2. Academic Validation
  3. Bladder cancer selective chemotherapy with potent NQO1 substrate co-loaded prodrug nanoparticles

Bladder cancer selective chemotherapy with potent NQO1 substrate co-loaded prodrug nanoparticles

  • J Control Release. 2022 Jul;347:632-648. doi: 10.1016/j.jconrel.2022.05.031.
Binbin Jiao 1,  Kunpeng Liu 2,  Haitao Gong 2,  Zhenshan Ding 3,  Xin Xu 3,  Jian Ren 3,  Guan Zhang 4,  Qingsong Yu 5,  Zhihua Gan 6
Affiliations

Affiliations

  • 1 Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Department of Urology, China-Japan Friendship Hospital, Beijing, China.
  • 2 The State Key Laboratory of Organic-inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China.
  • 3 Department of Urology, China-Japan Friendship Hospital, Beijing, China.
  • 4 Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Department of Urology, China-Japan Friendship Hospital, Beijing, China. Electronic address: gzhang2016@sina.com.
  • 5 The State Key Laboratory of Organic-inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China. Electronic address: yuqs@mail.buct.edu.cn.
  • 6 The State Key Laboratory of Organic-inorganic Composites, Beijing Laboratory of Biomedical Materials, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China. Electronic address: zhgan@mail.buct.edu.cn.
PMID: 35618186 DOI: 10.1016/j.jconrel.2022.05.031
Abstract

Currently, clinical intravesical instillation chemotherapy has been greatly compromised by the toxicological and physiological factors. New formulations that can specifically and efficiently kill bladder Cancer cells are in urgent need to overcome the low residence efficiency and dose limiting toxicity of current ones. The combination of mucoadhesive nanocarriers and Cancer cell selective prodrugs can to great extent address these limitations. However, the insignificant endogenous stimulus difference between Cancer cells and normal cells in most cases and the high local drug concentration make it essential to develop new drugs with broader selectivity-window. Herein, based on the statistically different NQO1 expression between cancerous and normal bladder tissues, the Reactive Oxygen Species (ROS) activatable epirubicin prodrug and highly potent NQO1 substrate, KP372-1, was co-delivered using a GSH-responsive mucoadhesive nanocarrier. After endocytosis, epirubicin could be promptly activated by the NQO1-dependent ROS production caused by KP372-1, thus specifically inhibiting the proliferation of bladder Cancer cells. Since KP372-1 is much more potent than some commonly used NQO1 substrates, for example, β-lapachone, the cascade drug activation could occur under much lower drug concentration, thus greatly lowering the toxicity in normal cells and broadening the selectivity-window during intravesical bladder Cancer chemotherapy.

Keywords

Bladder cancer; Epirubicin prodrug; Intravesical instillation chemotherapy; KP372–1; NQO1.

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