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

Leilei Guo1, Yurui Xu2, Anwei Zhou2

  • 1State 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.

Materials Science & Engineering. C, Materials for Biological Applications
|January 12, 2020
PubMed

Insights

Acquired resistance to doxorubicin (DOX) in cancer can be overcome by targeting MDM2-mediated p53 degradation. A novel pH-sensitive liposomal formulation (LipD/M@CMCS) containing DOX and an MDM2 inhibitor (MI-773) effectively reverses this resistance.

Area of Science:

  • Oncology
  • Drug Delivery
  • Molecular Biology

Background:

  • Drug resistance is a significant challenge in cancer therapy.
  • MDM2-mediated p53 degradation contributes to acquired resistance to doxorubicin (DOX).

Purpose of the Study:

  • To develop a pH-sensitive liposomal formulation of DOX and MI-773 (LipD/M@CMCS) to overcome DOX resistance in hepatocellular carcinoma.
  • To investigate the efficacy of targeting MDM2-p53 interaction for cancer treatment.

Main Methods:

  • Formulation of pH-sensitive liposomes (LipD/M@CMCS) with doxorubicin and MDM2 inhibitor MI-773.
  • Evaluation of liposome stability and tumor-specific drug release in acidic tumor microenvironments.
  • Assessment of cellular uptake, apoptosis induction, and tumor growth inhibition in HepG2 tumor spheroids.

Main Results:

  • LipD/M@CMCS demonstrated stability at pH 7.4 and rapid conversion to cationic liposomes at pH 6.5, enhancing tumor specificity and cellular uptake.
  • The formulation effectively induced apoptosis and significantly inhibited tumor growth in HepG2 tumor spheroids.
  • Minimal adverse effects were observed with the targeted delivery system.

Conclusions:

  • Targeting MDM2-mediated p53 degradation is a promising strategy to overcome doxorubicin resistance in cancer.
  • The pH-sensitive liposomal formulation (LipD/M@CMCS) offers a potential therapeutic approach for hepatocellular carcinoma management.
Keywords:
ChemotherapyDrug resistanceMDM2 inhibitorTumor spheroidspH sensitive delivery systems

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