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
Highlights
Chemotherapy remains the predominant therapy in cancer treatment due to its versatility and high efficiency [1,2,3,4]
Preparation and characterization of DHA dimeric NPs Firstly, the DHA2-SS was synthesized through the esterification reaction of DHA with dicarboxylic acid (Additional file 1: Fig. S1) [23]
From Gene Ontology (GO) and pathway analysis results, we discovered that the metabolic process was involved in the inhibition of tumor cells proliferation, we carried out network statistical analysis on the protein–protein interaction (PPI) of these genes correlated with metabolism
Summary
Introduction Currently, chemotherapy remains the predominant therapy in cancer treatment due to its versatility and high efficiency [1,2,3,4]. Some existing problems, for example strong hydrophobicity, nonspecific distribution, and rapid elimination from the body, impede the application of DHA in cancer treatment [10,11,12] To overcome these limitations, nano drug-delivery systems have been employed to increase the solubility, prolong systemic circulation, and promote passive tumor targeting owing to EPR effect [13,14,15,16,17]. A DHA dimer containing disulfide bond linker, which has been proven to possess dualresponsiveness [47,48,49], was designed and successfully synthesized, named as DHA2-SS This DHA dimer could self-assembly into nanoparticles (SS NPs) in aqueous media by nanoprecipitation method. Scheme 1 Schematic illustration of (a) the construction of disulfide bond linker-bridged dihydroartemisinin dimeric prodrug nanoparticles (SS NPs) and (b) their application for antitumor therapy and antitumor efficacy of SS NPs have been studied, and the gene expression of tumor cells after SS NPs treatment was analyzed by RNA-seq analysis (Scheme 1)
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