Co-Delivery of Glycyrrhizin and Paclitaxel via Gelatin-Based Core-Shell Nanoparticles Ameliorates 1,2-Dimethylhydrazine-Induced Precancerous Lesions in Colon.

Abstract

Colorectal cancer is a lethal malignancy that begins from acquired/inherent premalignant lesions. Thus, targeting these lesions at an early stage of the disease could impede the oncogenesis and maximize the efficacy. The present work underscores a combinatorial therapy of paclitaxel (PTX) and glycyrrhizin (GL) delivered via gelatin-derived core-shell nanoparticles [AC-PCL(GL + PTX)-GNPs] for effective management of precancerous lesions. The desolvation method was adopted to prepare GL-loaded gelatin nanoparticles (GL-GNPs), which were coated with PTX and AC-PCL. The prepared NPs exhibited optimal physical attributes and had spherical morphology, as analyzed by transmission electron microscopy and field-emission scanning electron microscopy. In vitro release studies revealed sustained release for ∼96 h. Cell culture studies in HTC 116, and HT-29 cells showed synergistic action with CI < 0.9 and DRI > 1. Moreover, AC-PCL(GL + PTX)-GNPs exhibited amplified intracellular uptake and thus significantly reduced IC₅₀. Pharmacokinetic studies revealed substantiated pharmacokinetic parameters (AUC_0-∞, C_max, etc.). In vivo studies in a 1,2-dimethyl hydrazine-induced model revealed a decrease in the number of lesions, mucin depletion, and subside infiltrations. An immunohistochemical study revealed elevated expression of caspase-9 and suppressed expression of VEGF and K_i-67. Toxicity studies showed insignificant changes in systemic biomarkers along with no alterations in organ morphology and hemocompatibility. In essence, AC-PCL(GL + PTX)-GNPs render a competent and safer tactic to regulate early-stage precancerous lesions.