Stimuli responsive Magnetic-Silica-Poly lactic-co-glycolic acid hybrid nanoparticles for targeted cancer chemo-immunotherapy

Abstract

Abstract Due to the emergence of drug resistance by tumor cells against chemotherapeutic agents by multiple mechanisms i.e. apoptosis suppression, alteration in drug metabolism and efflux mechanisms, epigenetic factors and DNA repair mechanism and T cells tolerance, there is necessity to develop combined therapeutic strategies employing chemotherapy and immunotherapies. To facilitate co-delivery of chemotherapeutic and immunotherapeutic agent to the target cancer cell, engineered nanoparticles are being developed. Herein, a pH-responsive polymer PLGA coated magnetic-silica nanoparticles (Fe3O4-SiO2-PLGA-PDA NPs) encapsulating paclitaxel (PTX) and siRNA against Programmed Cell Death Ligand-1 (PD-L1) are developed. The dual PTX+ PD-L1 siRNA NPs were synthesized in four steps, displayed characteristic peaks of iron oxide, silica, PLGA and PDA in infra-red spectroscopy and observed as ⁓230 nm spherical particles. These particles also demonstrated pH sensitive sustained drug release upto 10 days. In vitro 4T1 cell studies showed efficient cellular uptake, PD-L1 gene downregulation and apoptosis. Further, in vivo efficacy studies carried out in tumor bearing mice model demonstrated significantly reduction of the tumour growth following treatment with dual PTX+ PD-L1 siRNA NPs as compared to monotherapy with PTX NPs. The high therapeutic efficacy observed with dual PTX+PD-L1 siRNA NPs was mainly due to cytotoxic effect of PTX combined with targeted silencing of gene of interest; PD-L1 and increased sensitivity of cancer cells towards PTX killing. Thereby, dual PTX+PD-L1 siRNA NPs may have a promising anticancer treatment potential against breast cancer, however the beneficial effects of PTX+PD-L1 siRNA may be corroborated in lung, and colorectal cancer models as well as in clinical trials.