Abstract A031: Development of poly lactic acid based biodegradable nanoparticles for co-delivery of pirarubicin and gemcitabine for synergistic anti-tumor efficacy

Abstract

Abstract Nanoparticles based drug delivery systems have provided a befitted solution for the poor pharmacokinetic properties and systemic toxicity caused by the chemo drugs because of their ability to improve bioavailability of the drugs at the desired site and thereby decreasing extracellular toxicity. The present work investigates the single or dual chemo drugs loaded PLA-based biodegradable polymeric nanoparticles for improved anti-tumor efficacy as compared to free drug formulations. For the study, an amphiphilic block copolymer; mPEG PLA has been synthesized and characterized using Gel permeation chromatography (GPC) for its molecular weight and poly dispersity index as well as with Nuclear magnetic resonance (NMR) and Fourier-transform Infrared (FT-IR) spectroscopies. Thereafter, two different chemo drugs Pirarubicin (PIRA, THP analogue of Doxorubicin) and Gemcitabine (GEM) have been chemically conjugated individually to mPEG PLA block copolymer via a linker molecule, Levulinic acid to give an acid labile polymer-drug conjugate and the % drug conjugation efficiency has been calculated using High performance liquid chromatography (HPLC). The synthesized polymer-drug conjugates have been employed to prepare PIRA/GEM single or dual-loaded nanoparticles via nanoprecipitation technique and the physiochemical properties including size, zeta potential, and stability were analyzed using Dynamic Light Scattering (DLS) and High-resolution transmission electron microscopy (HR-TEM). To carry out toxicity assessment of the mPEG PLA nanoparticles, both cytocompatibility and hemocompatibility were checked using MTT assay and Hemolysis assay respectively. Moreover, the cellular internalization studies of dye-loaded mPEG PLA nanoparticles were done using Confocal microscopy on SUM-149, breast cancer cells.  Besides, the drug release kinetic studies of the free PIRA/GEM from the PIRA/GEM single or dual-loaded nanoparticles were carried out in different pH environments; pH 7.4 and pH 5.0. The in-vitro cell proliferation inhibition studies of PIRA/GEM or dual-loaded nanoparticles were carried out on different human and murine breast cancer cell lines including MCF-7, MDA-MB-468, SUM 149, MDA-MB-231 and 4T1 and half-maximal inhibitory concentrations (IC50 values) were compared to that of respective free drug formulations. The overall results suggested that the prepared sub-nano sized PIRA/GEM single or dual-loaded particles are highly stable, uniformly spherical in size and biocompatible in nature. They were found to possess high cellular uptake, sustained drug release rate and synergistic efficacy and potential against both human and murine breast cancer cells in-vitro conditions. Citation Format: Priya Gupta. Development of poly lactic acid based biodegradable nanoparticles for co-delivery of pirarubicin and gemcitabine for synergistic anti-tumor efficacy [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A031.