Controllable release of self-assembled reduction-sensitive paclitaxel dimer prodrug and tetrandrine nanoparticles promotes synergistic therapy against multidrug-resistant cancer

Xing Li; Zhen Qin; Qingmei Yuan; Yadong Song; Qinming Xu; Jingang Yang; Xiaocui Deng

doi:10.1016/j.bbagen.2023.130362

Controllable release of self-assembled reduction-sensitive paclitaxel dimer prodrug and tetrandrine nanoparticles promotes synergistic therapy against multidrug-resistant cancer

Biochim Biophys Acta Gen Subj. 2023 Jul;1867(7):130362. doi: 10.1016/j.bbagen.2023.130362. Epub 2023 Apr 7.

Authors

Xing Li¹, Zhen Qin², Qingmei Yuan³, Yadong Song², Qinming Xu⁴, Jingang Yang², Xiaocui Deng⁵

Affiliations

¹ School of Materials and Energy, National Center for International Research on Photoelectric and Energy Materials, Yunnan University, Kunming, Yunnan 650091, PR China. Electronic address: xingheli@mail.ynu.edu.cn.
² School of Materials and Energy, National Center for International Research on Photoelectric and Energy Materials, Yunnan University, Kunming, Yunnan 650091, PR China.
³ School of Materials and Energy, National Center for International Research on Photoelectric and Energy Materials, Yunnan University, Kunming, Yunnan 650091, PR China. Electronic address: qmyuan@ynu.edu.cn.
⁴ School of Materials and Energy, National Center for International Research on Photoelectric and Energy Materials, Yunnan University, Kunming, Yunnan 650091, PR China. Electronic address: xqm@mail.ynu.edu.cn.
⁵ School of Materials and Energy, National Center for International Research on Photoelectric and Energy Materials, Yunnan University, Kunming, Yunnan 650091, PR China. Electronic address: dengxc@mail.ynu.edu.cn.

PMID: 37031808
DOI: 10.1016/j.bbagen.2023.130362

Abstract

Background: Multidrug resistance (MDR) is the main reason for chemotherapy failure. Nanocarriers combined delivery of anti-cancer drugs and MDR inhibitors is an effective strategy to avoid MDR and improve the anti-cancer activity of drugs.

Methods: Two paclitaxel (PTX) molecules are linked by disulfide bonds into PTX₂. Then, the PTX₂ and tetrandrine (TET) are coated together by mPEG-PLGA self-assembled NPs for combinational treatment. Microstructure, physiological stability, and cytotoxicity are characterized for the co-loaded NPs.

Results: The NPs exhibit excellent suitability and blood safety for intravenous injection, specifically responsive to pH 6-7, and promptly initiate chemical degradation. Ex vivo fluorescence microscopy image studies indicate that co-loaded NPs increase drug penetration into cancer cells compared with free drugs. MTT assay demonstrates that co-loaded NPs have higher cytotoxicity against HeLa and the flow cytometric analysis shows that co-loaded NPs trigger more apoptosis than the free drugs. Reactive oxygen species (ROS) assay indicates that the drug-loaded NPs generated higher levels of ROS to accelerate apoptosis in HeLa cells.

Conclusions: TET can get desirable effects of inhibiting the MDR in advance by binding with the active site on P-gp, then the disulfide bond of PTX₂ is broken by glutathione (GSH) in cancer cells and decomposed into PTX to inhibit cancer cell proliferation.

General significance: Our studies indicate that the co-loaded NPs can potentially overcome the MDR of conventional chemotherapeutic agents.

Keywords: Co-delivery; Controlled release; Multidrug resistance; Paclitaxel dimer; Tetrandrine.

Publication types

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

MeSH terms

Disulfides
Drug Resistance, Multiple
Drug Resistance, Neoplasm
HeLa Cells
Humans
Nanoparticles* / chemistry
Neoplasms*
Paclitaxel / pharmacology
Polymers / chemistry
Prodrugs* / chemistry
Prodrugs* / pharmacology
Reactive Oxygen Species / metabolism

Substances

Paclitaxel
Prodrugs
tetrandrine
Reactive Oxygen Species
Polymers
Disulfides