siRNA-Based Carrier-Free System for Synergistic Chemo/Chemodynamic/RNAi Therapy of Drug-Resistant Tumors.
Yifan JiangYichang LiuMin WangZhi LiLichao SuXin XuChao XingJinyu LiLisen LinChunhua LuHuang-Hao YangPublished in: ACS applied materials & interfaces (2021)
Multiple drug-resistance mechanisms originate from defensive pathways in cancer and are associated with the unsatisfied efficacy of chemotherapy. The combination of small interfering RNA (siRNA) and chemotherapeutics provides a strategy for reducing drug efflux but requires more delivery options for clinical translation. Herein, multidrug resistance protein 1 (MDR1) siRNA is used as the skeleton to assemble chemotherapeutic cisplatin (CDDP) and divalent copper ion (Cu 2+ ) for constructing a carrier-free Cu-siMDR-CDDP system. Cu-siMDR-CDDP specifically responds and disassembles in the acidic tumor microenvironment (TME). The released CDDP activates cascade bioreactions of NADPH oxidases and superoxide dismutase to generate hydrogen peroxide (H 2 O 2 ). Then a Cu 2+ -catalyzed Fenton-like reaction transforms H 2 O 2 to hydroxyl radicals (HO • ) and causes glutathione (GSH) depletion to disrupt the redox adaptation mechanism of drug-resistant cancer cells. Besides, delivery of MDR1 siRNA is facilitated by HO • -triggered lysosome destruction, thus inhibiting P-glycoprotein (P-gp) expression and CDDP efflux. The unique design of Cu-siMDR-CDDP is to exploit siRNA as building blocks in regulating the self-assembly behavior, and integration of functional units simultaneously alleviates limitations caused by drug-resistance mechanisms. Such a carrier-free system shows synergistic chemo/chemodynamic/RNA interference therapy in suppressing tumor growth in vivo and has the reference value for overcoming drug resistance.
Keyphrases
- drug resistant
- cancer therapy
- multidrug resistant
- hydrogen peroxide
- acinetobacter baumannii
- drug delivery
- aqueous solution
- metal organic framework
- nitric oxide
- photodynamic therapy
- hyaluronic acid
- signaling pathway
- locally advanced
- poor prognosis
- emergency department
- stem cells
- combination therapy
- papillary thyroid
- binding protein
- wastewater treatment
- long non coding rna
- mouse model
- radiation therapy
- amino acid