2. Academic Validation
  3. A stimuli-responsive combination therapy for recovering p53-inactivation associated drug resistance

A stimuli-responsive combination therapy for recovering p53-inactivation associated drug resistance

  • Mater Sci Eng C Mater Biol Appl. 2020 Mar;108:110403. doi: 10.1016/j.msec.2019.110403.
Leilei Guo 1,  Yurui Xu 2,  Anwei Zhou 2,  Lei Zhang 2,  Lei Sun 2,  Ya Gao 2,  Jianmei Chen 2,  Xue Shan 2,  Jikang Zhang 2,  Junliang Ge 2,  Xueying An 3,  Xiaoxuan Liu 4,  Yu Zhang 5,  Xinghai Ning 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, Center of Advanced Pharmaceutics and Biomaterials, China Pharmaceutical University, Nanjing 210009, China; National Laboratory of Solid State Microstructures, College of Engineering and Applied Sciences, Nanjing University, Nanjing 210093, China; Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing 210093, China.
  • 2 National Laboratory of Solid State Microstructures, College of Engineering and Applied Sciences, Nanjing University, Nanjing 210093, China; Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing 210093, China.
  • 3 Laboratory for Bone and Joint Diseases, Model Animal Research Center, Nanjing University, Nanjing 210093, China.
  • 4 State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, Center of Advanced Pharmaceutics and Biomaterials, China Pharmaceutical University, Nanjing 210009, China. Electronic address: xiaoxuanliucpu@163.com.
  • 5 National Laboratory of Solid State Microstructures, College of Engineering and Applied Sciences, Nanjing University, Nanjing 210093, China; Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing 210093, China. Electronic address: zhangyu2016@nju.edu.cn.
  • 6 National Laboratory of Solid State Microstructures, College of Engineering and Applied Sciences, Nanjing University, Nanjing 210093, China; Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing 210093, China. Electronic address: xning@nju.edu.cn.
PMID: 31923941 DOI: 10.1016/j.msec.2019.110403
Abstract

Drug resistance is a major hindrance in the Anticancer treatment, which encourages the development of effective therapeutic strategies. For the first time, MDM2-mediated p53 degradation was identified as a critical factor for developing acquired resistance of doxorubicin (DOX) in HepG2 tumor spheroids, which could be effectively reversed by MDM2 Inhibitor MI-773, thereby improving Anticancer effects. Therefore, a pH-sensitive liposomal formulation of DOX and MI-773 (LipD/M@CMCS) were developed for recovering p53-mediated DOX resistance in hepatocellular carcinoma. LipD/M@CMCS were composed of cationic liposomes covered with carboxymethyl chitosan (pI = 6.8), and were stable in the physiological condition (pH 7.4), but rapidly converted to cationic liposomes in tumor acidic microenvironment (pH 6.5), endowing them with tumor specificity and enhanced cellular uptake. We showed that LipD/M@CMCS could not only effectively induce cell Apoptosis in HepG2 tumor spheroids, but significantly inhibit tumor growth with minimal adverse effects. In summary, selective regulation of MDM2 in Cancer cells is a promising strategy to overcome DOX resistance, and may provide a perspective on the management of malignant tumors.

Keywords

Chemotherapy; Drug resistance; MDM2 inhibitor; Tumor spheroids; pH sensitive delivery systems.

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