Abstract
Abstract Purpose/Objective(s): Androgen deprivation therapy (ADT) has been a clinical standard of care for the treatment of castration sensitive prostate cancer (CSPC). However, it is not curative, and ADT has significant systemic effects including hot flashes, osteoporosis, anemia, etc. We sought to identify agents that would inhibit AR signaling without causing these systemic effects. Histone deacetylase inhibitors (HDACis) are attractive agents because they impede AR signaling and DNA damage repair in PCa and show epigenetic modifications in prostate cancer (PCa) development and progression. This study demonstrated romidepsin as an alternative to ADT and the development of a romidepsin encapsulated CSPC PCa targeted nanoparticle for PCa cell killing and growth inhibition without the toxicity associated with free romidepsin or ADT. Materials/Methods: Three PCa cell lines, LNCaP, 22Rv1 and PC3 that express different androgen receptor (AR) levels were used for this study. Cell viability was tested by real-time cell analysis (RTCA), protein expression by western blot analysis, and quantification of γ-H2AX double stranded DNA (dsDNA) breaks by immunofluorescent microscopy. We developed a poly (D,L-lactide-co-glycolide) (PLGA) and 1, 2-Distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol (DSPE-PEG) polymer-lipid nanoparticle coated with vipivotide tetraxetan(PSMA-617) for prostate specific membrane antigen (PSMA) targeting. Nanoparticles were characterized by transmission electron microscope (TEM), dynamic light scattering (DLS) analysis, and nanoparticle tracking analysis (NTA). Romidepsin encapsulation efficiency was quantified by high-performance liquid chromatography(HPLC). Results: RTCA showed free romidepsin inhibited cell growth in all three PCa cell lines in a dose dependent manner. The addition of ADT exhibited an additive effect with low romidepsin doses, but did not significantly improve cell growth inhibition when combined with high doses of romidepsin. Western blot and γ-H2AX foci staining confirmed that romidepsin inhibited AR signaling and increased dsDNA damage, respectively. HPLC showed nanoparticle encapsulated romidepsin of 0.7%wt and TEM/DLS/NTA showed a size of 130 ±20nm. Furthermore, PSMA-617 coated nanoparticles exhibited enhanced uptake in LNCaP cells compared to non-coated nanoparticles. Conclusion: Our study showed that the romidepsin has a dual effect on inhibiting AR signaling as well as downregulating DNA damage repair genes. Additionally, we developed a PCa targeted nanoparticle for specific PCa delivery of romidepsin. PSMA-targeted, romidepsin-encapsulated nanoparticles would reduce the systemic effects of free romidepsin and a potential replacement for ADT. Citation Format: Wendi Ma, Daiki Hara, Yu-Ping Yang, Olivia Yolande Bosquet, Wei Zhang, Emre Dikici, Huayang Feng, Tim Horton, Wensi Tao, Jessi Hersh, Junwei Shi, Sylvia Daunert, Sapna Deo, Alan Pollack. Prostate cancer androgen receptor signaling inhibition via romidepsin encapsulated lipid-polymer hybrid nanoparticle with PSMA617 targeting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1996.
