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还原响应性肝靶向聚合物胶束的制备及其载药性能

冯荟如 刘艳勤 董营 于香香 巩凯

冯荟如, 刘艳勤, 董 营, 于香香, 巩 凯. 还原响应性肝靶向聚合物胶束的制备及其载药性能[J]. 功能高分子学报,2022,35(6):566-574 doi: 10.14133/j.cnki.1008-9357.20220329001
引用本文: 冯荟如, 刘艳勤, 董 营, 于香香, 巩 凯. 还原响应性肝靶向聚合物胶束的制备及其载药性能[J]. 功能高分子学报,2022,35(6):566-574 doi: 10.14133/j.cnki.1008-9357.20220329001
FENG Huiru, LIU Yanqin, DONG Ying, YU Xiangxiang, GONG Kai. Preparation of Reduction-Responsive Liver-Targeted Polymeric Micelles and Their Drug-Loading Properties[J]. Journal of Functional Polymers, 2022, 35(6): 566-574. doi: 10.14133/j.cnki.1008-9357.20220329001
Citation: FENG Huiru, LIU Yanqin, DONG Ying, YU Xiangxiang, GONG Kai. Preparation of Reduction-Responsive Liver-Targeted Polymeric Micelles and Their Drug-Loading Properties[J]. Journal of Functional Polymers, 2022, 35(6): 566-574. doi: 10.14133/j.cnki.1008-9357.20220329001

还原响应性肝靶向聚合物胶束的制备及其载药性能

doi: 10.14133/j.cnki.1008-9357.20220329001
基金项目: 中央高校基本科研业务费专项资金(JUSRP21940)
详细信息
    作者简介:

    冯荟如(1997—),女,硕士,主要研究方向为纳米药物递送系统。E-mail:yy403622@163.com

    通讯作者:

    巩 凯,E-mail:kingong222@163.com

  • 中图分类号: R94

Preparation of Reduction-Responsive Liver-Targeted Polymeric Micelles and Their Drug-Loading Properties

  • 摘要: 首先,以七(6-叠氮-6-脱氧)-β-环糊精、3-炔基丁基-β-D-半乳糖苷为原料,经Click反应合成具有肝靶向功能的半乳糖-β-环糊精(Gal7-CD);其次,以胱胺二盐酸盐、十八烷酸为原料,经氨基保护、酰化反应、脱保护等步骤,得到胱胺基十八酰胺(NH2-SS-SA);再次,以金刚烷甲酸活性酯、双端氨基聚乙二醇为原料,经酰化反应得到金刚烷基聚乙二醇胺(Ad-PEG1000-NH2),该产物与丁二酸酐反应,得到金刚烷基聚乙二醇胺丁二酸(Ad-PEG1000-COOH);接下来,NH2-SS-SA和Ad-PEG1000-COOH反应得到金刚烷基聚乙二醇胺十八酰胺(Ad-PEG1000-SS-C18);最后,采用透析法,Gal7-CD与Ad-PEG1000-SS-C18经主客体自组装形成两亲性聚合物,进而形成聚合物胶束半乳糖-胱胺-十八酰胺(Gal7-SS-C18),并以阿霉素(DOX)为模型药物,制备了相应载药聚合物胶束Gal7-SS-C18-DOX。利用动态光散射仪(DLS)测得聚合物胶束和载药聚合物胶束粒径分别为(169.2±1.3) nm和(177.9±3.0) nm。利用紫外-可见分光光度计测得载药聚合物胶束的载药量为(21.2±0.7)%,包封率为(71.1±0.5)%。在模拟正常生理环境的磷酸盐缓冲液(PBS)中,载药聚合物胶束的药物释放缓慢;在模拟癌细胞还原性微环境下的PBS中,48 h内药物释放率可达到82.38%。以肝癌细胞(HepG2)和正常组织细胞(HEK-293)为细胞模型,评价聚合物胶束的细胞毒性及抗肿瘤活性。研究结果表明,聚合物胶束具有良好的生物相容性,载药聚合物胶束表现出良好的靶向性和药物可控释放性能,对肝癌细胞的抑制作用强于游离DOX,对正常细胞的毒性较低,具有良好的治疗选择性。

