目的 探讨透明质酸修饰的乳腺癌微环境响应纳米粒的制备方法,并对其理化性质,体外功能进行评价。方法 首先通过腙键将透明质酸(HA)与聚天冬氨酸(PASP)连接,制备聚合物HA-PASP,并且采用聚乙二醇(PEG)制备对照聚合物PEG-PASP。以多柔比星(DOX)为模型药物,采用透析法制备纳米粒HA-PASP-NPs@DOX和PEG-PASP-NPs@DOX。采用粒度测定仪和透射电镜(TEM)观察纳米粒粒径、形态及Zeta电位;纳米粒的理化性质从包封率、载药量、稳定性、释药能力等方面进行评价;体外功能从乳腺癌细胞靶向性、肿瘤微环境响应性进行评价。结果 HA-PASP-NPs@DOX呈球形大小均一,平均粒径为(143±21)nm,平均Zeta电位(-27.8±3.8)mV,包封率和载药量为58.3%和5.2%;在pH 7.4条件下纳米粒结构稳定超过30 d,在pH 6.5条件下药物释放高达96%;HA-PASP-NPs@DOX对MDA-MB-231细胞具有靶向性,提高肿瘤细胞对DOX的摄取。结论 透析法制备的HA-PASP-NPs@DOX粒径均一,能有效包裹DOX,实现对乳腺癌细胞的靶向以及在肿瘤酸性的环境中高效释放药物,从而提高抗肿瘤活性。
Abstract
OBJECTIVE To prepare hyaluronic acid(HA)-modified breast cancer microenvironment respond nanoparticles and investigate their physicochemical properties as well as in vitro function. METHODS The polymer HA-PASP was prepared by linking HA with polyaspartic acid (PASP) through a hydrazone bond . Polyethylene glycol (PEG) was used as contrast material for PEG-PASP. Using Doxorubicin(DOX) as a model drug, HA-PASP-NPs@DOX and PEG-PASP-NPs@DOX were prepared by dialysis method. Particle size, morphology and Zeta potential of nanoparticles were observed by particle size tester and transmission electron microscope (TEM). The physical and chemical properties of nanoparticles were evaluated including encapsulation efficiency, drug loading, stability and drug release ability. In vitro function was evaluated including breast cancer cell targeting and tumor microenvironmental response. RESULTS HA-PASP-NPs@DOX was spherical and uniform, size was (143±21) nm and Zeta potential was (-27.8±3.8) mV, encapsulation efficiency was 28.3% and drug loading was 5.2%. Under pH 7.4, the structure of nanoparticles was stable for more than 30 d, but under pH 6.5 the drug release up to 96%. HA-PASP-NPs@DOX was targeted to MDA-MB-231 cells, which increased DOX uptake by tumor cells. CONCLUSION The HA-PASP-NPs@DOX could be successfully prepared by dialysis method, which target breast cancer cells and release drugs efficiently in an acidic environment, what′s more, increase cytotoxicity activity.
关键词
乳腺癌 /
抗肿瘤活性 /
CD44 /
酸敏 /
纳米粒
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Key words
breast cancer /
anti-tumor activity /
CD44 /
acid sensitivity /
nanoparticle
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中图分类号：
R944
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参考文献
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脚注
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基金
陕西省科技统筹创新工程计划项目资助(2016KTCL03-14);陕西省创新药物研究中心资助(2017YWZX-02)
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