Design of targeted PLGA-SO3 nanoparticles encapsulating PARP and PD-L1 inhibitors for BRCA-mutated breast cancer therapy

Breast cancer (BC) is the most frequently diagnosed cancer and the second most common cause of cancer mortality in women worldwide. Approximately 15% of all BC are triple negative (TNBC), among them, 30% are BRCA1 or BRCA2 mutated. These tumors are highly aggressive and invasive. Recently, inhibition of poly(ADP-ribose)polymerase-1 (PARP1), a DNA repair enzyme, was shown to induce synthetic lethality in BRCA-mutated BC resulting in prolonged progression-free survival. This led to the FDA approval of PARP inhibitors (PARPi) for the treatment of BRCA-mutated BC. Despite their promise, resistance mechanisms to PARPi often develop affecting drug availability, (de)PARylation enzymes, restoration of Homologous Recombination (HR), or restoration of replication fork stability. Moreover, PARPi have been shown to have an impact on cancer-associated immunity, and their combination with immune checkpoint therapy (ICT) has been explored in clinical trials. Therefore, we aimed to rationally-design a nanomedicine combining PARPi with a programmed death-ligand 1 (PD-L1) inhibitor, an immunosuppressive checkpoint ligand inhibitor. We postulated that delivery of these therapeutic agents would result in enhanced therapeutic efficacy in BRCA-mutated cancers. We observed increased expression of PD-L1 following treatment with PARPi on EMT6, murine BRCA-mutated BC cell line. This was subsequently abrogated following treatment with a newly-synthesized PD-L1 inhibitor small molecule. Up to now, we encapsulated the two drugs in four types of PLGA NPs. As the EPR effect varies between tumor types, we synthesized NPs that actively target P-Selectin, an adhesion molecule expressed in our 3D EMT6 spheroids models. These nanocarriers were characterized and evaluated for their biocompatibility and capability to internalize into 3D cell culture models. Here, we will focus on the rational design and physico-chemico-biological characterization of precision nanomedicines combining PARPi with immunotherapy to treat this aggressive BC. Based on our previous experience with several drug combinations, we hypothesize that the proposed nanocarriers will increase the half-life of the encapsulated drugs, selectively target them to release the active compounds at the tumor site while reducing their side-effects.