrug-activating Enzyme

“…Monoclonal antibodies conjugated to the enzyme, as well as viral vectors and non-viral vectors, have been used to achieve this goal (6-13). Recent studies have demonstrated prostate cancer cell-specific nanoparticle delivery of bCD to tumor xenografts by specific targeting of prostate-specific membrane antigen that resulted in improved tumor control (13,14) following localized conversion of 5-FC to 5-FU.However, many types of cancer do not express cancer cell-specific surface receptors or antigens, making it important to determine the effect of 5-FU formed from bCD in the absence of targeted delivery. The therapeutic effect of bCD/5-FC in a metastatic disease setting remains sparsely evaluated (15-17).…”

“…Monoclonal antibodies conjugated to the enzyme, as well as viral vectors and non-viral vectors, have been used to achieve this goal (6-13). Recent studies have demonstrated prostate cancer cell-specific nanoparticle delivery of bCD to tumor xenografts by specific targeting of prostate-specific membrane antigen that resulted in improved tumor control (13,14) following localized conversion of 5-FC to 5-FU.…”