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

合成

• 批准号: 8168490
• 负责人: Millicent O Sullivan
• 金额: $ 41.46万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168490
• 关键词: Address; Binding; Biological; Cells; Cleaved cell; Computer Retrieval of Information on Scientific Projects Database; Cues; Cytosol; Development; Drug Delivery Systems; Encapsulated; Evolution; Fibroblasts; Funding; Grant; Inflammatory; Institution; Location; Methods; Nucleic Acids; Peptide Hydrolases; Peptides; Polymers; Positioning Attribute; Research; Research Personnel; Resources; Rupture; Series; Serum; Site; Solutions; Source; Stimulus; Stromal Neoplasm; Structure; System; Therapeutic; Transport Vesicles; Treatment Efficacy; United States National Institutes of Health; Vertebral column; Vesicle; Vision; aqueous; capsule; copolymer; 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. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 对于治疗功效至关重要。不幸的是，许多药物输送方法通常是高度的 由于非理想的血清稳定性，跨生物屏障的运输以及在目标部位释放而效率低下。 为了解决这些问题，我们将为选择性创建生物响应性的聚合物纳米容器 将治疗化合物递送到预定的细胞位置。我们将结合解决方案自组装 具有选择性靶向和切割肽键的块共聚物的块共聚物以允许囊泡 响应关键环境刺激的进化，最终导致特定于现场的释放 封装有效载荷。 在第一个特定目的中，我们将创建新颖的含肽的块共聚物和 在水溶液中表征他们的自组装。这些两亲性共聚物将设计为 组装成囊泡结构。旨在促进内吞摄取（1）和内体的肽 释放（2）将连续合并到A块共聚物的亲水性主链中 分层时尚。在第二个特定目标中，我们将评估蛋白酶的敏感性和靶向 每个肽层的效率。每个肽序列的蛋白酶可及性以及囊泡 稳定性将作为在囊泡电晕中肽位置的函数进行评估。细胞帮助结合， 还将评估囊泡的囊泡内在化和囊泡的内溶液活性。在第三 具体目的，我们将验证肽将囊泡转运和破裂的能力 在细胞质中，我们将评估无有效载荷和细胞毒素的细胞毒性 囊泡。囊泡破裂将通过选择性放置（2）近端的选择性诱导 聚合物的疏水块。 我们对该项目的长期视野是开发用于 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DE 模块化囊泡纳米胶囊的Novo设计，其中包含一系列位置特定位置的“ Sheddable”壳 为了响应每个运输屏障的环境提示，直接有效载荷运输。