ARTIFICIAL POLYMERIC LIPOPROTEINS AS DRUG CARRIERS

描述（改编自申请人摘要）：纳米生物材料 能够模拟生物运输系统的结构方面， 例如脂蛋白和病毒是有希望的靶向转运系统 用于低分子量药物、重组蛋白和基因。 聚环氧乙烷-聚L-氨基酸嵌段共聚物自组装 进入胶束，超分子核/壳结构， 脂蛋白 因此，它们已显示出延长的停留时间， 血液和巨噬细胞的低摄取。 长期目标是 研究是将这些二嵌段共聚物胶束开发成 脂蛋白样转运系统用于疏水性药物。 的核心 这些胶束可以由L氨基酸或非天然L氨基酸构建， 提供具有不同性质的非极性区域，例如极性和 粘度 核的这些性质影响药物溶解、药物释放和药物释放。 释放和胶束破裂。 因此，PEO-b-PLAA的胶束可以是 根据对药物特性的了解， 药品运输要求。 这一概念将被探讨为阿替西霉素 B（AmB），治疗系统性真菌病的关键药物。 膜活性 药物还具有免疫调节和抗病毒活性。 但由于其 水溶性差，毒性大，其作为药物的潜力还没有 被充分利用。 最近，研究表明， AmB的聚集物种和单体AmB是无毒的，但活性 对抗真菌细胞 如果AmB可以锚定在人工脂蛋白上 并以单体状态运输到靶细胞或器官， 为AmB疗法开辟了新的视野。 本提案的具体目标是： (1)为了制备由一系列同系物组成的PEO-b-PLAA胶束， 脂肪族L氨基酸或非天然L氨基酸，模拟 脂蛋白 (2)为了表征这些胶束，特别是性质 用荧光探针技术检测核的荧光强度。 (3)评价 通过这些胶束溶解AmB，评估溶解水平， 聚集状态和胶束中的位置（光谱研究）。 （四） 以释放速率评价AmB从这些胶束中的释放 和聚集状态，评估药物向脂质囊泡或固醇的转移。 (5)评价其体外抗真菌活性和体内外抗真菌活性 基于PEO-b-PLAA的胶束转运AmB的毒性，进行比较 PEO-b-PLAA。

DESCRIPTION (Adapted from Applicant's Abstract): Nanoscopic biomaterials that are able to mimic structural aspects of biological transport systems such as lipoproteins and viruses are promising targetable transport systems for low molecular weight drugs, recombinant proteins, and genes. Poly(ethylene oxide)-block-poly(L amino acid) (PEO-b-PLAA) self-assembles into micelles, supramolecular core/shell structures, which mimic lipoproteins. As such, they have demonstrated prolonged residence time in blood and low uptake by macrophages. The long-term objective of this research is the development of these diblock copolymer micelles into lipoprotein-like transport systems for hydrophobic drugs. The cores of these micelles may be built from L amino acids or unnatural L amino acids, providing nonpolar domains with varied properties, such as polarity and viscosity. These properties of the core affect drug solubilization, drug release, and micellar break-up. Hence, micelles of PEO-b-PLAA may be tailored for an individual drug, based on knowledge of its properties and drug transport requirements. This concept will be explored for amphotericin B (AmB), the key drug for systemic fungal diseases. The membrane-active drug also has immunomodulatory and antiviral activity. However, due to its poor water solubility and high toxicity, its potential as a drug has not been fully exploited. Recently, it has been shown that the toxicity is due to aggregated species of AmB and that monomeric AmB is non-toxic, but active against fungal cells. If AmB could be anchored onto artificial lipoproteins and transported to target cells or organs in a monomeric state, this would open up new horizons in AmB therapy. The specific aims of this proposal: (1) To prepare micelles of PEO-b-PLAA composed of a homologous series of aliphatic L amino acids or unnatural L amino acids, mimicking the cores of lipoproteins. (2) To characterize these micelles, especially the properties of the cores by fluorescent probe technique. (3) To evaluate the solubilization of AmB by these micelles, assessing solubilized levels, aggregation state, and location in the micelles (spectroscopic study). (4) to evaluate the release of AmB from these micelles in terms of release rate and aggregation state, assessing drug transfer to lipid vesicles or sterols. (5) To evaluate the in vitro antifungal activity and the in vitro/in vivo toxicity of AmB transported by micelles based PEO-b-PLAA, making comparisons with PEO-b-PLAA.