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去唾液酸糖蛋白受体(ASGP-R)靶向的第四代多巴胺胺树状聚合物(G(4)-PAMAM)的合成和生物学评估。 ASGP-R靶向树状聚合物是通过将乳酸基乳酸(La)与G(4)-PAMAM树状聚合物缀合,然后对游离氨基进行乙酰化(Ac),以减少与细胞膜的非特异性相互作用而获得的。此外,通过额外嫁接荧光素(FITC),很容易表征目标树状聚合物Ac-La-G(4)-PAMAM-FITC的内在途径和细胞内命运。在HepG-2和HLE细胞系上进行的体外实验可以研究树状聚合物影响细胞活力的能力。共聚焦显微镜和细胞荧光分析证实,Ac-La-G(4)-PAMAM-FITC树状聚合物在高分化和表达ASGP-R的人肝癌细胞系HepG-2中具有更高的结合和摄取能力,而与未表达的HLE细胞相比则更高。载有索拉非尼的Ac-La-G(4)-PAMAM-FITC树状聚合物稳定并显示索拉非尼持续释放。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,树状大分子中包含的索拉非尼保持了其有效性,并能够在一段时间内产生更长的持久作用。这种新的靶向树状聚合物看来是将索拉非尼递送至表达ASGP-R的肝癌细胞的合适载体。

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