Disulfide-containing polymer delivery of C527 and a Platinum(IV) prodrug selectively inhibited protein ubiquitination and tumor growth on cisplatin resistant and patient-derived liver cancer models

Kun Shang; Lingpu Zhang; Yingjie Yu; Haihua Xiao; Yajuan Gao; Liu Yang; Jia Huang; Haiqin Song; Hongbin Han

doi:10.1016/j.mtbio.2023.100548

Disulfide-containing polymer delivery of C527 and a Platinum(IV) prodrug selectively inhibited protein ubiquitination and tumor growth on cisplatin resistant and patient-derived liver cancer models

Mater Today Bio. 2023 Jan 13:18:100548. doi: 10.1016/j.mtbio.2023.100548. eCollection 2023 Feb.

Authors

Kun Shang¹, Lingpu Zhang², Yingjie Yu², Haihua Xiao³, Yajuan Gao^{4

5}, Liu Yang^{4

6}, Jia Huang⁷, Haiqin Song⁸, Hongbin Han^{4

9}

Affiliations

¹ Institute of Medical Technology, Peking University Health Science Center, Beijing, 100191, China.
² State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing, 100029, China.
³ Beijing National Laboratory for Molecular Science, State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Science, Beijing, 100190, China.
⁴ Department of Radiology, Peking University Third Hospital, Beijing, 100191, China.
⁵ NMPA key Laboratory for Evaluation of Medical Imaging Equipment and Technique, Beijing, 100191, China.
⁶ Beijing Key Laboratory of Magnetic Resonance Imaging Devices and Technology, Peking University Third Hospital, Beijing, 100191, China.
⁷ Department of Hepatobiliary Surgery, China-Japan Friendship Hospital, Beijing, 100029, China.
⁸ Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, 20023, China.
⁹ Peking University Shenzhen Graduate School, Shenzhen, 518055, China.

Abstract

USP1 (Ubiquitin-specific protease 1) is closely related to the prognosis of patients with liver cancer and plays an important role in DNA damage repair. C527 is a selective USP1 inhibitor (USP1i), which can regulate the protein ubiquitination to effectively inhibit the proliferation of cancer cells. However, its clinical application is hindered due to the poor water solubility and lack of tumor targeting. Moreover, the efficacy of single use of USP1i is still limited. Herein, a glutathione (GSH) sensitive amphiphilic polymer (poly (2-HD-co-HPMDA)-mPEG, PHHM) with disulfide bonds in the main chain was designed to encapsulate the USP1i as well as platinum (IV) prodrug (Pt (IV)-C12), resulting in the formation of composite nanoparticles, i.e., NP-Pt-USP1i. NP-Pt-USP1i can inhibit the DNA damage repair by targeting USP1 by the encapsulated USP1i, which ultimately increases the sensitivity of tumor cells to cisplatin and enhances the anti-cancer efficacy of cisplatin. Finally, an intraperitoneal tumor mice model and a patient-derived xenograft (PDX) of liver cancer mice model were established to prove that NP-Pt-USP1i could effectively inhibit the tumor growth. This work further validated the possibility of therapeutically target USP1 by USP1i in combination with DNA damaging alkylating agents, which could become a promising cancer treatment modality in the future.

Keywords: PDX model; Resistance of platinum drugs; Ubiquitination.