Micelle surface engineering for active targeting by acidic tumor extracellular pH

胶束表面工程通过酸性肿瘤细胞外 pH 值主动靶向

• 批准号: 7130778
• 负责人: You Han Bae
• 金额: $ 26.54万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-22 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7130778
• 关键词: extracellular; micelles; neoplasm /cancer

DESCRIPTION (provided by applicant): This application proposes to create and assess a new mode of active targeting for anticancer agents to solid tumors that develop an acidic extracellular environment. The current paradigm of active tumor targeting technology in chemotherapy is based on active internalization of drug carriers into cells by binding between a tumor specific antigen and its monoclonal antibody (mAb) or between a ligand and its corresponding receptor. In an attempt to shift this paradigm, an intelligent polymeric micelle system will be devised. The micelle will hide a particular moiety during circulation, which has the strong capability to translocate the micelle into cells, and expose the moiety in the tumor extracellular environment to facilitate the internalization process. Thus, micelle technology turns a non-specific cell internalizing vector into a tumor specific tool. For this purpose, the slightly acidic tumor extracellular pH (pHe: pH 6.6-7.0) has been selected as a triggering signal for exposure of the moiety because this acidity is natural in most solid tumors and is confined to extracellular space. This new system will broaden the range of solid tumors that can be treated using targeted chemotherapy and it is expected to replace cumbersome and expensive mAb-based targeting technology. The goal of this application is to design and construct a super pH-sensitive surface on a micelle core structure to provide exposure mechanisms for an internalizing agent. When this technology is successful, the micelle system will be capable of targeting anticancer drugs to most solid tumors that have pHe values below 7.0. This triggering pH was found to be reasonable, judging from our feasibility results obtained from two different micelle systems. In this application, a model cell penetrating peptide (CPP) TAT is utilized, which does not require particular antigens or receptors for cellular localization.

描述（由申请人提供）：本申请提议创建和评估抗癌剂对酸性细胞外环境的抗癌剂的新型主动靶向模式。化学疗法中活性肿瘤靶向技术的当前范式是基于药物载体通过肿瘤特异性抗原及其单克隆抗体（MAB）或配体及其相应受体之间的结合，基于将药物载体的活性内在化。为了改变这种范式，将设计一个智能的聚合物胶束系统。胶束将在循环过程中隐藏一个特定的部分，该部分具有很强的能力，可以将胶束迁移到细胞中，并暴露于肿瘤外环境中的部分以促进内在化过程。因此，胶束技术将非特异性细胞内化载体变成了特定的肿瘤工具。为此，已经选择了略带酸性肿瘤的细胞外pH（PHE：pH 6.6-7.0）作为触发部分的触发信号，因为这种酸度在大多数实体瘤中是自然的，并且被局限于细胞外空间。这个新系统将扩大可以使用靶向化疗进行治疗的实体瘤范围，并有望取代繁琐且昂贵的基于单元的靶向技术。该应用程序的目的是在胶束核心结构上设计和构建对超pH敏感的表面，以为内在化剂提供暴露机制。当该技术成功时，胶束系统将能够将抗癌药物靶向大多数PHE值低于7.0的实体瘤。从我们从两个不同的胶束系统获得的可行性结果来看，发现这种触发pH值是合理的。在此应用中，使用了模型细胞穿透肽（CPP）TAT，该肽不需要特定的抗原或受体来进行细胞定位。