Abstract B29: Nanoformulations and sustained delivery systems for the PARP inhibitors Olaparib and Talazoparib

Abstract

Abstract Introduction: Poly(ADP-ribose) Polymerase (PARP) plays an important role in a number of DNA repair pathways. PARP inhibitors (PARPi) such as Olaparib and Talazoparib exploit the concept of synthetic lethality by selectively targeting cancer cells with defective DNA repair pathways. These drugs are currently only available in oral form which results in limited bioavailability, poor tumor accumulation, and systemic toxicity, specifically when combined with other DNA damaging agents. Here we report the development of two different delivery techniques including nanoformulations of Olaparib and Talazoparib and a biodegradable implant for localized delivery of Talazoparib. The nanoformulations allow for intravenous or intraperitoneal delivery, providing greater bioavailability and tumor accumulation, while limiting systemic toxicities and the implant provides a sustained release for intratumoral delivery to enhance the dose at the tumor site thereby limiting systemic toxicity. Methods: Nanoparticle formulations of Olaparib and Talazoparib were synthesized and characterized via TEM, DLS, and HPLC to elucidate size, loading, and release before testing in vivo. In vitro experiments for testing nanoformulations include dose response with a panel of ovarian cancer cell lines. In vivo, NanoOlaparib was tested in an IP spread model using 404 cells derived from BRCA2-/-, TP53-/-, PTEN-/- genetically engineered mouse models. Animals were treated IP with NanoOlaparib alone, and in combination with cisplatin. The 1-2 mm long Talazoparib implant was characterized with SEM and HPLC for structure, loading, and release. A spontaneous tumor forming breast cancer model was used to test the Talazoparib implant. Implants were directly injected into the tumor of Brca1Co/Co;MMTV-Cre;p53+/- mice for a one time treatment. Results: PA1 demonstrated high sensitivity to NanoOlaparib which may be attributed to genetic instability at 11/13 polymorphic loci. Both PTEN and BRCA deficiencies resulted in comparable IC50's likely due to synthetic lethality attributed to dysfunctional homologous recombination pathways. NanoTalazoparib is more potent than NanoOlaparib, resulting in a similar relationship in cell line sensitivity with overall lower IC50's. Bioluminescence images illustrated that NanoOlaparib administered IP daily in the ovarian cancer model resulted in a greater inhibition of tumor growth than those treated with oral Olaparib daily. The Talazoparib implant released therapeutically relevant doses of Talazoparib over multiple weeks. In vivo the implant reduced tumors 50% following the one time treatment, while untreated tumors increased significantly in size. Conclusions: Robust nanoparticle formulations of NanoTalazoparib and NanoOlaparib have been successfully developed and characterized. These results show that NanoOlaparib and NanoTalazoparib amplify the efficacy of PARP inhibitors in vivo. The Talazoparib implant provides a safe strategy for sustained local delivery of Talazoparib directly to the tumor. These strategies provide opportunities to increase the efficacy of PARP inhibitors via tailored delivery to the type of tumor. This work was supported by the DOD Ovarian Cancer Research Program under Army- W81XWH-14-1-0092 and IGERT grant NSF-DGE- 0965843. Citation Format: Paige Baldwin, Anders Ohman, Jodi Belz, Jeremy Thong, Noelle Castilla Ojo, Karen Liby, Daniela Dinulescu, Srinivas Sridhar. Nanoformulations and sustained delivery systems for the PARP inhibitors Olaparib and Talazoparib. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B29.