     

  • 图  1  Ad-PEG1000-SS-C18的合成路线

    Figure  1.  Synthetic routes of Ad-PEG1000-SS-C18

    图  2  Gal7-CD的合成路线

    Figure  2.  Synthetic route of Gal7-CD

    图  3  Gal7-SS-C18-DOX的制备与药物释放示意图

    Figure  3.  Schematic representation of formation and drug release of Gal7-SS-C18-DOX

    图  4  Ad-PEG1000-SS-C18和Gal7-SS-C181H-NMR图谱

    Figure  4.  1H-NMR spectra of Ad-PEG1000-SS-C18 and Gal7-SS-C18

    图  5  样品的FT-IR图谱

    Figure  5.  FT-IR spectra of samples

    图  6  (a) 聚合物胶束lg ρI384/I373的关系;(b) 聚合物胶束和载药聚合物胶束的粒径分布图;(c)聚合物胶束的粒径变化;(d) 载药聚合物胶束的体外药物释放曲线

    Figure  6.  (a) Relationship between lg ρ and I384/I373 of polymer micelles; (b) Particle size distributions of polymer micelles and drug-loaded polymer micelles; (c) Particle size changes of polymer micelles; (d) in vitro drug release profiles of drug-loaded micelles

    图  7  (a) 聚合物胶束对HepG2和HEK-293的体外毒性;载药聚合物胶束对(b) HepG2和(c) HEK-293的体外毒性

    Figure  7.  (a) in vitro toxicity of polymer micelles to HepG2 cells and HEK-293 cells; in vitro toxicity of drug-loaded polymer micelles to (b) HepG2 cells and (c) HEK-293 cells

    图  8  载药聚合物胶束在(a) HepG2和(b) HEK-293的荧光强度分布图和平均荧光强度图;载药聚合物胶束在 (c) HepG2和 (d) HEK-293中的共聚焦扫描显微镜图

    Figure  8.  Fluorescence intensity distribution and mean fluorescence intensity of drug-loaded polymer micelles in (a) HepG2 cells and (b) HEK-293 cells; CLSM images of drug-loaded polymer micelles in (c) HepG2 cells and (d) HEK-293 cells

  • [1] MATTIUZZI C, LIPPI J. Current cancer epidemiology [J]. Epidemiology and Global Health,2019,9(4):217-222. doi: 10.2991/jegh.k.191008.001
    [2] 郭敏, 侯光晖, 胥伟军, 钱军民. 刺激响应性共聚物修饰金纳米棒的制备及其抗肿瘤性能[J]. 功能高分子学报, 2022, 35(1): 44-53.

