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肝素在抗肿瘤药物递送系统中的应用

臧靖 柯学 慈天元

臧靖, 柯学, 慈天元. 肝素在抗肿瘤药物递送系统中的应用[J]. 功能高分子学报, 2021, 34(3): 215-229. doi: 10.14133/j.cnki.1008-9357.20200824001
引用本文: 臧靖, 柯学, 慈天元. 肝素在抗肿瘤药物递送系统中的应用[J]. 功能高分子学报, 2021, 34(3): 215-229. doi: 10.14133/j.cnki.1008-9357.20200824001
ZANG Jing, KE Xue, CI Tianyuan. Application of Heparin in Anti-Tumor Drug Delivery Systems[J]. Journal of Functional Polymers, 2021, 34(3): 215-229. doi: 10.14133/j.cnki.1008-9357.20200824001
Citation: ZANG Jing, KE Xue, CI Tianyuan. Application of Heparin in Anti-Tumor Drug Delivery Systems[J]. Journal of Functional Polymers, 2021, 34(3): 215-229. doi: 10.14133/j.cnki.1008-9357.20200824001

肝素在抗肿瘤药物递送系统中的应用

doi: 10.14133/j.cnki.1008-9357.20200824001
基金项目: 国家自然科学基金(81603048)
详细信息
    作者简介:

    臧靖:臧 靖(1997—),女,硕士,主要从事纳米药物递送载体研究。E-mail:zangjing97@163.com

    慈天元,2015年毕业于复旦大学高分子科学系,目前为上海中医药大学中药学院副教授,硕士生导师,主要从事缓控释递送系统及肿瘤免疫治疗等方面的研究。承担国家自然科学基金青年基金、江苏省青年基金等项目。迄今,以第一或通信作者在Science AdvancesJournal of Controlled ReleaseActa BiomaterialiaBiomaterials Science等国际期刊发表论文18篇

    通讯作者:

    慈天元,E-mail:citianyuan_cpu@163.com

    柯 学,E-mail:kexue1973@vip.sina.com

  • 中图分类号: O63

Application of Heparin in Anti-Tumor Drug Delivery Systems

  • 摘要: 肝素是一种高度硫酸化的糖胺聚糖,目前主要作为抗凝剂应用于临床。肝素具有一定的抗肿瘤转移的作用,而基于肝素此项功能的抗肿瘤药物递送系统亦被广泛研究。在这类药物传递系统中,肝素一方面可增强抗肿瘤药物的抑瘤效果,同时亦可发挥自身的抗肿瘤转移功能,使药物及载体协同作用。基于肝素的抗肿瘤转移作用机理及肝素在药物递送系统中的应用,围绕相关的设计思路与方法展开综述,以期为相关领域的研究提供参考。

     

  • 图  1  (a)肝素的化学结构;(b)以肝素为基础的药物递送系统;(c)肝素抗肿瘤转移机理

    Figure  1.  (a)Structure of heparin;(b)Heparin-based drug delivery system;(c)Anti-tumor mechanism of heparin

    图  2  LH-Lip/siBCL-2联合化疗对胰腺肿瘤及转移的影响:(a)LH-Lip/siBCL-2的制备;(b)给予小剂量PTX-Lip,调节肿瘤微环境,促进后续LH-Lip/siBCL-2释放;(c)给予LH-Lip/siBCL-2抑制肿瘤转移,下调BCL-2的表达[37]

    Figure  2.  Effect of LH-Lip/siBCL-2 combined chemotherapy on pancreatic tumor and metastasis:(a)Preparation of LH-Lip/siBCL-2;(b)A low dose of PTX-Lip was administered as a tumor-priming agent to regulate the tumor microenvironment and promote the delivery of nanodrugs;(c)LH-Lip/siBCL-2 was sequentially administrated to inhibit cancer metastasis and downregulate the expression of BCL-2 [37]

    图  3  (a)胶束纳米粒HD-DOX及其功能示意图;(b)治疗结束后,在小鼠尾静脉注射B16F10细胞,18 d后肺部图片(n = 6,mean ± SD);(c)小鼠肿瘤肺转移区域(n = 6,mean ± SD);(d)肺切片组织学分析[42]

    Figure  3.  (a)Constructions and functions of HD-DOX;(b)Pictures of lungs 18 d after injection of B16F10 cells via tail vein(n = 6, mean ± SD);(c)Metastasis areas of lungs(n = 6, mean ± SD);(d)Histological analysis of lung sections[42]

    图  4  (a)纳米粒的构建;(b)PTX/Cy5.5-loaded NPs活体成像图及定量分析结果;(c)72 h后处死负载鳞状癌细胞(SCC-7)的小鼠,各器官体外白光及近红外成像及定量分析结果[52]

    Figure  4.  (a)Construction of LNP;(b)In vivo noninvasive NIR images and quantification analysis of TX/Cy5.5-loaded NPs;(c)Ex vivo white light images and NIR images and quantification analysis of dissected organs of mice bearing SCC-7 cells sacrificed at 72 h[52]

    图  5  (a)肝素改性PEG水凝胶的合成;(b)利用活体成像监测肿瘤生长以及治疗后小鼠原发肿瘤质量;(c)第6周小鼠的活体成像图和癌细胞在第6周转移到器官的图像[70]

    Figure  5.  (a)Synthesis of heparin-modified polyethylene glycol hydrogels;(b)Monitoring tumor growth in vivo by bioluminescence imaging and primary tumour mass of mice;(c)Bioluminescence images of mice at week 6 and metastatic spread of cancer cells to organs at week 6[70]

