High drug loading pH-sensitive pullulan-DOX conjugate nanoparticles for hepatic targeting
High drug loading pH-sensitive pullulan-DOX conjugate nanoparticles for hepatic targeting
复制标题
用于肝脏靶向的高载药量 pH 敏感支链淀粉-DOX 缀合物纳米颗粒。
DOI：
10.1002/jbm.a.34680
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发表时间：
2014-01-01
影响因子：
4.9
通讯作者：
Zhang, Xingdong
中科院分区：
文献类型：
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作者：
Li, Huanan;Bian, Shaoquan;Zhang, Xingdong
普鲁兰多柔比星(DOX)在中性条件下稳定，但在弱酸性条件下易发生裂解，通过缩氮键将DOX连接到普鲁兰糖衍生物上，合成了pH敏感的普鲁兰-阿霉素(DOX)偶联物。通过改变DOX与普鲁兰糖衍生物的进料比例，可以得到载药量高达30wt%的偶联物。在水溶液中，偶联物自发形成了以DOX为核、普鲁兰多糖为壳的均匀的核壳结构纳米粒子。根据载药量的不同，纳米粒的直径在50~110 nm之间。体外释放实验表明，在pH为5.0的条件下，2 h内释放75%以上的DOX，而在pH为7.4的条件下，12 h释放的DOX不足15%。这种对pH敏感的DOX释放方式可能有助于DOX从酸性内涵体/溶酶体快速扩散和细胞内转移到细胞核。纳米粒表面的普鲁兰多糖通过与肝细胞膜上去唾液酸糖蛋白受体的特异性相互作用，使纳米粒具有主动靶向肝细胞的特性，而不需要引入任何额外的配体。这些普鲁兰-DOX偶联纳米粒有望成为肝靶向抗肿瘤化疗的药物载体。
pH-sensitive pullulan-doxorubicin (DOX) conjugates were synthesized by attaching DOX onto pullulan derivate through hydrazone bond that was stable under neutral environment but readily cleaved under mildly acidic condition. By changing the feed ratio of DOX to the pullulan derivate, conjugates with drug-loading content up to 30 wt % were obtained. In aqueous solution, the conjugates spontaneously formed uniform core-shell structured nanoparticles with DOX as core and pullulan as shell. The diameters of the nanoparticles ranged from 50 to 110 nm according to the drug-loading content. In vitro releasing experiments showed that more than 75% DOX released within 2 h at pH 5.0, while less than 15% DOX released after 12 h at pH 7.4. This pH-responsive manner of DOX release might assist the quick diffusion of DOX from the acidic endosome/lysosome and the intracellular transfer into the nucleus. Pullulan on the nanoparticles surface provided the nanoparticles with active targeting property to hepatic cells through specific interaction with asialoglycoprotein receptors on the membrane of hepatic cells, without the necessity of introducing any extra ligand. These pullulan-DOX conjugate nanoparticles were expected to be promising drug delivery system for liver targeting antitumor chemotherapy.