    GUO M, HOU G H, XU W J, QIAN J M. Preparation of stimulus-responsive copolymer-decorated gold nanorods and their anti-tumor effect[J]. Journal of Functional Polymers, 2022, 35(1): 44-53.
    [3] YANG J D, HAINAUT P, GORES G J, AMADOU A, PLYMOTH A, ROBERTS L R. A global view of hepatocellular carcinoma: Trends, risk, prevention and management [J]. Nat Rev Gastroenterol Hepatol,2019,16(10):589-604. doi: 10.1038/s41575-019-0186-y
    [4] ZHOU F L, TENG F F, DENG P Z, MENG N, SONG Z M, FENG R L. Recent progress of nano-drug delivery system for liver cancer treatment [J]. Anti-Cancer Agents in Medicinal Chemistry,2017,17(14):1884-1897.
    [5] ZHANG Y Q, SHEN Y, LIAO M M, MAO X, MI G J, YOU C, GUO Q Y, LI W J, WANG X Y, LIN N, WEBSTER T J. Galactosylated chitosan triptolide nanoparticles for overcoming hepatocellular carcinoma: Enhanced therapeutic efficacy, low toxicity, and validated network regulatory mechanisms [J]. Nanomedicine: Nanotechnology Biology and Medicine,2019,15(1):86-97. doi: 10.1016/j.nano.2018.09.002
    [6] XIA Y, ZHONG J Y, ZHAO M Q, TANG Y, HAN N, HUA L, XU T T, WANG C B, ZHU B. Galactose-modified selenium nanoparticles for targeted delivery of doxorubicin to hepatocellular carcinoma [J]. Drug Delivery,2019,26(1):1-11. doi: 10.1080/10717544.2018.1556359
    [7] KASHKOOLI F M, SOLTANI M, SOURI M. Controlled anti-cancer drug release through advanced nano-drug delivery systems: Static and dynamic targeting strategies [J]. Journal of Controlled Release,2020,327:316-349. doi: 10.1016/j.jconrel.2020.08.012
    [8] DENG Y D, ZHANG X D, SHEN H B, HE Q N, WU Z J, LIAO W Z, YUAN M M. Application of the nano-drug delivery system in treatment of cardiovascular diseases [J]. Frontiers in Bioengineering and Biotechnology,2020,7:489. doi: 10.3389/fbioe.2019.00489
    [9] TIAN B R, LIU Y M, LIU J Y. Smart stimuli-responsive drug delivery systems based on cyclodextrin: A review [J]. Carbohydrate Polymers,2021,251:116871. doi: 10.1016/j.carbpol.2020.116871
    [10] BALAURE P C, GRUMEZESCU A M. Smart synthetic polymer nanocarriers for controlled and site-specific drug delivery [J]. Current Topics in Medicinal Chemistry,2015,15(15):1424-1490. doi: 10.2174/1568026615666150414115852
    [11] ALSEHLI M. Polymeric nanocarriers as stimuli-responsive systems for targeted tumor (cancer) therapy: Recent advances in drug delivery [J]. Saudi Pharmaceutical Journal,2020,28(3):255-265. doi: 10.1016/j.jsps.2020.01.004
    [12] FANG Z J, PAN S B, GAO P, SHENG H G, LI L J, SHI L, ZHANG Y Q, CAI X Q. Stimuli-responsive charge-reversal nano drug delivery system: The promising targeted carriers for tumor therapy [J]. International Journal of Pharmaceutics,2020,575:118841. doi: 10.1016/j.ijpharm.2019.118841
    [13] LIU Y, LI Q, BAI Q, JIANG W. Advances of smart nano-drug delivery systems in osteosarcoma treatment [J]. Journal of Materials Chemistry B,2021,9(27):5439-5450. doi: 10.1039/D1TB00566A
    [14] 孙慧, 王菲, 汪云云, 巩凯. pH敏感聚合物胶束mPEG-GDE-OE的制备及其载药性能[J]. 功能高分子学报, 2020, 33(6): 570-579.

    SUN H, WANG F, WANG Y Y, GONG K. Preparation and drug delivery of pH-sensitive polymeric micelles mPEG-GDE-OE[J]. Journal of Functional Polymers, 2020, 33(6): 570-579.
    [15] RHEE Y S, MANSOUR H M. Nanopharmaceuticals I: Nanocarrier systems in drug delivery [J]. International Journal of Nanotechnology,2011,8(1-2):84-114.
    [16] ZHANG L D, LI H Q, SIK HA C, SUH H, KIM I. Fabrication of nanotubules and microspheres from the self-assembly of amphiphilic monochain stearic acid derivatives [J]. Langmuir,2010,26(23):17890-17895. doi: 10.1021/la103480p
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出版历程
  • 收稿日期:  2022-03-29
  • 录用日期:  2022-07-12
  • 网络出版日期:  2022-07-19
  • 刊出日期:  2022-12-01

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