Novel Lipid Analogs for Use in Nanocapsule Medicinal Agent Delivery

用于纳米胶囊药物递送的新型脂质类似物

• 批准号: 7477802
• 负责人: George Raymond NEGRETE
• 金额: $ 10.61万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7477802
• 关键词: Achievement; Address; Adverse effects; Aldehydes; Amino Acids; Applied Research; Asparagine; Biological; Biological Availability; Biology; Caliber; Chemical Structure; Chemicals; Chemistry; Choline; Coin; Collaborations; Compatible; Condition; Cysteine; Development; Diagnostic; Drug Formulations; Effectiveness; Encapsulated; Engineering; Environment; Extravasation; Foundations; Funding; Future; Goals; Health Sciences; Image; Investigation; Label; Laboratories; Lead; Letters; Lipid Bilayers; Lipids; Liposomes; Location; Malignant Neoplasms; Manuscripts; Modification; Nanosphere; Pharmaceutical Preparations; Pilot Projects; Preparation; Property; Radioisotopes; Radiology Specialty; Research; Sampling; Serine; Solutions; Staging; Surface; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Treatment outcome; Tumor Tissue; analog; base; cancer therapy; controlled release; cytotoxicity; design; experience; improved; nano; novel; prototype; research study; response; tumor

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.

描述（由申请人提供）：脂质体是球形脂质双层纳米胶囊（直径 20 至 >1000 nm），作为输送药剂的运输工具变得越来越重要。诊断或治疗化合物的纳米封装的潜在优势——降低毒性、提高稳定性、受控的生物利用度和选择性定位——促进了深入的基础和应用研究。癌症的治疗受益于纳米封装，目前有几种含有治疗剂的商业脂质体制剂可供使用，其他制剂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一般应用，特别是其在癌症治疗中的应用。这些拟议的试点研究解决了其中三个问题，这些研究旨在进一步加深对潜在现象的基本化学理解：（1）在与递送特性兼容的参数内设计脂质体稳定性，（2）指导纳米胶囊在患病组织中的积累， (3)设计一旦药物化合物在目标组织中积累就释放药物化合物的机制。具体目标 1 的研究将通过采用新型氨基酸脂质类似物来改变脂质体的热稳定性和 pH 稳定性来解决第一个问题。初步研究已经证明原型脂质类似物能够掺入脂质体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，用于检查这些材料的细胞毒性和其他脂质体稳定性研究。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，将研究增加脂质体内容物渗漏的新化学机制。该项目的长期目标是通过利用我们实验室发明的新型脂肪氨基酸类似物来增强用于药物递送的脂质体特性。该应用目标的实现可能会导致药物递送纳米胶囊的开发，从而提高有效性并降低毒性。这将显着改善治疗结果并减少与治疗药物毒性相关的负面副作用。