Specific targeting of adipose tissue-associated metastasis using bile salt nanoparticles.

Purpose: Mortality in ovarian cancer occurs in the setting of recurrent disease. Recurrent disease is known to arise from residual disease, which persists after the conclusion of standard of care, consequently rebuilding the tumor. Adipose tissue provides cancer cells with a unique microenvironment that can enhance survival by upregulating antiapoptosis genes or by decreasing drug bioavailability. Indeed, adipose-rich organs such as the omentum are not only preferential sites for metastasis but also main sites of residual disease in ovarian cancer. We hypothesized that targeting adipose-rich tissues could limit residual disease and prevent recurrence. Thus, the objective of this study was to develop effective drug delivery platforms that can specifically target residual disease in adipose-rich tissues. Methods: The delivery system is a nanoparticle platform composed of polymerized ursodeoxycholic acid (PUDCA) synthesized by esterification of UDCA monomer. Paclitaxel (PTX) or deep-infrared FL dye (DIR) was encapsulated to a final concentration of 24 ug or 5 mg per mg PUDCA, respectively. In vitro dose response studies were performed using mCherry+ human OCSC1-F2 ovarian cancer cells for 72 h. DMSO-resuspended PTX (DMSO-PTX) was used as control. In vivo studies were performed in athymic nude mice bearing i.p. tumors from mCherry+ OCSC1-F2 cells. For biodistribution studies, DIR-PUDCA was administered as one-time i.p. injection of 1.3 mg of DIR-PUDCA followed by ex vivo measurement of FL intensity after 14 days. DMSO-resuspended DIR (DMSO-DIR) was used as control. For efficacy studies, the groups were: (1) vehicle control; (2) taxol (PTX in Cremaphor; 12mg/kg) + DMSO-PTX (31.2 ug PTX); and (3) taxol + PUDCA-PTX. Treatment was administered i.p. twice a week for a total of 4 doses. Tumor burden and residual disease were determined by quantification of mCherry ROI FL area. Results: PUDCA-PTX demonstrated significantly improved efficacy both in vitro and in vivo. PUDCA-PTX demonstrated a six-fold reduction in in vitro GI50 compared to DMSO-PTX (23.04 nM PUDCA-PTX vs. 137.2 nM DMSO-PTX). Biodistribution studies showed delivery of DIR specifically to adipose-rich tissues (DIR mean FL intensity (MFI) for greater and lesser omentum = 76570±17808 vs. mesentery MFI = 22326±2956; p = 0.0297). Efficacy studies showed that PUDCA-PTX was significantly more effective in inhibiting tumor progression (p = 0.0191) and, more importantly, in preventing recurrent disease compared to DMSO-PTX. Finally, PUDCA-PTX was able to significantly reduce omental-residual disease compared to DMSO-PTX (p=0.049). Conclusion: We demonstrate for the first time that PUDCA is able to target residual disease localized in adipocyte-rich tissues and that this significantly delays tumor progression and prevents recurrence. These results underscore the value of i.p.-delivered PUDCA as a drug delivery platform for enhanced targeting of cancer cells within adipose-rich tissues and its value in the management of ovarian cancer patients. Citation Format: Roslyn Tedja, Ayesha B. Alvero, Jung Seok Lee, Mary Pitruzzello, Tarek Fahmy, Gil G. Mor. Specific targeting of adipose tissue-associated metastasis using bile salt nanoparticles [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A01.