Screening of pH-responsive long-circulating polysaccharide-drug conjugate nanocarriers for antitumor applications
Screening of pH-responsive long-circulating polysaccharide-drug conjugate nanocarriers for antitumor applications
复制标题
用于抗肿瘤应用的pH响应性长循环多糖-药物缀合物纳米载体的筛选
DOI：
10.1039/c8tb02474j
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发表时间：
2019
影响因子：
7
通讯作者：
Wu Jun
中科院分区：
文献类型：
--
作者：
Zhang Xinyu;Li D;an;Huang Jun;Ou Kunyong;Yan Binyuan;Shi Fu;Zhang Jiayuan;Zhang Junfu;Pang Jun;Kang Yang;Wu Jun
在治疗恶性肿瘤方面，药物纳米载体具有较长的血液循环时间和靶向肿瘤微环境的能力，是一种很有前途的治疗药物。为了系统地研究多糖作为靶向肿瘤微环境药物纳米载体的作用和功能，通过席夫碱反应将不同类型的多糖(藻酸(Alg)、透明质酸(HA)和葡聚糖(Dex))与阿霉素(DOX)共价键合，形成具有酸敏亚胺键的pH敏感型多糖-DOX前药。经筛选，Dex-DOX载药量高，稳定性好，而Alg-DOX和HA-DOX可能存在氧化程度低、载药量有限或生理条件不稳定等缺点。Dex-DOX前体药能够在磷酸盐缓冲盐水(PBS)中自组装成稳定的纳米粒。由于Dex6k-DOX和Dex150k-DOX具有相似的药物结合率和较长的循环时间，因此选择Dex6k-DOX和Dex150k-DOX进一步比较。与Dex6k-DOX相比，主链较长的Dex150k-DOX在体外模拟酸性条件下具有更高的药物释放速率，显著抑制细胞增殖。进一步的体内实验表明，Dex150k-DOX能更有效地提高抗肿瘤效率和生存率，同时减少毒副作用。总之，这些筛选和比较为多糖-DOX前药平台作为潜在的抗肿瘤药物提供了详细和系统的信息。
For the treatment of malignant tumors, drug nanocarriers with long blood circulation time and ability to target the tumor microenvironment are promising therapeutic abilities. In this work, to systematically investigate the roles and functions of polysaccharides as drug nanocarriers targeting the tumor microenvironment, different types of polysaccharides (alginic acid (Alg), hyaluronic acid (HA), and dextran (Dex)) were covalently bonded with doxorubicin (DOX) through a Schiff base reaction to form a pH-sensitive polysaccharide–DOX prodrug having an acid-sensitive imine bond. After screening, Dex-DOX exhibited high drug loading content and good stability, while Alg-DOX and HA-DOX may have disadvantages such as low degree of oxidation, limited drug loading capacity, or instability in physiological conditions. Dex-DOX prodrugs were able to self-assemble into stable nanoparticles in phosphate buffered saline (PBS). Then, Dex6k-DOX and Dex150k-DOX were selected for further comparisons since they had similar drug-binding rates and long circulation time. When compared with Dex6k-DOX, the longer main-chain Dex150k-DOX showed a higher drug release rate under simulated acidic conditions in vitro, which significantly inhibited cell proliferation. Further in vivo experiments showed that Dex150k-DOX could more effectively improve the antitumor efficiency and survival rate while reducing side-effects. Overall, the screening and comparisons provided detailed and systematical information about the polysaccharide–DOX prodrug platform as potential antitumor drugs.