Novel Lipid Analogs for Use in Nanocapsule Medicinal Agent Delivery

描述（由申请人提供）：脂质体是球形的脂质双分子层纳米胶囊（直径20 - 1000nm），作为输送药物的运输工具变得越来越重要。诊断性或治疗性化合物的纳米包封的潜在优势——降低毒性、提高稳定性、控制生物利用度和选择性定位——促使了激烈的基础和应用研究。癌症的治疗得益于纳米胶囊化，目前有几种含有治疗剂的商业脂质体配方可供使用，其他的正处于不同的研究阶段。尽管取得了重大进展，但重大障碍阻碍了脂质体递送的应用，特别是在癌症治疗中的应用。这些拟议的试点研究解决了其中的三个问题，旨在进一步对潜在现象的基本化学理解：(1)在与输送特性相容的参数内设计脂质体稳定性；(2)指导纳米胶囊在病变组织中的积累；(3)设计药物化合物在靶向组织中积累后释放的机制。具体目标1的研究将通过采用新的基于氨基酸的脂质类似物来修饰脂质体的热稳定性和pH稳定性来解决第一个问题。初步研究已经证明，一种原型脂质类似物能够与脂质体结合，并增强脂质体在酸性环境中的稳定性。拟议的合成研究将导致制备结构多样的脂质类似物，以检查这些材料的细胞毒性和额外的脂质体稳定性研究。为了研究第二个问题，我们将开发化学转化，将目标寻找特征附加到脂质体表面。为了实现第三个目标，将对增加脂质体内容物泄漏的新化学机制进行研究。该项目的长期目标是通过开发我们实验室发明的新型脂肪酸氨基酸类似物来增强药物递送的脂质体性质。本申请目标的实现可能导致药物递送纳米胶囊的开发，其赋予改进的有效性和降低的毒性。这将显著改善治疗结果，减少与治疗药物毒性相关的负面副作用。

DESCRIPTION (provided by applicant): Liposomes are spherical, lipid bilayer nanocapsules (20 to >1000 nm diameter) that are becoming increasingly important as transport vehicles for delivering medicinal agents. The potential advantages of the nano-encapsulation of diagnostic or therapeutic compounds--reduced toxicity, improved stability, controlled bioavailability, and selectively localization--prompt intense basic and applied research. Treatment of cancers has benefited from nanoencapsulation and presently several commercial liposomal formulations containing therapeutic agents are available and others are at various investigational stages. Despite major advances, significant obstacles impede the application of liposomal delivery generally, and its use in cancer treatment specifically. Three of these problems are addressed by these proposed pilot studies, which seek to further the basic chemical understanding of the underlying phenomena: (1) engineering liposome stability within parameters that are compatible with delivery properties, (2) directing nanocapsule accumulation in diseased tissues, and (3) devising mechanisms that release medicinal compounds once accumulation at targeted tissues has occurred. Studies in specific aim 1 will address the first problem by employing novel amino acid-based lipid analogs to modify liposome thermal and pH stabilities. Preliminary studies have already demonstrated that a prototype lipid analog is capable of liposome incorporation and enhances liposome stability in acidic environments. Proposed synthetic studies will lead to the preparation of structurally diverse lipid analogs for examining the cytotoxicity of these materials and for additional liposome stability studies. To investigate the second problem, we will develop chemical transformations that attach target-seeking features to the liposome surface. In pursuit of the third aim, studies will be conducted on novel chemical mechanisms that will increase the leakage of liposome contents. The long-term goal of this project is to enhance liposome properties for medicinal agent delivery by exploiting novel fatty amino acid analogs invented in our laboratory. The achievement of the goals of this application may lead to the development of medicinal agent delivery nanocapsules that impart improved effectiveness and decreased toxicity. This would significantly improve treatment outcomes and diminish the negative side effects associated with the toxicities of therapeutic drugs.