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Enzyme-instructed self-assembly of a novel histone deacetylase inhibitor with enhanced selectivity and anticancer

Yang Gao1, Congrou Zhang, Jinglin Chang

  • 1Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300192, China. renchunhua0815@126.com.

Biomaterials Science
|January 24, 2019
PubMed

Insights

This study introduces a novel peptide prodrug that enhances chemotherapy selectivity and reduces side effects. The innovative enzyme-instructed self-assembly (EISA) approach boosts anticancer efficacy at lower concentrations.

Area of Science:

  • Biomedical Engineering
  • Nanotechnology
  • Cancer Therapy

Background:

  • Improving chemotherapy drug selectivity and reducing side effects remain significant challenges in cancer research.
  • Enzyme-instructed self-assembly (EISA) offers a promising strategy for selective cancer therapy but often requires high concentrations for efficacy.
  • New approaches are needed to enhance the anticancer efficacy and selectivity of EISA-based therapies.

Purpose of the Study:

  • To design and synthesize a novel peptide-based prodrug, NapGDFDFpYSV, integrating EISA with the YSV anticancer peptide.
  • To investigate the prodrug's activity modulation via phosphorylation and subsequent dephosphorylation by alkaline phosphatase (ALP).
  • To evaluate the self-assembled nanodrug's efficacy, cellular uptake, and cytotoxicity in cancer cells overexpressing ALP.

Main Methods:

  • Synthesis of the peptide prodrug NapGDFDFpYSV with a masked tyrosine residue.
  • In situ dephosphorylation by alkaline phosphatase (ALP) to release the active monomer NapGDFDFYSV.
  • Investigation of self-assembly into nanostructures on the cell surface.
  • Assessment of cellular uptake, histone deacetylase (HDAC) activity, and cytotoxicity in ALP-overexpressing cells.

Main Results:

  • The prodrug NapGDFDFpYSV showed significantly reduced activity, restored upon ALP-catalyzed dephosphorylation.
  • The released monomer self-assembled into a nanodrug on the cell surface, enhancing cellular uptake.
  • The nanodrug exhibited selective high cytotoxicity towards ALP-overexpressing cells by targeting HDAC.
  • The effective cell inhibition concentration was substantially lower than the critical micelle concentration (CMC).

Conclusions:

  • The developed peptide prodrug effectively combines EISA with an anticancer peptide for enhanced therapeutic outcomes.
  • This strategy significantly improves the cytotoxicity selectivity and bioactivity of chemotherapy drugs.
  • The study presents a novel approach to boost the anticancer efficiency of EISA, offering a promising direction for cancer therapy development.

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