Self-emulsifying Nano-PND oral delivery systems of PND1186: In silico modeling for bioavailability estimation

Abstract

Focal adhesion kinase (FAK) inhibitors have proven to aid the therapeutic potential of anti-cancer agents. PND1186 (PND) is a FAK inhibitor disrupting the oncogenic processes such as cell survival, proliferation, adhesion, migration and angiogenesis, as well as remodeling of tumor microenvironment. However, the pharmacological potential of PND is limited by its poor solubility and bioavailability due to rapid precipitation of weakly basic PND in the intestinal milieu. As a solution, we have developed a self-nanoemulsifying PND oral delivery system (NanoPODS) for rapid dissolution of PND while Soluplus containing system (NanoPODS-S) was prepared to prevent the precipitation of PND. Optimized NanoPODS-S depicted a particle size of 107.0 ± 3.6 nm, PDI of 0.223 ± 0.016, and a surface potential of -4.2 ± 0.007 mV, along with > 70% PND released at pH 6.8. In silico pharmacokinetics predicted 99% oral bioavailability for NanoPODS-S. This study evaluates the efficacy of NanoPODS and NanoPODS-S for improved oral bioavailability with better cytotoxicity efficacy on Pancreatic Ductal Adenocarcinoma (PDAC) cell lines. NanoPODS-S is the first of its kind, self-nanoemulsifying system containing a polymeric precipitation inhibitor mimicking a "spring-parachute effect". It will be a novel platform technology for rapid and enhanced dissolution of poorly soluble molecules.

Keywords: In silico modeling; Oral bioavailability; PND1186; Pancreatic Adenocarcinoma; Self-emulsifying Systems; Soluplus.