Preparation of GSH-responsive nanoparticles for combined chemo-photothermal therapy codelivering 6-MP and Ce6

Abstract

A glutathione (GSH)-responsive nano-drug delivery system combining photodynamic therapy (PDT) and chemotherapy (CT) was developed for lymphoma. The small-molecule reduction-sensitive 6-mercaptopurine (PTA) and photosensitizer chlorine6 (Ce6) were loaded onto carboxymethyl chitosan (CMCS), a biocompatible and water-soluble carrier. Through ultrasonic self-assembly, dual drug combination nanoparticles (CCP NPs) with an average particle size of 169 ± 1.9 nm in the water have been developed. PTA is sensitive to GSH and degrades quickly in tumor cells with high GSH levels, which causes the disintegration of nanoparticles and the release of 6-mercaptopurine (6-MP). Immediately thereafter, the Ce6 embedded in the nanoparticles was released to achieve sequential drug release. The PTA structure's Michael receptor significantly reduces GSH levels in tumor cells, which diminishes GSH's antioxidant influence on photosensitizers' ability to produce reactive oxygen species (ROS) and enhances PDT in a synergistic way. The CCP NPs revealed a nanometric size distribution, optimal surface charge and excellent stability. An in vitro toxicity study revealed that 6-MP and Ce6 exhibited strong selectivity (SI = 4.23) and a synergistic impact (CI = 0.23) on Black Burkitt's lymphoma cells (Raji cells). Research on drug delivery systems that combine Ce6 and 6-MP is a valuable new strategy for lymphoma.