肝星状细胞靶向M6P-HSA修饰的氧化苦参碱聚合物泡囊给药系统构建及抗肝纤维化作用

Liver fibrosis and advanced fibrosis represent the final common pathway of virtually all chronic liver diseases,but lack of dependable and valid treatment drug.Oxymatrine, an extract from a traditional Chinese herb, Sophora ?avescens Ait,from Ningxia medicinal plants resource, has been widely used for the treatment of antihepatic fibrosis.Oxymatrine injection，the short elimination half-life and Poor distribution in liver result in Low biological availability. To enhance the treatment effect,patients have to be administer too large a dose.Dutch researchers have detected that the receptor-mediated M6PHSA-liposomes displays good targeting HSCs.It is a novel candidate for oxmatrine delivery carriers antifibrotic effects on liver fibrosis.My research previously showed that liposomes encapsulating oxymatrine is low stability and high leakage.As a novel class of synthetic carrier, polymersomes are self-assembled vesicles of amphiphilic block copolymers with thicker and tougher membrane than lipids. Polymersomes have the same advantages as liposomes and nanoparticles. Compared with liposomes,polymersomes are more stable. The internal aqueous cavity of the polymersome is expected to load more hydrophilic drugs including oxmatrine than nanoprticles.Moreover,the physical and chemical properties of polymersomes including particles size,membrane thickness, permeability, drug loading, surface modification, and even in vivo behavior may be broadly tunable through rich diversity of block copolymer chemistries.Basing on our early stage research work about drug delivery applications, M6PHSA is synthesized,and amphiphilic block-copolymers based on PEG-PCL is synthesized by ring-opening polymerization of cyclic esters. The polymerization of PEG-PCL gives block-copolymers with controllable molecular weights and a well defined structure.OM encapsulated polymersomes(OM-PMs) were prepared by pH gradient method.The study will focus on the preparation and evaluation of HSCs targeting of polymersomes encapsulating oxymatrine based molecular,where M6P-HSA as conjugated to the polymersomes' surface (M6PHSA-PMs-OM). This involves preparation of drug-loaded nanoparticles, characterization of drug-loaded nanoparticles(particle distribution, the drug encapsulation ef?ciency, Stability studies, In vitro drug release), in vivo and in vitro evaluation of their delivery property,and anti-fibrosis effect on liver fibrosis.The achievements in research will be provided some valuable reference for oxmatrine antifibrotic effects on liver fibrosis.

肝纤维化（HF）及肝硬化代表着各种慢性肝病的最终共同转归，目前尚缺乏有效治疗。氧化苦参碱（OM）是从宁夏特色中药材苦豆子中提取的生物碱之一，具有明确的抗HF作用，但半衰期短、肝脏分布少、剂量大、有副作用。M6P/GFll受体介导肝星状细胞（HSCs）靶向特异性给药可为OM抗HF治疗提供了新的思路。我们初步研究发现脂质体包载水溶性OM稳定性差、易于渗漏。聚合物泡囊（PMs）对亲水性药物包载能力高于其他纳米载体，稳定性强，且易于修饰。在前期工作基础上，拟合成M6PHSA为配体，合成不同分子量、嵌段比例PEG-PCL制备PMs，通过PH梯度法将OM包载于PMs中，构建一种受体介导HSC的新型M6HSA-PMs-OM抗HF靶向给药系统，探讨该系统的形成条件、理化特性、HSC体内外靶向性以及抗HF作用及机制，为OM抗HF有效治疗提供有价值的研究资料。

肝纤维化（HF）及肝硬化代表着各种慢性肝病的最终共同转归，目前尚缺乏有效治疗。氧化苦参碱（OM）是从宁夏特色中药材苦豆子中提取的生物碱之一，具有明确的抗 HF 作用，但半衰期短、肝脏分布少、剂量大、有副作用。本研究以聚合物泡囊（PMs）作为纳米给药载体，构建了RGD修饰的OM聚合物泡囊靶向给药系统为 OM 抗 HF治疗提供了新的思路。.基于以上科学假设，本研究制备了RGD修饰的氧化苦参碱聚合物泡囊靶向给药系统（RGD-PM-OM），该系统粒径约96 nm，Zeta电位接近中性，透射电镜观察其形态为球形或近球形.载药量（DLC）6.6%，包封率（DLE）39.72%。体外释药结果表明RGD-PM-OM 前2h有突释放现象，后期释放相对缓慢，与OM相比有明显缓释效果。体外细胞实验结果表明与OM及PM-OM相比，RGD-PM-OM对HSCs抑制作用明显，且能显著降低α-SMA 及collagen 1α1 型胶原 mRNA 表达水平，有利于减轻肝纤维化程度；细胞摄取及受体竞争抑制实验证实RGD修饰的PM可与活化HSC表面的 VI 型胶原受体相互作用增强其在活化HSC的摄取水平。药动学结果可知，OM溶液t1/2 为1.41 h，PM-OM和RGD-PM-OM的t1/2 分别为OM的2.12和2.31倍，表明聚合物泡囊可延长OM在血液中循环时间。从肝纤维化大鼠动物模型结果可知RGD-PM-OM的抗肝纤维化效果优于PM-OM组及普通OM溶液组，表明受体介导的RGD-PM-OM靶向活化HSC有利于增强OM的治疗肝纤维化作用，这与RGD修饰的氧化苦参碱聚合物泡囊具有HSC靶向性有关。.本研究成功将亲水性药物氧化苦参碱包载于PEG-PCL聚合物泡囊中，提高了亲水性药OM的载药量，对提高亲水性药物包载能力提供了新的思路；构建了RGD修饰的氧化苦参碱聚合物泡囊给药系统，通过活化HSC及肝纤维大鼠模型实验发现该给药系统有较强的治疗肝纤维化作用，对受体介导HSC的靶向给药提供了启示；建立了乙腈沉淀蛋白结合UPLC-MS/MS法，进行了该给药系统大鼠体内OM的药动学及小鼠体内组织分布研究。以上工作为 OM 抗 HF 有效治疗提供有价值的研究资料。

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