Science China-Materials
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2025
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IF 7.4
Zhao Weidong,Zheng Mengfei,Chu Hongyu,Zhang Jingxuan,Wang Kun,Yang Chenguang,Shen Na,Tang Zhaohui
β-Lapachone (β-Lap) is a promising ortho -naphthoquinone drug for cancer treatment and has been in clinical trials. Its application is constrained by the low aqueous solubility, and severe side effects. Even prodrug designation is an effective approach to render it with tumor selectivity, it is limited by the lack of modifiable groups on β-Lap. Herein, a novel azo bond primary cleavage and carbon–carbon (C–C) bond secondary cleavage-based polymeric β-Lap prodrug (Azo-Lap NP) is designed, in which the self-immolated para -aminobenzyl linker is connected to poly( l -glutamic acid) (PGlu) via azo linkage and the responsive drug release of β-Lap against tumors can be achieved under high NAD(P)H:quinone oxidoreductase 1 (NQO1) expression and low pH environment in tumors. The effective covalent loading of β-Lap by Azo-Lap NPs permitted a high administration dose of β-Lap and enabled significant tumor retention time. Moreover, Azo-Lap NPs markedly reduced the side effects of β-Lap by avoiding hemolysis and the production of methemoglobin. The safety of Azo-Lap NPs administration is validated in the antitumor experiment of mice. In the 4T1 model, Azo-Lap NPs exhibited a markedly higher tumor suppression rate than β-Lap. This work provides an effective and safe polymeric prodrug for tumor selective delivery of β-Lap.
研究领域:
药物化学
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肿瘤学
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生物医学工程
✓ 已验证
产品关联
DOI
高影响因子
Biomaterials Science
·
2023
·
IF 6.6
Tong Li,Dianwei Wang,Zhaopei Guo,Lin Lin,Meng Meng,Cong Liu,Kai Hao,Xuan Pang,Huayu Tian,Xuesi Chen
The emergence of nanocarriers has greatly improved the therapeutic efficacy of chemotherapeutic drugs. As emerging nanocarriers, covalent organic frameworks (COFs) have been increasingly used in biomedicine in recent years. However, due to their inherent chemical stability, existing COF nanocarriers hardly undergo in vivo degradation, which brings potential safety hazards to further applications. In this work, we introduce the azo bond into COFs. When the nanocarrier enters the cell, ˙OH generated by the coordinated Fe response to the H2O2 in the cell will break the azo bond and cause the degradation of the framework structure, accelerating the release of internally loaded DOX to effectively realize tumor treatment. We verified the degradation ability of the materials by constructing model compounds, in vitro drug release, MTT assay and antitumor experiments. Compared with the control groups, the degradable COF accelerates the release of DOX and shows a stronger killing effect on 4T1 cells. Serum biochemical analysis and H&E sections of organs show good biocompatibility for both COFs and degradation products. This work provides a new idea for the design of biodegradable COFs in vivo, and greatly explores the potential application of COF materials in the biomedical field.
研究领域:
纳米技术
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药学
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生物医学工程
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癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2024
·
IF 6.1
Mingye Li,Yuyu Dong,Zheng Wang,Yanjun Zhao,Yujie Dai,Baoxin Zhang
Glucose-6-phosphate dehydrogenase (G6PD) is a promising target in cancer therapy. However, poor cellular uptake and off-target toxicity impeded the clinical translation of a canonical G6PD inhibitor (6-aminonicotinamide/6AN). Here, we report a prodrug strategy to address this issue. The tailored 6AN prodrug contains an azo-bearing protection moiety. The hydrophobic prodrug showed increased cellular uptake than 6AN and is vulnerable to hypoxia, resulting in NAD(P)H quinone dehydrogenase 1 (NQO1)-triggered cleavage of azo bonds. Intriguingly, the prodrug shows configuration-dependent anti-cancer potency. Despite the lower thermodynamic stability, the cis isomer showed enhanced cellular uptake compared to the trans counterpart due to the increased aqueous solubility. Moreover, the boosted potency of cis isomer compared to the trans isomer resulted from the enhancement of NOQ1-catalyzed 6AN release under hypoxia, a hallmark of solid tumors. The discovery of hypoxia-responsive 6AN prodrugs in the current work opens new avenues of G6PD-targeting cancer medicines via redox manipulation.
研究领域:
药学
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癌症研究
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药物递送系统
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氧化还原生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2023
·
IF 8.2
Duo Li,Xiaoli Wang,Kaishuo Han,Yaqian Sun,Ting Ren,Guohui Sun,Na Zhang,Lijiao Zhao,Rugang Zhong
Carmustine (BCNU) is a typical chemotherapy used for treatment of cerebroma and other solid tumors, which exerts antitumor effect by inducing DNA damage at O 6 position of guanine. However, the clinical application of BCNU was extremely limited due to the drug resistance mainly mediated by O 6 -alkylguanine-DNA alkyltransferase (AGT) and absence of tumor-targeting ability. To overcome these limitations, we developed a hypoxia-responsive nanomicelle with AGT inhibitory activity, which was successfully loaded with BCNU. In this nano-system, hyaluronic acid (HA) acts as an active tumor-targeting ligand to bind the overexpressing CD44 receptors on the surface of tumor cells. An azo bond selectively breaks in hypoxic tumor microenvironment to release O 6 -benzylguanine (BG) as AGT inhibitor and BCNU as DNA alkylating agent. The obtained HA-AZO-BG NPs with shell core structure had an average particle size of 176.98 ± 11.19 nm and exhibited good stability. Meanwhile, HA-AZO-BG NPs possessed a hypoxia-responsive drug release profile. After immobilizing BCNU into HA-AZO-BG NPs, the obtained HA-AZO-BG/BCNU NPs exhibited obvious hypoxia-selectivity and superior cytotoxicity in T98G, A549, MCF-7 and SMMC-7721 cells with IC 50 at 189.0, 183.2, 90.1 and 100.1 μm, respectively, under hypoxic condition. Near-infrared imaging in HeLa tumor xenograft models showed that HA-AZO-BG/DiR NPs could effectively accumulate in tumor site at 4 h of post-injection, suggesting its good tumor-targetability. In addition, in vivo anti-tumor efficacy and toxicity evaluation indicated that HA-AZO-BG/BCNU NPs was more effective and less harmful compared to the other groups. After treatment, the tumor weight of HA-AZO-BG/BCNU NPs group was 58.46 % and 63.33 % of the control group and BCNU group, respectively. Overall, HA-AZO-BG/BCNU NPs was expected to be a promising candidate for targeted delivery of BCNU and elimination of chemoresistance.
研究领域:
药学
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纳米技术
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肿瘤学
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药物递送系统
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）