Design, Development and Characterization of Nanoparticulate Drug Delivery Systems for Targeted Delivery of Anticancer Agents

Abstract

Non-small cell lung cancer (NSCLC) is one of the most prevalent and deadliest forms of cancer. Despite being a potent anticancer agent, oncotherapy with currently marketed formulations of docetaxel (DT) is highly devalued by its poor bioavailability, resistance, non-specific cytotoxicity and severe side-effects. Nanoparticle assisted combination oncotherapy is one of the most cogent tools for empowering taxane-based oncotherapy. Ratiometric co-delivery of DT with natural NF-κB inhibitors like curcumin (CR) and propyl gallate (PG) can synergistically inhibit tumor proliferation through multi-molecular targeting at lower doses and also help overcome P-gp and MDR-mediated chemoresistance. The present research describes the development, optimization and characterization of PEGylated and folate conjugated nanostructured lipid carriers (NLCs) for targeted ratiometric co-delivery of DT with curcumin (DTCR-NLCs and FA-DTCR-NLCs) and propyl gallate (DTPG-NLCs and FA-DTPG-NLCs). The polysorbate-free NLCs were developed using a scaleable and solvent-free high pressure homogenization (HPH) technique and optimized employing suitable DoE approach. MTT cell viability analysis on NCI-H460 cells showed that the FA-DTCR-NLCs and FA-DTPG-NLCs have highest cytotoxicity amongst the pure drugs, synergistic drug combination ratio and unconjugated NLCs. The role of folate-receptor in endocytosis of FA-DTCR and FA-DTPG-NLCs was significantly increased AUC0-t (mg.h/l), MRT (h) and bioavailability of DT with FA-DTCR and FA-DTPG-NLCs as compared to their non-PEGylated counterparts and Taxotere®. In demonstrated significantly higher tumor regression with FA-DTCR-NLCs and FA-DTPGNLCs as compared to their PEGylated counterparts and Taxotere®. Tumor immunostaining with tumor differentiation biomarkers like, Ki67, p53, E-cadherin, and CD34 suggested considerably higher anti-proliferative, apoptotic, anti-metastatic and anti-angiogenic efficacy of FA-DTCR and FA-DTPG-NLCs as compared to PEGylated counterparts and Taxotere®. Hypersensitivity, hematological toxicity, hepatotoxicity or nephrotoxicity were not observed with the developed nanoformulations, suggesting their preeminence over Taxotere® for the treatment of NSCLC.