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

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 对治疗效果至关重要。不幸的是，许多用于药物递送的方法通常是高度依赖性的。 由于不理想的血清稳定性、穿过生物屏障的运输和在靶位点的释放而效率低下。 为了解决这些问题，我们将创造生物反应，聚合物纳米容器的选择性 将治疗化合物递送到预定的细胞位置。我们将联合收割机 具有选择性靶向和切割肽键的嵌段共聚物， 进化的关键环境刺激，最终导致特定地点的释放 封装的有效载荷。 在第一个具体目标中，我们将创建新的含肽嵌段共聚物， 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成 组装成囊状结构。设计用于促进内吞摄取的肽（1）和内体 释放物（2）将以亲水性的方式顺序地结合到嵌段共聚物的亲水性主链中， 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。每个肽序列的蛋白酶可及性，以及囊泡 稳定性将作为囊泡冠中肽位置的函数进行评估。细胞囊泡结合， 还将评价囊泡内化和囊泡的内体溶解活性。第三 具体的目的，我们将验证肽的能力，直接囊泡运输和破裂 在细胞质中，我们将评估无有效载荷和掺入细胞毒素的细胞毒性。 囊泡通过选择性地将肽（2）放置在囊泡的近端，将诱导囊泡破裂。 聚合物的疏水嵌段。 我们对这个项目的长期愿景是开发一种核酸输送系统， 选择性靶向肿瘤基质成纤维细胞和/或炎性细胞。我们设想， 包含一系列位置特异性“可脱落”壳的模块化泡状纳米胶囊的新设计 以响应于每个运输屏障处的环境线索来引导有效载荷运输。

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.