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

TL;DR

A glucose-coated nanosystem was developed to improve the targeting and effectiveness of antimalarial drugs.

Contribution

A redox-responsive prodrug nanosystem was created to enhance the targeting and efficacy of dihydroartemisinin against malaria.

Findings

The nanosystem effectively accumulates in Plasmodium via glucose transporters.

It degrades in a high glutathione environment, releasing dihydroartemisinin to kill parasites.

The system showed remarkable efficacy in inhibiting Plasmodium growth while maintaining biosafety.

Abstract

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.

D@GLU-PMs-SS was prepared through the nanoprecipitation method and subsequently administered intravenously to mice infected with Plasmodium. The nanoparticles were transported into the infective red blood cells and Plasmodium through glucose transporter (GLUT) and hexose transporter (HT). Following this, the prodrug nanoparticles degraded in the high glutathione (GSH) environment within Plasmodium, leading to the release of dihydroartemisinin (DHA). Ultimately, the intramolecular peroxide bridge of DHA generates reactive oxygen species (ROS) and depletes GSH levels, resulting in damage to the parasites.Unlabelled Image

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