A redox-responsive dihydroartemisinin dimeric nanoprodrug for enhanced antitumor activity

Abstract

Redox-responsive drug delivery system emerges as a hopeful platform for tumor treatment. Dihydroartemisinin (DHA) has been investigated as an innovative tumor therapeutic agent. Herein, a DHA dimeric prodrug bridged with disulfide bond as linker (DHA2-SS) has been designed and synthesized. The prepared prodrugs could self-assemble into nanoparticles (SS NPs) with high DHA content (> 90%) and robust stability. These SS NPs display sensitive redox responsive capability and can release DHA under the tumor heterogeneity microenvironment. SS NPs possess preferable antitumor therapeutic activity in contrast with free DHA. Moreover, the possible anti-cancer mechanism of SS NPs was investigated through RNA-seq analysis, bioinformatics and molecular biological method. SS NPs could induce apoptosis via mitochondrial apoptosis pathway, as well as glycolysis inhibition associate with the regulation of PI3K/AKT/HIF-1α signal path, which may offer an underlying therapeutic target for liver cancer. Our study highlights the potential of using redox responsive prodrug nanoparticles to treat cancer, meanwhile provides insights into the anti-cancer mechanism of DHA prodrug. Graphical Abstract

Self-assembly and self-delivery of the pure nanodrug dihydroartemisinin for tumor therapy and mechanism analysis

“…The instruments used in this work have been detailed in our previous work. 20–22,37 The Annexin V-FITC apoptosis detection kit was purchased from Shanghai Beyotime Biotechnology Co., Ltd. Ultrapure water was obtained from a Milli-Q system (Millipore, USA).…”

“…The experimental procedure is described in our previous work. 20–22,37 The experimental procedure in detail is shown in the ESI †…”

“…The protocol of mRNA library construction and Bioinformatics analysis were similar to those used in our previous work. 20–22,37 A detailed description of the protocol is shown in the ESI †…”

“…14–16 To overcome these shortcomings, considerable efforts have been dedicated to incorporating DHA into various nanomaterials. 17–22 Using these nanoplatforms, DHA can be efficiently delivered to the tumor site due to their enhanced permeability and retention (EPR) effect, thereby improving therapeutic efficiency and reducing side effects. Nevertheless, these reported nanoscale formulations always suffer from complicated preparation processes and relatively limited drug loading capacity.…”

Nanoscale dihydroartemisinin@zeolitic imidazolate frameworks for enhanced antigiardial activity and mechanism analysis

“…An antimalarial drug, artemisinin (ART), has been extracted from the Chinese plant Artemisia annua ( 8 , 9 ). In addition to high safety and antimalarial efficacy, ART has successfully treated many other parasitic infections, such as protozoan parasites that infect humans.…”