Lipid and TPGS based novel core-shell type nanocapsular sustained release system of methotrexate for intravenous application

Abstract

Core shell nanocapsules present an interesting system for attaining high loading of drug. In an attempt, lipid and TPGS based novel core-shell nanocapsule were prepared to achieve high drug loading with sustained release of model hydrophilic drug methotrexate (MTX). Antisolvent nanoprecipitation was utilized for the formulation of nanoparticles. Optimized formulation depicted 223.6 ± 24.1 nm particle size, 0.243 ± 0.034 PDI, zeta potential -2.07 ± 0.51 mV and 15.03 ± 1.92%drug loading. In vitro release showed biphasic release for 12 h with initial burst phase followed by sustained release phase. Haemolytic study on RBCs revealed haemocompatible nature of MTX-TPGS nanoparticles compared to Biotrexate^® (Zydus). In vitro cell culture studies depicted 3 folds and 2.66 folds increase in cellular uptake of MTX at 10 μg/ml and 15 μg/ml respectively for developed nanoparticles with 3.81 folds decrease in IC₅₀ value as compared to Biotrexate^®. Higher apoptosis and increased lysosomal membrane permeability were also depicted by MTX-TPGS nanoparticles. 2.45 folds increase in AUC and 3.68 folds increase in T_1/2 was achieved in pharmacokinetic study. Significant reduction in tumor burden and serum biochemical parameters depicted efficacy and safety respectively of the formulation as compared to Biotrexate^®. RBCs morphology was retained after MTX-TPGS exposure proving its haemocompatibility in vivo.

Keywords: Core shell nanocapsule; Drug loading; Efficacy; Methotrexate; Reduced toxicity; Sustained release.