2. Academic Validation
  3. Chitosan nanomedicine containing RGD peptide and PAD4 inhibitor based on phenyl boronate coupling inhibition of primary tumor growth and lung metastasis

Chitosan nanomedicine containing RGD peptide and PAD4 inhibitor based on phenyl boronate coupling inhibition of primary tumor growth and lung metastasis

  • Biomed Pharmacother. 2023 Dec:168:115826. doi: 10.1016/j.biopha.2023.115826.
Yijiang Jia 1,  Ayijiang Taledaohan 1,  Renbo Jia 1,  Xin Wang 1,  Yunshu Jia 1,  Jiawang Liu 2,  Yuji Wang 3
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmaceutical Sciences of Capital Medical University, 10 Xi Tou Tiao, You An Men, Beijing 100069, People's Republic of China; Department of Medicinal Chemistry, Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Beijing Laboratory of Biomedical Materials, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, 10 Xi Tou Tiao, You An Men, Beijing 100069, People's Republic of China.
  • 2 Medicinal Chemistry Core, Office of Research, University of Tennessee Health Science Center, Memphis, TN 38163, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA. Electronic address: jliu90@uthsc.edu.
  • 3 Department of Medicinal Chemistry, School of Pharmaceutical Sciences of Capital Medical University, 10 Xi Tou Tiao, You An Men, Beijing 100069, People's Republic of China; Department of Medicinal Chemistry, Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Beijing Laboratory of Biomedical Materials, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, 10 Xi Tou Tiao, You An Men, Beijing 100069, People's Republic of China. Electronic address: wangyuji@ccmu.edu.cn.
PMID: 37931514 DOI: 10.1016/j.biopha.2023.115826
Abstract

Stimulus-responsive nanodrugs have been extensively studied and their structural changes in the cells are important for controlled intracellular drug release. Histone citrullination of peptidylarginine deiminase 4 (PAD4) regulates the expression of tumor suppressor genes. In our previous study, compounds such as YW3-56 (356) were developed as potent PAD4 inhibitors with excellent anti-tumor activity in vitro and in vivo. To enhance the antitumor activity and improve the bioavailability, we further optimized the structure by modifying the phenylboronic acid moiety to the PAD4 inhibitor (4B). Taking advantage of the oxidative stress responsiveness of the phenylboronic acid moiety, in this study, we covalently attached 4B to RGD sequence peptide modified chitosan (K-CRGDV) to construct this new oxidative stress responsive nanodrug (K-CRGDV-4B). The modification of RGD sequence peptide conferred the nanodrug the ability to actively target tumors. The release mechanism was verified by UV-Vis spectroscopy, NMR. The anti-tumor and anti-metastatic properties of K-CRGDV-4B were demonstrated by in vitro cytotoxicity assay and in vivo mouse Lewis lung Cancer metastasis model. In addition, K-CRGDV-4B modulates the ratio of immune cells in LLC tumor-bearing mice. Immunosuppressive proteins such as PD1 were inhibited, while IFN-γ and IFN-β, which are stimulators of tumor immune responses, were upregulated. Overall, K-CRGDV-4B is a stimulus-responsive nanodrug that responds to the tumor microenvironment by inhibiting PAD4 activity, blocking the formation of neutrophil extracellular traps (NETs), and improving the tumor immune microenvironment.

Keywords

Oxidative stress responsive nanodrugs; Peptidyl arginine deiminase 4 (PAD4) inhibitors; Phenylboronic acid esters; RGD sequence peptides; Tumor immune microenvironment.

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