Re-programming pullulan for targeting and controlled release of doxorubicin to the hepatocellular carcinoma cells
Re-programming pullulan for targeting and controlled release of doxorubicin to the hepatocellular carcinoma cells
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DOI：
10.1016/j.ejps.2017.02.016
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发表时间：
2017-05-30
影响因子：
4.6
通讯作者：
Caliceti, Paolo
中科院分区：
文献类型：
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作者：
Balasso, Anna;Salmaso, Stefano;Caliceti, Paolo
通过支链淀粉重编程获得了一种用于肝细胞癌 (HCC) 靶向的新型生物缀合物，其中涉及骨架氧化以及靶向肽和阿霉素 (Doxo) 通过可释放连接体的缀合。初步体内研究表明，100 个吡喃葡萄糖单位 (GPU) 中的 40 个的氧化显着降低了支链淀粉的非特异性肝向性。这种氧化聚合物用 PreS1 进行功能化，以选择性地靶向 HCC，并用罗丹明 (Rhod) 作为标记来进行体外细胞摄取研究。 PreS1 和 Rhod 分别通过 3.4 和 2 kDa PEG 间隔基并通过还原胺化与沿氧化支链淀粉主链存在的醛缀合。所得的 PreS1-Pull-Rhod 每条氧化支链淀粉链平均含有 8 个 PreS1。使用过度表达丝氨酸 B3 受体的 HepG2/SERPINB3 细胞和不过度表达该受体的对照 HepG2/EMFTY 细胞进行细胞培养研究。使用 PreS1-Pull-Rhod 和 Pull-Rhod（对照聚合物）通过细胞荧光测定法和共焦显微镜进行的比较研究表明，PreS1 对缀合物具有高细胞选择性。然后，利用氧化普鲁兰多糖通过腙 pH 敏感键和 NH2-PEG(3.4) (kda)-PreS1 将 Doxo 与聚合物主链缀合，生成靶向药物递送系统。相对于对照 Pull-Doxo，PreS1-Pull-Doxo 缀合物对 HepG2/SERPINB3 细胞的抗癌活性增加两倍。 (C) 2017 Elsevier B.V. 保留所有权利。
A novel bioconjugate for hepatocellular carcinoma (HCC) targeting was obtained by pullulan re-programming, which involves the backbone oxidation and conjugation of targeting peptide and doxorubicin (Doxo) through a releasable linker. Preliminary in vivo studies showed that the oxidation of 40 glucopyranose units (GPU) out of 100 remarkably reduced the pullulan unspecific liver tropism. This oxidized polymer was functionalized with PreS1 to selectively target the HCC and with rhodamine (Rhod) as label to perform in vitro cell up-take investigations. PreS1 and Rhod were conjugated to the aldehydes present along the oxidized pullulan backbone through a 3.4 and 2 kDa PEG spacer, respectively, and by reductive amination. The resulting PreS1-Pull-Rhod contained a mean of 8 PreS1 per oxidized pullulan chain. Cell culture studies were performed by using HepG2/ SERPINB3 cells that overexpress the serpine B3 receptor and control HepG2/EMFTY cells that do not overexpress the receptor. A comparative study by cytofluorimetry and confocal microscopy performed using PreS1-Pull-Rhod and Pull-Rhod (control polymer) showed that PreS1 conveys to the conjugate high cell selectivity. Afterwards, the oxidized pullulan was exploited to generate a targeted drug delivery system by conjugation of Doxo to the polymer backbone through a hydrazone pH -sensitive bond and NH2-PEG(3.4) (kda)-PreS1. The PreS1-Pull-Doxo conjugate showed a two-fold increase of anticancer activity with respect to the control Pull-Doxo towards HepG2/ SERPINB3 cells. (C) 2017 Elsevier B.V. All rights reserved.