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Self-assembled Pt(II) metallacycles enable precise cancer combination chemotherapy.

ABSTRACT: Combination chemotherapy, which involves the simultaneous use of multiple anticancer drugs in adequate combinations to disrupt multiple mechanisms associated with tumor growth, has shown advantages in enhanced therapeutic efficacy and lower systemic toxicity relative to monotherapy. Herein, we employed coordination-driven self-assembly to construct discrete Pt(II) metallacycles as monodisperse, modular platforms for combining camptothecin and combretastatin A4, two chemotherapy agents with a disparate mechanism of action, in precise arrangements for combination chemotherapy. Formulation of the drug-loaded metallacycles with folic acid–functionalized amphiphilic diblock copolymers furnished nanoparticles with good solubility and stability in physiological conditions. Folic acids on the surface of the nanoparticles promote their internalization into cancer cells. The intracellular reductive environment of cancer cells induces the release of the drug molecules at an exact 1:1 ratio, leading to a synergistic anticancer efficacy. In vivo studies on tumor-bearing mice demonstrated the favorable therapeutic outcome and minimal side effects of the combination chemotherapy approach based on a self-assembled metallacycle.

SUBMITTER: Zhang P

PROVIDER: S-EPMC9171908 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Self-assembled Pt(II) metallacycles enable precise cancer combination chemotherapy.

Zhang Pengge P Zhou Zhixuan Z Long Wen W Yan Yuping Y Li Youshan Y Fu Ting T Liu Yanlan Y Zhao Zilong Z Tan Weihong W Stang Peter J PJ

Proceedings of the National Academy of Sciences of the United States of America 20220511 20

Combination chemotherapy, which involves the simultaneous use of multiple anticancer drugs in adequate combinations to disrupt multiple mechanisms associated with tumor growth, has shown advantages in enhanced therapeutic efficacy and lower systemic toxicity relative to monotherapy. Herein, we employed coordination-driven self-assembly to construct discrete Pt(II) metallacycles as monodisperse, modular platforms for combining camptothecin and combretastatin A4, two chemotherapy agents with a dis ...[more]

PMID: 35544688

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Project description:Rationale: Combinations of two or more therapeutic agents targeting different signaling pathways involved in tumor progression can have synergistic anticancer effects. However, combination chemotherapies are greatly limited by the different pharmacokinetics, tumor targeting, and cellular uptake capacities of the combined drugs. We have previously demonstrated the potential synergistic efficacy of paclitaxel (PTX) and the natural anti-angiogenic agent tetramethylpyrazine (TMP) for suppressing ovarian carcinoma growth. An efficient, facile, and smart nanosystem to deliver PTX and TMP simultaneously in vivo is greatly desired. Methods: We constructed a redox-sensitive nanosystem based on the amphiphilic PTX-ss-TMP conjugate, in which PTX and TMP are linked by a disulfide bond. We characterized the structure of the drug conjugate by 1H NMR and LC-MS, and then prepared PTX-ss-TMP NPs by a one-step nanoprecipitation method. We investigated the redox sensitivity, tumor-targeting ability, anticancer efficacy, and anti-angiogenesis activity of PTX-ss-TMP NPs in vitro and in vivo. Results: The amphiphilic PTX-ss-TMP conjugate readily self-assembled into stable nanoparticles in aqueous solution with a low critical association concentration of 1.35 µg/mL, well-defined spherical structure, small particle size (152 nm), high drug loading, redox-responsive drug release, high biocompatibility, and high storage stability. In cancer cells pretreated with GSH-OEt, PTX-ss-TMP NPs exhibited higher cytotoxicity, apoptosis rate, and cell-cycle arrest than monotherapy or combination therapy with free drugs, which was attributed to their improved cellular uptake and rapid intracellular drug release. Additionally, PTX-ss-TMP NPs also had a stronger anti-angiogenesis effect in HUVECs than free drug, which was mediated by VEGFR2-involved downstream signals. Finally, PTX-ss-TMP NPs showed tumor-specific accumulation and excellent antitumor activity in A2780 xenograft mice compared with free drug. Conclusions: These in vitro and in vivo results provide clear evidence that this redox-responsive carrier-free nanosystem with intrinsic amphiphilicity has great potential for combination cancer chemotherapy.

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Self-assembled Pt(II) metallacycles enable precise cancer combination chemotherapy.

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Self-assembled Pt(II) metallacycles enable precise cancer combination chemotherapy.

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