ARTIFICIAL POLYMERIC LIPOPROTEINS AS DRUG CARRIERS

描述(摘自申请者摘要)：纳米生物材料 能够模拟生物运输系统的结构方面 如脂蛋白和病毒是很有前景的靶向运输系统 用于低分子药物、重组蛋白质和基因。 聚(环氧乙烷)-嵌段-聚L氨基酸(PEO-b-PLAA)自组装 变成胶束，超分子核/壳结构，它模仿 脂蛋白。因此，他们表现出较长的居留时间 血液和巨噬细胞摄取低。这样做的长期目标是 研究是将这些两嵌段共聚物胶束开发成 疏水性药物的脂蛋白样转运系统。它的核心是 这些胶束可以由L氨基酸或非天然L氨基酸组成， 提供具有不同性质的非极区，例如极性和 粘度。核心的这些性质影响药物的增溶作用，药物 释放，胶束解体。因此，PEO-b-Plaa的胶束可以是 为个别药物量身定做，基于对其特性和 毒品运输要求。这一概念将被探索用于两性霉素 B(Amb)，治疗系统性真菌病的关键药物。膜的活性 药物还具有免疫调节和抗病毒活性。然而，由于其 水溶性差，毒性大，其作为药物的潜力还没有 已经被充分利用了。最近，有研究表明，这种毒性是由于 对AMB的聚集物种和单体AMB无毒，但有活性 对抗真菌细胞。如果Amb能被固定在人造脂蛋白上 并以单体状态输送到靶细胞或器官，这将 开辟AMB疗法的新天地。这项提议的具体目标是： (1)制备PEO-b-Plaa的胶束，该胶束由一系列同源的 脂肪族L氨基酸或非天然L氨基酸，模仿 脂蛋白。(2)表征胶束，特别是胶束的性质 通过荧光探头技术对岩心进行了分析。(3)评估 通过这些胶束增溶AMB，评估增溶程度， 聚集状态和胶束中的位置(光谱研究)。(4) 以释放速率为指标评价AMB从这些胶束中的释放 和聚集状态，评估药物向脂泡或甾醇的转移。 (5)评价其体外抗真菌活性及体内外抗真菌活性 PEO-b-Plaa胶束转运Amb的毒性比较 和PEO-B-Plaa一起。

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.