    表  1  以肝素为基础的药物递送系统

    Table  1.   Heparin-based drug delivery system

    Structure of drug delivery system Active drugEffect of heparin Reference
    Nano-based drug delivery system-liposome
    LMWH-coated doxorubicin-liposomeDoxorubicinAnti-tumor metastasis[36]
    Heparin-coated liposome loaded with BCL-2 siRNAPaclitaxelReducing the toxicity of cationic liposome, improving the
     efficacy of preparation against tumor metastasis
    [37]
    Curcumin liposome modified with LMWHCurcuminChanging the surface charge of liposome[38]
    Co-delivery of doxorubicin and epacadostat via heparin coated
     pH-sensitive liposome
    Epacadostat DoxorubicinImproving the stability of the preparation, promoting cells
     uptake, anti-tumor metastasis
    [39]
    LMWH modified redox doxorubicin liposomeDoxorubicinAnti-tumor metastasis [40]
    Nano-based drug delivery system-micelle
    Poly(lactide-co-glycolide)nanoparticle to deliver imatinib and   curcuminImatinib, CurcuminReducing the toxicity of preparations[41]
    Doxorubicin-loaded heparin-based Micelle pH-sensitiveDoxorubicinReducing the toxicity of preparations, anti-tumor metastasis [42]
    micelle composed of heparin, phospholipids, and histidineZinc phthalocyanineIncreasing anti-tumor activity, skeleton of micelle[43]
    Docetaxel-loaded pH-triggered micelle comprising alpha-
     tocopherol and heparin
    PaclitaxelIncreasing anti-tumor activity, skeleton of micelle[44]
    Gambogic acid grafted LMWH micelleGambogic acidIncreasing hydrophilicity, anti-angiogenic[45]
    Redox-sensitive heparin-β-sitosterol micelleDoxorubicinAnti-tumor metastasis [46]
    Nano-based drug delivery system-nanogel
    Reducible heparin nanogelHeparinInducing cells apoptosis[47]
    Heparin nanogel-containing liposomeRibonucleaseSkeleton of nanogel[48]
    Bioreducible heparin-based nanogelDoxorubicinLong-circulation, anti-tumor metastasis [49]
    Doxorubicin-loaded heparin-poloxamer nanogelDoxorubicinInhibiting tumor cells proliferation and invasion, anti-
     angiogenic, anti-tumor metastasis
    [50]
    Self-assembled heparin-pluronic nanogels with RNase A RNase A Skeleton of nanogel[51]
    Nano-based drug delivery system-nanoparticle
    Paclitaxel-loaded pluronic nanoparticles with a glycol chitosan/heparin compositePaclitaxelLong-circulation[52]
    Redox-responsive heparin-chlorambucil nanoparticleChloramphenicolSkeleton of nanoparticle, anti-tumor metastasis [53]
    Heparin-paclitaxel nanoparticle using amino acid as linkerPaclitaxelSkeleton of nanoparticle, anti-tumor metastasis [54]
    Folate and cRGD were conjugated with heparin to self-assemble   heparin-folate-cRGD-NPscRGDSkeleton of nanoparticle, anti-angiogenic[55]
    LMWH-Cholesterol based nanoparticle for intravenous delivery
      of doxorubicin
    DoxorubicinSkeleton of nanoparticle, anti-tumor metastasis [56]
    LMWH-all-trans retinoic acid nanoparticleDoxorubicinSkeleton of nanoparticle, anti-angiogenic[57]
    A novel combination nanosystem of LMWH and ursolic acidUrsolic acidSkeleton of nanoparticle, anti-angiogenic[58]
    LMWH-based reduction-sensitive nanoparticleDoxorubicin Skeleton of nanoparticle, anti-tumor metastasis [59]
    Taxol-loaded heparin-PEG-folate nanoparticlePaclitaxelSkeleton of nanoparticle, anti-tumor metastasis [60]
    LyP-1 peptide-modified low-molecular-weight heparin-
     quercetin nanoparticle
    Gambogic acidSkeleton of nanoparticle, anti-angiogenic[61]
    Heparin immobilized gold nanoparticleHeparinSolubilization, anti-inflammatory, anti-angiogenic[62]
    Gold and silver nanoparticles conjugated with heparinHeparinAnti-angiogenic[63]
    Doxorubicin-conjugated heparin-coated superparamagnetic iron
      oxide nanoparticle
    Doxorubicin Reducing the toxicity of doxorubicin, sustained release[64]
    Heparin-reduced graphene oxide nanocomposites for curcumin
     delivery
    CurcuminImproving the stability and biocompatibility of nanoparticle[65]
    N-deacetylated heparin coated silica nanoparticleDoxorubicinControlled drug-release[66]
    Mesoporous silica nanoparticles covalently bound to heparinDoxorubicinImproving the biocompatibility and dispersibility of
     nanoparticle, showing synergistic effect with doxorubicin
     in treating cancer
    [67]
    Micro-based drug delivery system
    DOX-loaded heparin/chitosan microcapsuleDoxorubicinInducing cells apoptosis, skeleton of microcapsule[68]
    Hydrogel
    Heparin loaded biodegradable and injectable thermoresponsive
      hydrogel
    HeparinAnti-tumor metastasis [69]
    Heparin-modified polyethylene glycol hydrogelDoxorubicinSkeleton of hydrogel, anti-tumor metastasis [70]
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  • 收稿日期:  2020-08-24
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