2. Academic Validation
  3. A Tumor-specific ROS Self-supply Enhanced Cascade-responsive Prodrug Activation Nanosystem for Amplified Chemotherapy against Multidrug-Resistant Tumors

A Tumor-specific ROS Self-supply Enhanced Cascade-responsive Prodrug Activation Nanosystem for Amplified Chemotherapy against Multidrug-Resistant Tumors

  • Acta Biomater. 2023 Apr 16;S1742-7061(23)00207-6. doi: 10.1016/j.actbio.2023.04.014.
Jing Wang 1,  Hanxi Zhang 1,  Jiazhen Lv 1,  Yue Zheng 1,  Mengyue Li 1,  Geng Yang 1,  Xiaodan Wei 1,  Ningxi Li 1,  Honglin Huang 1,  Tingting Li 1,  Xiang Qin 1,  Shun Li 1,  Chunhui Wu 1,  Wei Zhang 2,  Yiyao Liu 3,  Hong Yang 4
Affiliations

Affiliations

  • 1 Department of Orthopedics, Sichuan Provincial People's Hospital, and School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan, P.R. China.
  • 2 Department of Orthopedics, Sichuan Provincial People's Hospital, and School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan, P.R. China. Electronic address: [email protected].
  • 3 Department of Orthopedics, Sichuan Provincial People's Hospital, and School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan, P.R. China; TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, No. 39 Shi-er-qiao Road, Chengdu 610072, Sichuan, P.R. China. Electronic address: [email protected].
  • 4 Department of Orthopedics, Sichuan Provincial People's Hospital, and School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, Sichuan, P.R. China. Electronic address: [email protected].
PMID: 37072069 DOI: 10.1016/j.actbio.2023.04.014
Abstract

Chemotherapy remains the mainstay of Cancer treatment, and doxorubicin (DOX) is recommended as a first-line chemotherapy drug against Cancer. However, systemic adverse drug reactions and multidrug resistance limit its clinical applications. Here, a tumor-specific Reactive Oxygen Species (ROS) self-supply enhanced cascade responsive prodrug activation nanosystem (denoted as PPHI@B/L) was developed to optimize multidrug resistance tumor chemotherapy efficacy while minimizing the side effects. PPHI@B/L was constructed by encapsulating the ROS-generating agent β-lapachone (Lap) and the ROS-responsive doxorubicin prodrug (BDOX) in acidic pH-sensitive heterogeneous nanomicelles. PPHI@B/L exhibited particle size decrease and charge increase when it reached the tumor microenvironment due to acid-triggered PEG detachment, to favor its endocytosis efficiency and deep tumor penetration. Furthermore, after PPHI@B/L internalization, rapidly released Lap was catalyzed by the overexpressed quinone oxidoreductase-1 (NQO1) Enzyme NAD(P)H in tumor cells to selectively raise intracellular ROS levels. Subsequently, ROS generation further promoted the specific cascade activation of the prodrug BDOX to exert the chemotherapy effects. Simultaneously, Lap-induced ATP depletion reduced drug efflux, synergizing with increased intracellular DOX concentrations to assist in overcoming multidrug resistance. This tumor microenvironment-triggered cascade responsive prodrug activation nanosystem potentiates antitumor effects with satisfactory biosafety, breaking the chemotherapy limitation of multidrug resistance and significantly improving therapy efficiency. STATEMENT OF SIGNIFICANCE: Chemotherapy remains the mainstay of Cancer treatment, and doxorubicin (DOX) is recommended as a first-line chemotherapy drug against Cancer. However, systemic adverse drug reactions and multidrug resistance limit its clinical applications. Here, a tumor-specific Reactive Oxygen Species (ROS) self-supply enhanced cascade responsive prodrug activation nanosystem (denoted as PPHI@B/L) was developed to optimize multidrug resistance tumor chemotherapy efficacy while minimizing the side effects. The work provides a new sight for simultaneously addressing the molecular mechanisms and physio-pathological disorders to overcome MDR in Cancer treatment.

Keywords

Prodrug; cascade response; micelles; multidrug resistance; β-Lapachone.

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