Abstract
Chemo and siRNA synergic treatments for tumors is a promising new therapeutic trend. Selenocystine, a selenium analog of cysteine, has been considered a potential antitumor agent due to its redox perturbing role. In this study, we developed a nanocarrier for siRNA based on a selenocystine analog engineered polyetherimide and achieved traceable siRNA delivery and the synergic killing of tumor cells. Notably, we applied the label-free Schiff base fluorescence mechanism, which enabled us to trace the siRNA delivery and to monitor the selenocystine analogs’ local performance. A novel selenocystine-derived fluorescent Schiff base linker was used to crosslink the polyetherimide, thereby generating a traceable siRNA delivery vehicle with green fluorescence. Moreover, we found that this compound induced tumor cells to undergo senescence. Together with the delivery of a siRNA targeting the anti-apoptotic BCL-xl/w genes in senescent cells, it achieved a synergistic inhibition function by inducing both senescence and apoptosis of tumor cells. Therefore, this study provides insights into the development of label-free probes, prodrugs, and materials towards the synergic strategies for cancer therapy.
Highlights
Selenocystine (SeC) is a diselenide compound and selenium analog of cysteine but is more reactive than cystine due to the chemical property of selenium
Nanodelivery technology facilitates the synergetic therapy by both chemo agents and siRNA, which has been a promising new trend towards achieving better therapeutic effects and less drug resistance for multiple diseases [13,14,15,16]. siRNA-based therapeutics have rapidly crowed into clinical trials, and some of them have already been approved for the market due to the relatively higher specificity and ease of synthesis [17]
The lower molecular weight branched PEI exhibited a reduced cytotoxicity compared with linear PEI and was used to form the siRNA-PEI complex [25,26]
Summary
Selenocystine (SeC) is a diselenide compound and selenium analog of cysteine but is more reactive than cystine due to the chemical property of selenium. Selenocystine can be reduced by glutathione (GSH), thioredoxin reductase, or excess cysteine to highly reactive selenolate, which generates oxidative stress and perturbs redox homeostasis in the cell [9]. Emerging studies have demonstrated that novel nanotechbased strategies can robustly enhance drug and siRNA delivery, which offers synergetic treatment potentials for multiple diseases [19,20,21,22,23,24]. Cationic polymeric vectors are the most studied siRNA delivery vectors [25]. Difficulties, such as high cytotoxicity, low transfection efficiency, and uncontrollable and untraceable gene transfer, still hamper its progression into clinical applications of gene therapy [26]. The attainment of gene delivery systems that are safe, highly efficient, smart, and multiple-functional is imperative
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