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功能高分子引发生物矿化实现肿瘤阻断治疗

刘洋 庄雅灵 丁建勋

刘洋, 庄雅灵, 丁建勋. 功能高分子引发生物矿化实现肿瘤阻断治疗[J]. 功能高分子学报. doi: 10.14133/j.cnki.1008-9357.20221109001
引用本文: 刘洋, 庄雅灵, 丁建勋. 功能高分子引发生物矿化实现肿瘤阻断治疗[J]. 功能高分子学报. doi: 10.14133/j.cnki.1008-9357.20221109001
LIU Yang, ZHUANG Yaling, DING Jianxun. Functional Polymer-Initiating Biomineralization for Tumor Blockade Therapy[J]. Journal of Functional Polymers. doi: 10.14133/j.cnki.1008-9357.20221109001
Citation: LIU Yang, ZHUANG Yaling, DING Jianxun. Functional Polymer-Initiating Biomineralization for Tumor Blockade Therapy[J]. Journal of Functional Polymers. doi: 10.14133/j.cnki.1008-9357.20221109001

功能高分子引发生物矿化实现肿瘤阻断治疗

doi: 10.14133/j.cnki.1008-9357.20221109001
基金项目: 国家自然科学基金(52273158,U21A2099,52022095,52073280,51973216,51873207,51833010);吉林省科技发展计划(20210509005RQ,20210504001GH,20200404182YY)
详细信息
    作者简介:

    刘洋:刘 洋(1995—),女,博士研究生,主要研究方向为生物矿化介导的肿瘤阻断治疗。E-mail:yangl@ciac.ac.cn

    通讯作者:

    丁建勋,E-mail:jxding@ciac.ac.cn

  • 中图分类号: O633.2

Functional Polymer-Initiating Biomineralization for Tumor Blockade Therapy

  • 摘要: 作为一种不依赖于肿瘤组织渗透的治疗策略,阻断疗法通过阻碍肿瘤与周围微环境之间的物质交换而有效抑制肿瘤的生长和转移。然而,血管阻断、细胞外基质构建等手段存在系统毒性大、肿瘤杀伤不完全、有效持续时间短等问题。受生物体矿化过程的启发,在肿瘤周围构筑生物矿化层成为一种新兴、安全、有效且持久的肿瘤阻断治疗创新模式。基于此,本研究团队首先将阿仑膦酸钠(ALN)键合到1,2-二硬脂酰基-sn-甘油-3-磷酸乙醇胺-N-聚乙二醇-琥珀酰亚胺酯(DSPE-PEG-NHS)的末端,合成了功能高分子DSPE-PEG-ALN(DPA)。其中,DSPE端可以插入到细胞膜上,另一端的双膦酸可以高效吸附环境中的钙离子等阳离子而引发矿物沉积的连锁反应,在肿瘤周围形成生物矿化层,阻断肿瘤进展。为了进一步提高矿化策略的选择性,我们设计并合成了肿瘤酸度触发的生物矿化引发聚氨基酸纳米粒子(BINP)。在中性条件下BINP上的长烷基链组装在纳米粒子的内部,而在肿瘤组织的弱酸性环境中暴露,实现肿瘤细胞膜的特异性插入,原位引发生物矿化,选择性阻断肿瘤进展。原位引发生物矿化的功能高分子的设计和应用为肿瘤阻断治疗提供了具有临床应用前景的创新思路。

     

  • 图  1  DPA有效抑制骨肉瘤生长和肺转移[11]:(a) DPA通过诱导肿瘤组织周围形成生物矿化层并降低破骨细胞的活性抑制骨肉瘤进展;(b) 皮下143B肿瘤组织的micro-CT图像(标尺=0.5 cm);(c) 以生理盐水作为对照组(Control)、Ca、DPA或DPAC治疗后原位143B骨肉瘤的生长曲线;(d) 体外原位143B骨肉瘤照片(标尺=2 cm);(e) 从人143B骨肉瘤异种移植小鼠分离的肺切片的H&E染色图像(标尺=3 mm,箭头表示肺转移结节);(f) 在用生理盐水、Ca、DPA或DPAC治疗后,接种原位143B骨肉瘤的小鼠胫骨平台的抗酒石酸酸性磷酸酶(TRAP)染色图像(标尺=0.2 mm)

    Figure  1.  Effective inhibition of osteosarcoma growth and pulmonary metastasis by DPA[11]: (a) Facilely synthesized DPA for osteosarcoma therapy by initiating biomineralization in peripheral region of tumor tissue and inhibiting activity of osteoclasts; (b) Micro-CT images of resected subcutaneous 143B tumors (scale bar = 0.5 cm); (c) Growth curves of orthotopic 143B osteosarcoma after treatment with normal saline as Control, Ca, DPA, or DPAC; (d) Ex vivo orthotopic 143B osteosarcoma photo (scale bar = 2 cm); (e) H&E-staining images of lung slices isolated from human 143B osteosarcoma-xenografted mice after various treatments (scale bar = 3 mm, arrows indicate pulmonary metastatic nodules); (f) TRAP-staining images of tibial platforms of mice bearing orthotopically xenografted 143B osteosarcoma after treatment with normal saline as Control, Ca, DPA, or DPAC (scale bar = 0.2 mm)

    图  2  BINP选择性抑制骨肉瘤生长和肺转移[12]:(a) 酸响应性BINP抑制骨肉瘤进展;(b) BINP的动态光散射和透射电子显微图像(右上角插图,标尺=500 nm);(c) 以生理盐水为对照、TPZ、BINP或BINP+TPZ给药期间原位肿瘤区域的体积;(d) 通过光声成像表征原位骨肉瘤区域的血流状况(标尺=3 mm);(e) 治疗结束时肿瘤区域乏氧免疫荧光染色的共焦激光扫描显微成像(标尺=100 μm)

    Figure  2.  Selective inhibition of osteosarcoma growth and pulmonary metastasis by BINP[12]: (a) Suppression of osteosarcoma progression by acidity-responsive BINP; (b) Dynamic light scattering and transmission electron microscopic images (insets in the top right corner) of BINP (scale bar = 500 nm); (c) Volume of orthotopic tumor region during administration with normal saline as Control, TPZ, BINP, or BINP+TPZ; (d) Characterization of blood flow condition in orthotopic osteosarcoma regions by photo acoustic imaging (scale bar = 3 mm); (e) confocal laser scanning microscopy imaging of hypoxia immunofluorescence staining in tumor region at the end of treatments (scale bar = 100 μm)

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出版历程
  • 收稿日期:  2022-11-09
  • 录用日期:  2022-11-10
  • 网络出版日期:  2022-11-14

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