Design, development, and evaluation of CDK-4/6 inhibitor loaded 4-carboxy phenyl boronic acid conjugated pH-sensitive chitosan lecithin nanoparticles in the management of breast cancer

Abstract

Our main aim to design and develop a novel 4-carboxy phenyl boronic acid (4-CPBA) conjugated Palbociclib (PALB) loaded pH-sensitive chitosan lipid nanoparticles (PPCL) to enhance the anti-cancer efficacy of the PALB in in-vitro cell line studies by loading into 4-CPBA conjugated chitosan lipid nanoparticles. 4-CPBA was conjugated to chitosan by carbodiimide chemistry and formation of conjugate was confirmed by 1HNMR, ATR-FTIR spectroscopic techniques. Ionic-gelation method was used for the fabrication of PPCL and particles size, PDI, zeta potential were found to be 226.5 ± 4.3 nm, 0.271 ± 0.014 and 5.03 ± 0.42 mV. Presence of pH-sensitive biological macromolecule i.e. chitosan in the carrier system provides pH-sensitivity to PPCL and sustainedly released the drug upto 144 h. The PPCL exhibited approximately 7.2, 6.6, and 5-fold reduction in IC50 values than PALB in MCF-7, MDA-MB-231 and 4T1 cells. Receptor blocking assay concluded that the fabricated nanoparticles were internalized into MCF-7 cells might be through sialic acid-mediated endocytosis. PPCL caused extensive mitochondrial depolarization, enhanced ROS generation, apoptosis (DAPI nuclear staining, acridine orange/ ethidium bromide dual staining), and reduced % cell migration than pure PALB. It was concluded that the hybrid lipid-polymer nanoparticles provides an optimistic approach for the treatment of breast cancer.