原文献：Oral delivery system for low molecular weight protamine-dextran-poly(lactic-co-glycolic acid) carrying exenatide to overcome the mucus barrier and improve intestinal targeting efficiency

文献链接：https://pubmed.ncbi.nlm.nih.gov/31088322/

作者：Yina Song,Yanan Shi, Liping Zhang, Haiyan Hu, Chunyan Zhang, Miaomiao Yin,Xuemei Zhang & Kaoxiang Sun

摘要：Aim: This study aimed to explore the effect of nanoparticles loaded with exenatide in overcoming the mucus barrier and improving intestinal targeting efficiency, to improve the oral bioavailability. Materials & methods: Low molecular weight protamine (LMWP)-dextran-poly(lactic-co-glycolic acid)Was used to create LMWP-dextran-poly(lactic-co-glycolic acid)-nanoparticles (LDPs) encapsulating exenatide-Zn2+ complex.Results & conclusion: LDPs showed improved penetration of the mucus barrier, and LMWP was helpful for mediating cell translocation through protein transduction domains. The absorption sites and distribution rates of LDPs were verified by intestinal localization experiments and in vivo distribution experiments. Cell uptake and transmembrane experiments confirmed the absorption efficiency in the intestinal epithelium. Furthermore, the relative bioavailability after oral administration of exenatide-Zn2+-LDPs was 8.4%, with a significant hypoglycemic effect on Type 2 diabetic mice.

LMWP是一种细胞穿透肽由天然鱼精蛋白酶解制备的，是有效的蛋白转导域（PTD）肽，PLGA是一种聚合物，具有良好的生物相容性、安全性和生物降解性，可以延长化合物在体内的停留时间。采用低分子量鱼精蛋白-右旋糖-聚（乳酸-共乙醇酸）（LMWP-DEX-PLGA）作为聚合物材料，含艾塞那肽的LMWP-DEX-PLGA-NPs（LDPs）具有克服黏液屏障、提高肠道靶向效率的效果，可以提高大分子蛋白药物的口服生物利用度。以下是LMWP-DEX-PLGA-NPs的制备过程：

图：LMWP-DEX-PLGA纳米颗粒克服肠上皮细胞的多种屏障的经上皮转运示意图

将LMWP-DEX-PLGA加入DMSO中，摇晃至完全溶解。然后将二氯甲烷加入到DMSO溶液中，在摇晃和混合后成为油相。在油相中加入艾塞那肽-zn2+，用超声细胞粉碎机超声处理得到初乳。将复合乳液分散到聚乙烯醇溶液中。最后保留透析袋中，通过透析去除有机溶剂，得到LDPs。采用相同的方法以DEX-PLGA作为载体材料制备DPs。载药DPs具有较大的粒径和较低的电位，这是由于带负电荷的艾塞那肽的封装导致NPs的整体电位的降低。此外，空白LDPs和艾塞那肽-zn2+-LDPs的电位都较低，粒径更大。这可能是由于带负电荷的LMWP的存在造成的。DPs和LDPs之间的电位差异不明显。这可能是因为PLGA和DEX的分子量都远高于LMWP，而其电学性能主要由PLGA和DEX决定。

结论： 由LMWP-DEX-PLGA制备的LDPs提高了黏液屏障的穿透能力，LMWP通过蛋白转导域介导细胞易位。通过肠道定位实验和体内分布实验验证了LDPs的吸收部位和分布速率。细胞摄取和跨膜实验证实了其对肠上皮细胞的吸收效率。