Purpose

Gallic acid (GA) is a polyphenolic compound with proven efficacy against hepatic fibrosis in experimental animals. However, it suffers from poor bioavailability and rapid clearance that hinders its clinical investigation. Accordingly, we designed and optimized reverse micelle-loaded lipid nanocapsules (RMLNC) using Box-Behnken design that can deliver GA directly into activated-hepatic stellate cells (aHSCs) aiming to suppress hepatic fibrosis progression.

Methods

GA-RMLNC was prepared using soft energy, solvent free phase inversion temperature method. Effects of formulation variables on particle size, zeta potential, entrapment efficiency (EE%) and GA release were studied. In-vivo biodistribution of GA-RMLNC in rats and in-vitro activities on aHSCs were also explored.

Results

Nano-sized GA-RMLNCs (30.35 ± 2.34 nm) were formulated with high GA-EE% (63.95 ± 2.98% w/w) and physical stability (9 months). The formulated system showed burst GA release in the first 2 h followed by sustained release profile. In-vivo biodistribution imaging revealed that RMLNC-loaded with rhodamine-B accumulated mainly in rats’ livers. Relative to GA; GA-RMLNC displayed higher anti-proliferative activities, effective internalization into aHSCs, marked down-regulation in pro-fibrogenic biomarkers’ expressions and elevated HSCs’ apoptosis.

Conclusions

These findings emphasize the promising application of RMLNC as a delivery system in hepatic fibrosis treatment, where successful delivery of GA into aHSCs was ensured via increased cellular uptake and antifibrotic activities.

中文翻译：

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反胶束负载脂质纳米胶囊对没食子酸递送至活化的肝星状细胞的影响：一种有前途的肝纤维化治疗方法。

目的

没食子酸（GA）是一种多酚化合物，已被证明对实验动物的肝纤维化有效。然而，它的生物利用度差和快速清除阻碍了其临床研究。因此，我们使用 Box-Behnken 设计设计并优化了反胶束脂质纳米胶囊 (RMLNC)，该胶囊可以将 GA 直接递送到活化的肝星状细胞 (aHSC) 中，从而抑制肝纤维化进展。

方法

采用软能、无溶剂相转变温度法制备GA-RMLNC。研究了配方变量对粒径、zeta 电位、包封率 (EE%) 和 GA 释放的影响。还探讨了GA-RMLNC 在大鼠体内的生物分布和aHSC 的体外活性。

结果

纳米级 GA-RMLNC (30.35 ± 2.34 nm) 的配制具有高 GA-EE% (63.95 ± 2.98% w/w) 和物理稳定性（9 个月）。配制的系统在前 2 小时内显示出 GA 的爆发释放，然后是持续释放曲线。体内生物分布成像显示，负载罗丹明-B 的 RMLNC 主要在大鼠肝脏中积累。相对于GA；GA-RMLNC 显示出更高的抗增殖活性、有效内化到 aHSC 中、显着下调促纤维化生物标志物的表达并提高 HSC 的凋亡。

结论

这些发现强调了 RMLNC 作为肝纤维化治疗中递送系统的应用前景，其中通过增加细胞摄取和抗纤维化活性确保将 GA 成功递送至 aHSC。