SYNTHESIS & ASSEMBLY OF BIO-RESPONSIVE COPOLYMER VESICLES FOR PAYLOAD TRANSPORT

合成

• 批准号: 8360584
• 负责人: Millicent O Sullivan
• 金额: $ 31.05万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360584
• 关键词: Address; Binding; Biocompatible Materials; Biological; Cells; Cleaved cell; Cues; Cytosol; Development; Drug Delivery Systems; Encapsulated; Evolution; Fibroblasts; Funding; Grant; Inflammatory; Location; Methods; National Center for Research Resources; Nucleic Acids; Peptide Hydrolases; Peptides; Polymers; Positioning Attribute; Principal Investigator; Research; Research Infrastructure; Resources; Rupture; Series; Serum; Site; Solutions; Source; Stimulus; Stromal Neoplasm; Structure; System; Therapeutic; Transport Process; Transport Vesicles; Treatment Efficacy; United States National Institutes of Health; Vertebral column; Vesicle; Vision; aqueous; capsule; copolymer; cost; cytotoxicity; design; nano; nano container; novel; protein aminoacid sequence; response; self assembly; uptake

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. critically important for therapeutic efficacy. Unfortunately, many methods for drug delivery are often highly inefficient due to non-ideal serum-stability, transport across biological barriers, and release at the target site. To address these problems, we will create bio-responsive, polymeric nano-containers for the selective delivery of therapeutic compounds to pre-determined cellular locations. We will combine the solution selfassembly of block copolymers with selective targeting and cleaving peptide linkages to permit vesicle evolution in response to critical environmental stimuli, eventually leading to site-specific release of the encapsulated payload. In the first specific aim, we will create novel peptide-containing block copolymers and characterize their self-assembly in aqueous solution. These amphiphilic copolymers will be designed to assemble into vesicular structures. Peptides designed to promote endocytotic uptake (1) and endosomal release (2) will be sequentially incorporated into the hydrophilic backbone of the block copolymer in a layered fashion. In the second specific aim, we will evaluate the protease-sensitivity and targeting efficiency of each peptide layer. The protease accessibility of each peptide sequence, as well as vesicle stability, will be assessed as a function of peptide position in the vesicle's corona. The cell-vesicle binding, vesicle internalization, and endosomolytic activity of the vesicles also will be evaluated. In the third specific aim, we will validate the ability of the peptides to direct vesicle transport to and rupture within the cytosol, and we will evaluate the cytotoxicity of both payload-free and cytotoxinincorporating vesicles. Vesicle rupture will be induced by selective placement of peptide (2) proximal to the hydrophobic block of the polymer. Our long-term vision for this project is the development of a nucleic acid delivery system for the selective targeting of tumor stromal fibroblasts and/or inflammatory cells. We envision the complete de novo design of modular vesicular nano-capsules containing a series of location specific "sheddable" shells to direct payload transport in response to environmental cues at each transport barrier.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 对于治疗效果至关重要。不幸的是，许多药物输送方法通常都非常困难。 由于不理想的血清稳定性、跨生物屏障的运输以及在目标位点的释放而导致效率低下。 为了解决这些问题，我们将创建生物响应性聚合物纳米容器，用于选择性 将治疗化合物递送至预定的细胞位置。我们将结合解决方案自组装 具有选择性靶向和裂解肽键以允许囊泡的嵌段共聚物 响应关键环境刺激的进化，最终导致特定地点的释放 封装的有效负载。 在第一个具体目标中，我们将创造新型的含肽嵌段共聚物和 表征它们在水溶液中的自组装。这些两亲性共聚物将被设计为 组装成囊泡结构。旨在促进内吞摄取 (1) 和内体摄取的肽 释放(2)将按顺序并入嵌段共聚物的亲水主链中 分层时尚。在第二个具体目标中，我们将评估蛋白酶敏感性和靶向性 每个肽层的效率。每个肽序列以及囊泡的蛋白酶可及性 稳定性，将根据囊泡冠中肽位置的函数进行评估。细胞-囊泡结合， 还将评估囊泡的内化和内体溶解活性。在第三个 为了实现特定目标，我们将验证肽引导囊泡运输和破裂的能力 在细胞质内，我们将评估无有效负载和结合细胞毒素的细胞毒性 囊泡。通过选择性地将肽 (2) 放置在邻近的位置来诱导囊泡破裂 聚合物的疏水性嵌段。 我们对该项目的长期愿景是开发核酸递送系统 选择性靶向肿瘤基质成纤维细胞和/或炎症细胞。我们设想完整的德 模块化囊泡纳米胶囊的新颖设计，包含一系列特定位置的“可脱落”壳 根据每个运输障碍处的环境线索来指导有效载荷运输。