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: 7893033
• 负责人: You Han Bae
• 金额: $ 25.77万
• 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/7893033
• 关键词: Acidity; Animal Model; Animals; Antibodies; Antigens; Antineoplastic Agents; Binding; Biodistribution; Blood Circulation; Bystander Effect; Cell Line; Cell model; Cells; Cetuximab; Charge; Comparative Study; Complex; Control Groups; Doxorubicin; Drug Carriers; Drug Kinetics; Electrostatics; Endocytosis; Endosomes; Engineering; Environment; Epidermal Growth Factor Receptor; Extracellular Space; Fluorescent Probes; Folic Acid; Goals; Hydrophobic Interactions; In Vitro; Kinetics; Label; Ligands; Lysosomes; Malignant neoplasm of ovary; Micelles; Modeling; Monoclonal Antibodies; Multi-Drug Resistance; Organ; Organelles; Peptides; Performance; Physiological; Polymers; Process; Research Personnel; Rest; Roche brand of trastuzumab; Role; Signal Transduction; Solid Neoplasm; Structure; Surface; System; Technology; Testing; Trastuzumab; Tumor Antigens; Tumor Cell Line; Tumor Suppression; antibody conjugate; base; cell killing; chemotherapy; comparative; cytotoxicity; density; design; design and construction; efficacy testing; engineering design; erbB-2 Receptor; extracellular; in vitro testing; in vivo; nanocarrier; neoplastic cell; performance tests; polyanion; prevent; programs; receptor; tool; tumor; vector

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）：本申请提出创建并评估一种抗癌剂主动靶向实体瘤的新模式，该实体瘤形成酸性细胞外环境。当前化疗中主动肿瘤靶向技术的范例是基于通过肿瘤特异性抗原与其单克隆抗体（mAb）或配体与其相应受体之间的结合将药物载体主动内化到细胞中。为了改变这种范式，我们将设计一种智能聚合物胶束系统。胶束在循环过程中会隐藏特定的部分，具有很强的将胶束转移到细胞内的能力，并将该部分暴露在肿瘤细胞外环境中以促进内化过程。因此，胶束技术将非特异性细胞内化载体转变为肿瘤特异性工具。为此，选择微酸性肿瘤细胞外 pH（pHe：pH 6.6-7.0）作为该部分暴露的触发信号，因为这种酸度在大多数实体瘤中是天然的，并且仅限于细胞外空间。这一新系统将扩大可以使用靶向化疗治疗的实体瘤的范围，并有望取代繁琐且昂贵的基于单克隆抗体的靶向技术。该应用的目标是在胶束核心结构上设计和构建超 pH 敏感表面，为内化剂提供暴露机制。当这项技术成功时，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。从我们从两种不同胶束系统获得的可行性结果来看，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，其不需要特定的抗原或受体来进行细胞定位。

项目成果

Endosomolytic reducible polymeric electrolytes for cytosolic protein delivery.

• DOI: 10.1021/bm400337f
• 发表时间: 2013-08-12
• 期刊: BIOMACROMOLECULES
• 影响因子: 6.2
• 作者: Tian, Li;Kang, Han Chang;Bae, You Han
• 通讯作者: Bae, You Han

Drug targeting and tumor heterogeneity.

• DOI: 10.1016/j.jconrel.2008.09.074
• 发表时间: 2009-01-05
• 期刊: JOURNAL OF CONTROLLED RELEASE
• 影响因子: 10.8
• 作者: Bae, You Han

Cancer nanomedicines targeting tumor extracellular pH.

• DOI: 10.1016/j.colsurfb.2011.10.039
• 发表时间: 2012-11-01
• 期刊: COLLOIDS AND SURFACES B-BIOINTERFACES
• 影响因子: 5.8
• 作者: Tian, Li;Bae, You Han
• 通讯作者: Bae, You Han