Glucose-functionalized redox-responsive dihydroartemisinin prodrug nanosystem for targeted malaria therapy

Although malaria has been effectively controlled, it still poses a threat to global health. Artemisinins are the first-line antimalarial drugs. However, their therapeutic efficacy is significantly limited by poor solubility and short biological half-life. To overcome these limitations and enhance drug accumulation in Plasmodium, we developed a glucose-functionalized redox-responsive dihydroartemisinin (DHA) prodrug nanosystem (D@GLU-PMs-SS). The nanosystem was prepared by using DHA-dithiodipropionic acid-octadecylamine prodrug and D-α-Tocopherol polyethylene glycol 1000 succinate-arbutin conjugate. The resultant D@GLU-PMs-SS exhibited excellent stability under conditions of storage and physiological environment. D@GLU-PMs-SS could be activated by glutathione (GSH), leading to the dissociation of nanoparticles and subsequent release of free DHA. In vitro experiments revealed that the host erythrocyte uptake of glucose-functionalized nanoparticles was significantly enhanced via GLUT-mediated transport. Cellular experiments illustrated that D@GLU-PMs-SS effectively reduced GSH concentrations in Plasmodium. Furthermore, D@GLU-PMs-SS displayed remarkable efficacy in inhibiting the growth of Plasmodium while maintaining biosafety. Overall, this study developed a strategy to enhance the targeting of nanoparticles to improve their therapeutic efficacy against malaria, warranting further investigation in clinical trials.