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  2. Targeting the Mitochondria with Pseudo-Stealthy Nanotaxanes to Impair Mitochondrial Biogenesis for Effective Cancer Treatment

Targeting the Mitochondria with Pseudo-Stealthy Nanotaxanes to Impair Mitochondrial Biogenesis for Effective Cancer Treatment

  • ACS Nano. 2022 Jul 12. doi: 10.1021/acsnano.1c08008.
Lulu Ren 1 2 3 Peirong Xu 1 4 Jie Yao 1 4 Zihan Wang 5 Kewei Shi 1 Weidong Han 3 Hangxiang Wang 1 2
Affiliations

Affiliations

  • 1 NHC Key Laboratory of Combined Multi-Organ Transplantation, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, People's Republic of China.
  • 2 Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong 250117, People's Republic of China.
  • 3 Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, People's Republic of China.
  • 4 Department of Chemical Engineering, Zhejiang University, Hangzhou, Zhejiang 310027, People's Republic of China.
  • 5 College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, People's Republic of China.
Abstract

The clinical success of Anticancer therapy is usually limited by drug resistance and the metastatic dissemination of Cancer cells. Mitochondria are essential generators of cellular energy and play a crucial role in sustaining cell survival and metastatic escape. Selective drug strategies targeting mitochondria are able to rewire Mitochondrial Metabolism and may provide an alternative paradigm to treat many aggressive cancers with high efficiency and low toxicity. Here, we present a pseudo-stealthy mitochondria-targeted pro-nanotaxane and test it against recurrent and metastatic tumor xenografts. The nanoparticle encapsulates a mitochondria-targetable pro-taxane agent, which can be converted into the chemically unmodified cabazitaxel drug, with further surface cloaking with a low-density lipophilic triphenylphosphonium cation. The resultant nanotaxane could be effectively taken up by cells and consequently specifically localized to the mitochondria. The in situ activated cabazitaxel causes mitochondrial dysfunction and ultimately results in potent cell Apoptosis. After intravenous administration to Animals, pro-nanotaxane mimics the stealthy behavior of polyethylene glycol-cloaked nanoparticles to provide a long circulation time. The antitumor efficacy of this mitochondria-targeted system was validated in multiple preclinical drug-resistant tumor models. Notably, in a patient-derived metastatic melanoma model that was initially pretreated with cabazitaxel, nanotaxane administration not only produced durable tumor reduction but also substantially suppressed metastatic recurrence. Taken together, these results demonstrate that this combination of a pseudo-stealthy platform with a rationally designed pro-drug is an attractive approach to target mitochondria and enhance drug efficacy.

Keywords

drug resistance; metastasis; mitochondrial delivery; pro-drug engineering; pseudo-stealthy nanotaxane.

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