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Published on: February 18, 2020
Development of artesunate intelligent prodrug liposomes based on mitochondrial targeting strategy
Liwei Gu1, Jiaxing Zhang2, Dandan Liu1
1Artemisinin Research Center and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, People's Republic of China.
Abstract:
Breast cancer is the leading cause of cancer-related deaths in women and remains a formidable therapeutic challenge. Mitochondria participate in a myriad of essential cellular processes, such as metabolism, and are becoming an ideal target for cancer therapy. Artemisinin and its derivatives have demonstrated multiple activities in the context of various cancers. Mitochondrial autophagy(mitophagy) is one of the important anti-tumor mechanisms of artemisinin drugs. However, the lack of specific tumor targeting ability limits the anti-tumor efficacy of artemisinin drugs. In this study, a GSH-sensitive artesunate smart conjugate (TPP-SS-ATS) was synthesized and liposomes (TPP-SS-ATS-LS) that target tumor cells and mitochondria were further prepared. The advantages of TPP-SS-ATS-LS targeting to the breast tumor were verified by in vivo and in vitro evaluations. In our study, the cytotoxicity was obviously enhanced in vitro and tumor growth inhibition rate was increased from 37.7% to 56.4% at equivalent artesunate dosage in breast cancer orthotopic implanted mice. Meanwhile, mitochondrial dysfunction, suppression of ATP production and respiratory capacity were detected in breast cancer cells. We further discovered that TPP-SS-ATS-LS inhibited tumor cells proliferation through mitophagy by regulating PHB2 and PINK1 expression. These results provide new research strategies for the development of new artemisinin-based anti-tumor drugs.
Insights
Researchers developed targeted liposomes (TPP-SS-ATS-LS) to enhance artesunate
Area of Science:
- Biomedical Engineering
- Cancer Biology
- Mitochondrial Biology
Background:
- Breast cancer poses a significant therapeutic challenge, with mitochondria emerging as a key target.
- Artemisinin derivatives show anti-cancer activity, but their efficacy is limited by poor tumor targeting.
- Mitochondrial autophagy (mitophagy) is a crucial anti-tumor mechanism exploited by artemisinin drugs.
Purpose of the Study:
- To synthesize a GSH-sensitive artesunate conjugate (TPP-SS-ATS) and formulate it into tumor- and mitochondria-targeting liposomes (TPP-SS-ATS-LS).
- To evaluate the in vivo and in vitro efficacy of TPP-SS-ATS-LS for breast cancer treatment.
- To elucidate the mechanism of TPP-SS-ATS-LS-induced anti-cancer effects, focusing on mitophagy.
Main Methods:
- Synthesis of a glutathione-sensitive artesunate conjugate (TPP-SS-ATS).
- Formulation of TPP-SS-ATS into targeted liposomes (TPP-SS-ATS-LS).
- In vitro and in vivo evaluation of TPP-SS-ATS-LS in breast cancer models, including cytotoxicity assays, tumor growth inhibition studies, and assessment of mitochondrial function (ATP production, respiratory capacity).
- Analysis of mitophagy-related protein expression (PHB2, PINK1).
Main Results:
- TPP-SS-ATS-LS demonstrated enhanced targeting to breast tumors in vivo and in vitro.
- In vitro cytotoxicity was significantly increased compared to non-targeted formulations.
- In orthotopic breast cancer mouse models, TPP-SS-ATS-LS increased tumor growth inhibition from 37.7% to 56.4% at equivalent artesunate doses.
- Mitochondrial dysfunction, reduced ATP production, and suppressed respiratory capacity were observed in treated breast cancer cells.
- TPP-SS-ATS-LS inhibited tumor cell proliferation via mitophagy, mediated by the regulation of PHB2 and PINK1 expression.
Conclusions:
- Targeted liposomal delivery of artesunate (TPP-SS-ATS-LS) enhances anti-cancer efficacy against breast cancer.
- The enhanced efficacy is attributed to improved tumor targeting and induction of mitophagy, leading to mitochondrial dysfunction.
- This study presents a promising strategy for developing novel artemisinin-based therapeutics for breast cancer with improved targeting capabilities.
