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A redox-responsive self-assembling COA-4-arm PEG prodrug nanosystem for dual drug delivery suppresses cancer metastasis and drug resistance by downregulating hsp90 expression.

ABSTRACT: Metastasis and resistance are main causes to affect the outcome of the current anticancer therapies. Heat shock protein 90 (Hsp90) as an ATP-dependent molecular chaperone takes important role in the tumor metastasis and resistance. Targeting Hsp90 and downregulating its expression show promising in inhibiting tumor metastasis and resistance. In this study, a redox-responsive dual-drug nanocarrier was constructed for the effective delivery of a commonly used chemotherapeutic drug PTX, and a COA-modified 4-arm PEG polymer (4PSC) was synthesized. COA, an active component in oleanolic acid that exerts strong antitumor activity by downregulating Hsp90 expression, was used as a structural and functional element to endow 4PSC with redox responsiveness and Hsp90 inhibitory activity. Our results showed that 4PSC/PTX nanomicelles efficiently delivered PTX and COA to tumor locations without inducing systemic toxicity. By blocking the Hsp90 signaling pathway, 4PSC significantly enhanced the antitumor effect of PTX, inhibiting tumor proliferation and invasiveness as well as chemotherapy-induced resistance in vitro. Remarkable results were further confirmed in vivo with two preclinical tumor models. These findings demonstrate that the COA-modified 4PSC drug delivery nanosystem provides a potential platform for enhancing the efficacy of chemotherapies.

SUBMITTER: Zhou Y

PROVIDER: S-EPMC10372829 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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A redox-responsive self-assembling COA-4-arm PEG prodrug nanosystem for dual drug delivery suppresses cancer metastasis and drug resistance by downregulating hsp90 expression.

Zhou Yi Y Miao Yingling Y Huang Qiudi Q Shi Wenwen W Xie Jiacui J Lin Jiachang J Huang Pei P Yue Chengfeng C Qin Yuan Y Yu Xiyong X Wang He H Qin Linghao L Chen Jianhai J

Acta pharmaceutica Sinica. B 20221125 7

Metastasis and resistance are main causes to affect the outcome of the current anticancer therapies. Heat shock protein 90 (Hsp90) as an ATP-dependent molecular chaperone takes important role in the tumor metastasis and resistance. Targeting Hsp90 and downregulating its expression show promising in inhibiting tumor metastasis and resistance. In this study, a redox-responsive dual-drug nanocarrier was constructed for the effective delivery of a commonly used chemotherapeutic drug PTX, and a COA-m ...[more]

PMID: 37521875

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Project description:Non-toxic prodrugs have proved of great value in medicinal chemistry programmes for cancer, due to their ability to selectively deliver toxic components at tumour sites once they are activated by a localised mechanism. Since activation of the prodrug to afford the toxic drug is a prerequisite for success of the approach, much interest has focused on the localised chemical and enzymatic mechanisms for activating the prodrugs. Bioorthogonal chemistry has positively impacted this area by providing biocompatible reactions that enable on-demand prodrug activation and active drug release. However, to be effective, it is essential that one of the components of the bioorthogonal reaction is localised at the tumour, in order to initiate the on-demand and on-target activation of the prodrug. Polymers such as poly(ethylene glycol) (PEG) are known to target solid tumours by passive targeting via the enhanced permeability and retention (EPR) effect. In this paper, the feasibility of derivatising long PEG chains to afford bioorthogonal activators (PEG-azide and PEG-tetrazine) for prodrug activation via the Staudinger ligation and the tetrazine ligation reactions, respectively, is evaluated. The molecular weight of the PEG in the activator and the type of linkage in the prodrug moiety were shown to significantly affect the rate of prodrug activation and hence the rate of drug release. In vitro cytotoxicity studies on breast cancer cells (MCF-7 and MDA-MB-231) showed ∼68-76% restoration of the parent drug's cytotoxicity for the Staudinger ligation-based prodrug activation strategy, and 100% restoration of the parent drug's cytotoxicity for the tetrazine ligation-based prodrug activation strategy. Restoration of doxorubicin's ability to intercalate with DNA upon activation of the prodrug by the PEG-activators was also demonstrated via fluorescence spectroscopy. Moreover, conjugation of the tetrazine bioorthogonal activator to a 10 kDa PEG polymer improved its serum stability in comparison with other reported tetrazine activators that completely lose their stability in serum over the same period of time. The feasibility of the combined passive targeting/bioorthogonal prodrug activation approach has therefore been demonstrated using a range of prodrugs, activation mechanisms, and in vitro assays.

Dataset Information

A redox-responsive self-assembling COA-4-arm PEG prodrug nanosystem for dual drug delivery suppresses cancer metastasis and drug resistance by downregulating hsp90 expression.

Publications

A redox-responsive self-assembling COA-4-arm PEG prodrug nanosystem for dual drug delivery suppresses cancer metastasis and drug resistance by downregulating hsp90 expression.

Similar Datasets

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