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）：有效药物输送的最大障碍之一是特定的细胞靶向。脂质体长期以来一直用于药物输送，但不具备靶向能力。可以通过胶体递送系统与肽，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的表面涂层来规避这种局限性。这些涂料中的每一个都有明显的缺点。一种用于药物输送的理想化系统将稳定的“迷你蛋白质”配体与胶体输送车结合在一起。我们先前的研究表明，肽 - 抑制剂在同一分子中都存在肽“头部组”和类似脂质的“尾巴”，可用于设计类似胶原蛋白的三螺旋或α-螺旋螺旋蛋白。尾巴可以稳定头部组的结构元素。这些肽 - 抑制物的设计可与具有高亲和力的特定细胞表面受体结合，同时降低。在初步研究中，我们已经使用靶向肽 - 抑制剂配体的黑色素瘤制备了脂质体，并表明这些脂质体是稳定的，肽 - 抑制剂保留的三螺旋结构，并选择性地递送了封装的荧光染料。在本提案中，我们将利用黑色素瘤蛋白酶的黑色素瘤受体靶向和脂质体激活，开发肽 - 抑制脂质体和polypro树枝状聚合物作为新的药物输送车。通过掺入肽 - 抑制剂的细胞膜掺入细胞膜，也将改善药物进入细胞的转移。多种生物物理和生物学技术将用于评估肽 - 抑制结构功能关系。将在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）分析肽型胶体递送车的选择性。