Abstract A81: A novel nano-formulation for systemic administration of PARPi-olaparib (Nano-Olaparib) for radiosensitization, chemosensitization, and combinatorial therapy in prostate cancer.
Authors: Tangutoori Shifalika , Korideck Houari , Makrigiorgos Mike , Cormack Robert , Sridhar Srinivas 
Published: August 2014

Introduction: PARP (Poly ADP Ribose Polymerase) plays a crucial role in the DNA repair pathways in a cell. In cancer cells that often exhibit DNA repair, PARP can be deemed as the "Achilles Heel." Several PARP inhibitors (PARPi) are currently in clinical trials. Olaparib is the first inhibitor which is clinically proven to be the most potent and successful to date. Olaparib is an orally administered drug, which binds competitively to the NAD+ binding site of PARP, thus attenuating the DNA repair mechanisms mediated by PARP. Here we report a novel and well characterized "Nano-Olaparib," thus enabling a platform which can provide a safe vehicle for intravenous delivery specifically targeted to the tumor, thereby increasing the bioavailability. Our nanopaltform can also be tailored for the combinatorial drug delivery for both chemo and radiosensitization in prostate cancer.

Methods: A nanoparticle formulation Nano-Olaparib of the PARP inhibitor olaparib has been successfully formulated and tested in vitro. Initial studies showed that lipid based nanoparticles were better than polymer based nanoparticles to achieve the high loading efficiency needed. Cell viability of PC3 and VCaP after various treatments was determined by MTS assay. The effect of radiosensitization using 220 keV beam was studied for 2 Gy and 4 Gy radiation doses on all the treatment groups using MTS (2 days) and clonogenic assays (9 days).

Results: Our Nano-Olaparib formulation is defined by nanoparticles of 120 nm (mean diameter), ∼ +15mV (zeta potential), polydispersity index ∼0.05 and loaded with at clinically relevant concentrations of olaparib (400μM to 2.3mM). As determined by MTS assay immediately after irradiation, we observed that there is a ∼10% cell death with irradiation alone compared to the untreated cells. The effect of irradiation is observed to be the greatest with nanoolaparib treated cells (∼50 % cell death) compared with Olaparib (∼20% cell death). The long term effects of radiosensitization were also determined using the clonogenic assay. We observed a decrease in cell viability after radiation alone, at 2 Gy and 4 Gy. As expected, Olaparib showed a decrease in the cell viability, indicating a lasting effect of Olaparib on the cells, irrespective of radiation treatment. Nano-Olaparib (formulation ST-18-2) treated groups displayed higher susceptibility to radiosensitization at 2 Gy and 4 Gy, when compared with olaparib, where the maximum effect was observed at 4 Gy.

Conclusions: A robust nanoparticle formulation of the PARP inhibitor, Olaparib, has been successfully demonstrated. Both chemo sensitization and radio sensitization were studied in PC3, VCaP cell lines. Combinatorial administration of Nano (Olaparib+Cisplatin) showed greater cell death than Cisplatin alone or Cisplatin+Olaparib. The effect of radiosensitization with olaprib and Nano-Olaparib, was studied using 2 Gy and 4Gy radiation doses. We observed a significant enhancement in the cell killing ability (both immediate and delayed) with Nano-Olaparib when compared to olaparib alone. These results imply a very role for the Nano-Olaparib formulation as a chemo and radiosensitizer.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A81.

Citation Format: Shifalika Tangutoori, Houari Korideck, Mike Makrigiorgos, Robert Cormack, Srinivas Sridhar. A novel nano-formulation for systemic administration of PARPi-olaparib (Nano-Olaparib) for radiosensitization, chemosensitization, and combinatorial therapy in prostate cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A81.