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    王月, 沈娜, 卫琦, 汤朝晖. 高分子键合血管阻断剂与BLZ945纳米药物协同治疗肿瘤[J]. 功能高分子学报, 2020, 33(6): 522-531. doi: 10.14133/j.cnki.1008-9357.20200612001
    引用本文: 王月, 沈娜, 卫琦, 汤朝晖. 高分子键合血管阻断剂与BLZ945纳米药物协同治疗肿瘤[J]. 功能高分子学报, 2020, 33(6): 522-531. doi: 10.14133/j.cnki.1008-9357.20200612001
    WANG Yue, SHEN Na, WEI Qi, TANG Zhaohui. Co-Bonded Vascular Disrupting Agents and BLZ945 Polymeric Nanodrug for Synergistic Cancer Therapy[J]. Journal of Functional Polymers, 2020, 33(6): 522-531. doi: 10.14133/j.cnki.1008-9357.20200612001
    Citation: WANG Yue, SHEN Na, WEI Qi, TANG Zhaohui. Co-Bonded Vascular Disrupting Agents and BLZ945 Polymeric Nanodrug for Synergistic Cancer Therapy[J]. Journal of Functional Polymers, 2020, 33(6): 522-531. doi: 10.14133/j.cnki.1008-9357.20200612001

    高分子键合血管阻断剂与BLZ945纳米药物协同治疗肿瘤

    Co-Bonded Vascular Disrupting Agents and BLZ945 Polymeric Nanodrug for Synergistic Cancer Therapy

    • 摘要: 聚(L-谷氨酸)接枝聚乙二醇单甲醚/康普瑞汀A4(C-NPs)具有良好的肿瘤血管靶向性和疗效,然而,C-NPs可导致M2型肿瘤相关巨噬细胞(M2-TAMs)浸润,进而使肿瘤复发,其应用受到了限制。首先验证了BLZ945能诱导M2-TAMs凋亡,并可与C-NPs协同抑制肿瘤生长,然后设计并制备了高分子键合血管阻断剂与BLZ945纳米药物聚(L-谷氨酸)接枝聚乙二醇单甲醚/康普瑞汀A4/BLZ945(CB-NPs),用于协同治疗肿瘤。通过核磁和红外光谱分析确认了其化学结构;动态光散射测试结果表明其水合半径为(59 ± 19) nm;高效液相色谱测试结果表明康普瑞汀A4(CA4)和BLZ945的载药量分别为10.7%和8.4%。体内抑瘤结果表明CB-NPs对初始体积410 mm3的肿瘤生长抑制率为79%,抑瘤效果显著。

       

      Abstract: Vascular disrupting agents (VDAs) have aroused increasing interest due to their great potential in cancer therapy. As compared to combretastatin A4 phosphate (CA4P), a polymeric VDA prodrug which has been in Phase III clinical trials, poly(L-glutamic acid)-g-methoxy poly(ethylene glycol)/combretastatin A4 (C-NPs), can significantly improve the tumor blood vessels targeting and enhance therapeutic effect due to the low permeability of nanodrug in solid tumors. However, C-NPs was found to induce the polarization of TAMs toward an M2-like phenotype (M2-TAMs) and further tumor recurrence, thereby limiting its antitumor application. BLZ945 was a highly selective CSF-1R inhibitor which can decrease the number of M2-TAMs through inhibiting CSF-1/CSF-1R signal pathway. However, CSF-1R is widely expressed in most cells of mononuclear phagocytic system, resulting in the lack of tumor selectivity and therapeutic side effect of BLZ945. Firstly, the reduction of M2-TAMs after BLZ945 treatment was verified by flow cytometry analysis; and in vivo antitumor efficacy showed that the combination of C-NPs and BLZ945 remarkably enhanced anticancer efficacy with a tumor suppression rate of 74.1%. Then, the co-bonded nanodrug poly(L-glutamic acid)-g-methoxy poly(ethylene glycol)-combretastatin A4/BLZ945 (CB-NPs) was developed for further enhance the synergistic anticancer efficacy. The chemical structure of CB-NPs was confirmed by nuclear magnetic resonance (NMR) and Fourier transform infrared spectroscopy (FT-IR). The obtained CB-NPs had a hydrodynamic radius of (56 ± 19) nm in aqueous solution determined by dynamic light scattering (DLS). The drug loading content of CA4 and BLZ945 in CB-NPs measured by HPLC was 10.7% and 8.4%, respectively. An in vivo study with the C26 murine colon carcinoma model showed that CB-NPs exhibited the most prominent suppression of tumor growth, significantly higher than the combination therapy with C-NPs plus BLZ945. The tumor suppression rate to C26 tumor with an initial volume of 410 mm3 was 79%. Therefore, CB-NPs enhanced tumor targeting ability of BLZ945 and improved its synergistic antitumor ability. This work provides a valuable cooperative strategy therapeutic choice of VDAs for solid tumor therapy.

       

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