Reported here is the synthesis and biological evaluation of the asialoglycoprotein receptor (ASGP-R) targeted fourth generation poliamidoamine dendrimer (G(4)-PAMAM) loaded with sorafenib. The ASGP-R targeted dendrimer was obtained by conjugation of Lactobionic acid (La) to the G(4)-PAMAM dendrimer, followed by acetylation (Ac) of the free amino groups in order to reduce the non-specific interactions with the cell membrane. Moreover, by additionally grafting fluorescein (FITC), it was easy to characterize the internalization pathway and the intracellular fate of the targeted dendrimer Ac-La-G(4)-PAMAM-FITC. In vitro experiments performed on HepG-2 and HLE cell lines, allowed to study the ability of the dendrimers to affect the cell vitality. Confocal microscopy and cytofluorimetric analysis confirmed higher binding and uptake ability of the Ac-La-G(4)-PAMAM-FITC dendrimer in well differentiated and ASGP-R expressing human liver cancer cell line HepG-2 compared non-expressing HLE cells. Ac-La-G(4)-PAMAM-FITC dendrimer loaded with sorafenib was stable and showed sustained sorafenib release. As evidenced by the cytotoxicity studies, sorafenib included in the dendrimer maintained its effectiveness, and was able to produce a longer lasting effect over the time compared to molar equivalent doses of free sorafenib. This new targeted dendrimer appears to be a suitable carrier for the delivery of sorafenib to liver cancer cells expressing ASGP-R.

译文

此处报道的是载有索拉非尼的靶向第四代丙酰胺胺树状分子 (G(4)-PAMAM) 的去唾液酸糖蛋白受体 (asgp-r) 的合成和生物学评估。通过将乳糖酸 (La) 与G(4)-PAMAM树状大分子偶联,然后对游离氨基进行乙酰化 (Ac) 以减少非特异性相互作用,从而获得asgp-r靶向的树状大分子细胞膜。此外,通过另外接枝荧光素 (FITC),很容易表征目标树状分子Ac-La-G(4)-PAMAM-FITC的内化途径和细胞内命运。在HepG-2和HLE细胞系上进行的体外实验允许研究树状大分子影响细胞活力的能力。共聚焦显微镜和细胞荧光分析证实,与未表达的HLE细胞相比,Ac-La-G(4)-PAMAM-FITC树状聚合物在分化良好且表达asgp-r的人肝癌细胞系HepG-2更高的结合和摄取能力。载有索拉非尼的Ac-La-G(4)-PAMAM-FITC树枝状大分子稳定,并显示出持续的索拉非尼释放。正如细胞毒性研究所证明的那样,与摩尔当量剂量的游离索拉非尼相比,包含在树枝状聚合物中的索拉非尼保持了其有效性,并且能够在一段时间内产生更长的持久效果。这种新的靶向树枝状聚合物似乎是将索拉非尼递送到表达asgp-r的肝癌细胞的合适载体。

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