Peptide-amphiphile biomimetics for targeted therapies

用于靶向治疗的肽两亲生物模拟物

• 批准号: 6967036
• 负责人: GREGG B FIELDS
• 金额: $ 26.87万
• 依托单位: FLORIDA ATLANTIC UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6967036
• 关键词: amphiphilicity; biomimetics; colloids; drug delivery systems; drug vehicle; fluorescent dye /probe; liposomes; melanoma; membrane permeability; neoplastic cell; peptide analog; polymers; protein engineering; tissue /cell culture

DESCRIPTION (provided by applicant): One of the biggest obstacles for efficient drug delivery is specific cellular targeting. Liposomes have long been used for drug delivery, but do not possess targeting capabilities. This limitation may be circumvented by surface coating of colloidal delivery systems with peptides, proteins, carbohydrates, vitamins, or antibodies that target cell surface receptors or other biomolecules. Each of these coatings has significant drawbacks. One idealized system for drug delivery combines stabilized "mini-protein" ligands with a colloidal delivery vehicle. Our prior studies have shown that peptide-amphiphiles, whereby both a peptide "head group" and a lipid-like "tail" are present in the same molecule, can be used to engineer collagen-like triple-helical or alpha-helical mini-proteins. The tails serve to stabilize the head group structural elements. These peptide-amphiphiles can be designed to bind to specific cell surface receptors with high affinity, while being minimally degraded. In preliminary studies, we have prepared liposomes using a melanoma targeting peptide-amphiphile ligand, and shown that these liposomes were stable, the peptide-amphiphile retained triple-helical structure, and an encapsulated fluorescent dye was selectively delivered to cells. In the present proposal we will develop peptide-amphiphile liposomes and polyPro dendrimers as a new class of drug delivery vehicles, taking advantage of melanoma receptor targeting and liposome activation by melanoma proteases. Transfer of drug into the cell will also be improved by incorporation of cell membrane traversing peptide-amphiphiles. A variety of biophysical and biological techniques will be used to evaluate peptide-amphiphile structure-function relationships. The selectivity of peptideamphiphile colloidal delivery vehicles will be analyzed using metastatic melanoma cells and other cell types (fibroblasts, endothelial cells) found in the melanoma microenvironment.

描述（由申请人提供）：有效药物递送的最大障碍之一是特定的细胞靶向。脂质体长期以来被用于药物递送，但不具备靶向能力。这种限制可以通过用肽、蛋白质、碳水化合物、维生素或靶向细胞表面受体或其他生物分子的抗体对胶体递送系统进行表面涂覆来规避。这些涂层中的每一种都具有显着的缺点。一种理想的药物递送系统将稳定的“微型蛋白质”配体与胶体递送载体结合起来。我们之前的研究表明，肽两亲物（即肽“头基”和脂质“尾部”同时存在于同一分子中）可用于设计胶原蛋白样三螺旋或 α 螺旋微型结构。蛋白质。尾部用于稳定头部结构元件。这些肽两亲物可以设计为以高亲和力结合特定的细胞表面受体，同时降解程度最低。在初步研究中，我们使用靶向黑色素瘤的肽-两亲物配体制备了脂质体，并表明这些脂质体是稳定的，肽-两亲物保留了三螺旋结构，并且封装的荧光染料被选择性地递送至细胞。在本提案中，我们将利用黑色素瘤受体靶向和黑色素瘤蛋白酶的脂质体激活，开发肽两亲性脂质体和聚Pro树状聚合物作为新型药物递送载体。通过掺入穿过细胞膜的肽两亲物，也将改善药物向细胞的转移。各种生物物理和生物技术将用于评估肽-两亲物结构-功能关系。将使用黑色素瘤微环境中发现的转移性黑色素瘤细胞和其他细胞类型（成纤维细胞、内皮细胞）来分析肽两亲性胶体递送载体的选择性。