Reduction-sensitive platinum (IV)-prodrug nano-sensitizer with an ultra-high drug loading for efficient chemo-radiotherapy of Pt-resistant cervical cancer in vivo

Kejun Luo; Wenxuan Guo; Yanting Yu; Simeng Xu; Min Zhou; Keqi Xiang; Kun Niu; Xianqi Zhu; Guangying Zhu; Zheng An; Qingsong Yu; Zhihua Gan

doi:10.1016/j.jconrel.2020.06.005

Reduction-sensitive platinum (IV)-prodrug nano-sensitizer with an ultra-high drug loading for efficient chemo-radiotherapy of Pt-resistant cervical cancer in vivo

J Control Release. 2020 Oct 10:326:25-37. doi: 10.1016/j.jconrel.2020.06.005. Epub 2020 Jun 9.

Authors

Kejun Luo¹, Wenxuan Guo¹, Yanting Yu¹, Simeng Xu², Min Zhou¹, Keqi Xiang¹, Kun Niu¹, Xianqi Zhu¹, Guangying Zhu³, Zheng An⁴, Qingsong Yu⁵, Zhihua Gan⁶

Affiliations

¹ State Key Laboratory of Organic-Inorganic Composite Materials, Beijing University of Chemical Technology, Beijing 100029, China; Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China; College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China; Key Laboratory of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology), Ministry of Education, Beijing 100029, China.
² College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China.
³ Department of radiation oncology, China-Japan Friendship Hospital, Beijing 100029, China.
⁴ Proton therapy center, China-Japan Friendship Hospital, Beijing 100029, China.
⁵ State Key Laboratory of Organic-Inorganic Composite Materials, Beijing University of Chemical Technology, Beijing 100029, China; Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China; College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China; Key Laboratory of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology), Ministry of Education, Beijing 100029, China. Electronic address: yuqs@mail.buct.edu.cn.
⁶ State Key Laboratory of Organic-Inorganic Composite Materials, Beijing University of Chemical Technology, Beijing 100029, China; Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, China; Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, Beijing 100029, China; College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China; Key Laboratory of Biomedical Materials of Natural Macromolecules (Beijing University of Chemical Technology), Ministry of Education, Beijing 100029, China. Electronic address: zhgan@mail.buct.edu.cn.

PMID: 32531414
DOI: 10.1016/j.jconrel.2020.06.005

Abstract

Cisplatin is widely used in the chemoradiotherapy (CRT) of cervical cancers. However, despite the severe systemic side effects, the therapeutic efficacy of cisplatin is often compromised by the development of drug resistance, which is closely related to the elevated intracellular thiol-containing species (especially glutathione (GSH)) and the adenosine triphosphate (ATP)-dependent glutathione S-conjugate pumps. The construction of a safe and redox-sensitive nano-sensitizer with high disulfide density and high Pt(IV) prodrug loading capacity (up to 16.50% Pt and even higher), as described herein, is a promising way to overcome the cisplatin resistance and enhance the CRT efficacy. The optimized nanoparticles (NPs) (referred to as ^SSCV₅) with moderate Pt loading (7.62% Pt) and median size (c.a. 40 nm) was screened out and used for further biological evaluation. Compared with free cisplatin, more drugs could be transported and released inside the cisplatin resistant cells (Hela-CDDP) by ^SSCV₅ NPs. With the synergistic effect of GSH scavenging and mitochondrial damage, ^SSCV₅ NPs can easily reverse the cisplatin resistance. Moreover, the higher nucleus DNA binding Pt content of ^SSCV₅ NPs not only caused the DNA damage and apoptosis of Hela-CDDP cells but also sensitized these cells to X-Ray radiation. The in vivo safety and efficacy results showed that ^SSCV₅ NPs effectively accumulated inside tumor and inhibited the growth of cisplatin resistant xenograft models while alleviating the serious side effect associated with cisplatin (the maximum tolerated cisplatin equivalent of single injection is higher than 20 mg/kg body weight). The intervention of exogenous radiation further improved the anticancer efficacy of ^SSCV₅ NPs and caused the shrinkage of tumor volume, thus making this safe and facile nano-sensitizer a promising route for the neoadjuvant CRT of cervical cancers.

Keywords: Cervical cancer; Chemoradiotherapy; Cisplatin resistance; Glutathione; Pt(IV)-prodrug NPs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents*
Cell Line, Tumor
Chemoradiotherapy
Cisplatin
Female
Humans
Nanoparticles*
Platinum
Prodrugs*
Uterine Cervical Neoplasms* / drug therapy

Substances

Antineoplastic Agents
Prodrugs
Platinum
Cisplatin