An ultra-selective drug delivery platform technology using modular viral fusogen-actuated liposomes

使用模块化病毒融合剂驱动脂质体的超选择性药物递送平台技术

• 批准号: 9794641
• 负责人: Victor Alexander Garcia
• 金额: $ 3.83万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2022-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9794641
• 关键词: Ablation; Adverse drug effect; Adverse reactions; Affinity; Binding; Binding Proteins; Biological Assay; Breast Cancer Cell; Breast Cancer Model; Breast Cancer therapy; CD46 Antigen; Cancerous; Cell Culture Techniques; Cell Death; Cell Line; Cell Surface Receptors; Cell fusion; Cell surface; Cells; Characteristics; Chemistry; Clinical; Coculture Techniques; Competence; Complex; Cytosol; Decision Making; Directed Molecular Evolution; Disease; Drug Delivery Systems; ERBB2 gene; Engineering; Extracellular Space; Future; Genetic Materials; Genetic Transcription; Hemagglutinin; In Vitro; Integral Membrane Protein; Libraries; Ligands; Liposomes; Malignant Neoplasms; Measles; Membrane; Membrane Fusion; Methods; Modality; Mutation; Organ; Outcome; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Population; Property; Proteins; Regulation; Reporter; SLAM protein; Sendai virus; Structure; System; Technology; Therapeutic; Tissues; Traction; Translations; Tropism; Variant; Vesicle; Viral; Viral Fusion Proteins; Work; base; cancer cell; cell type; design; experimental study; improved; in vitro Assay; interest; liposomal delivery; minimal risk; nanoliposome; nectin; novel; protein complex; protein expression; proteoliposomes; receptor; receptor binding; reconstitution; response; stoichiometry; targeted delivery

Project Summary/Abstract Liposomal drug encapsulation has recently gained significant traction as a therapeutic delivery modality, especially as a means of enhancing localized drug release or direct delivery in cancerous tissues with reduced drug side effects. The majority of “targeted” liposome technologies feature vesicles displaying ligands or binding proteins that bind to specific cell-surface moieties on target cells to enable selective liposome attachment. Absent any further mechanistic regulation of these systems, liposomes are fated to release contents to the extracellular space near the target cell or enter target cells via endosomal pathways, which limits the type of drug that can be delivered as well as the efficiency of cytoplasmic delivery. A few liposome technologies exist which feature proteins or liposomal chemistries that enable membrane fusion to allow either direct entry of drug payloads into the cytosol or endosomal escape. However, these approaches are greatly limited by their inability to simultaneously target predefined receptors of interest with minimal risk of non- specific delivery to other cell types in heterogeneous tissues or organs, while enabling direct cytosolic entry through membrane fusion between the liposome and the target cell. In this work, we propose to develop a modular, ultra-selective liposomal delivery platform technology which utilizes a system of retargeted viral fusion proteins that bind a target receptor of interest to directly trigger membrane fusion at the cell surface and enable cytosolic payload delivery, while minimizing off-target delivery. As proof-of-concept, we will employ this system to deliver payloads to HER2-positive cells in an expression-dependent manner, to demonstrate ultra-selective delivery to breast cancer cells in heterogeneous cultures.

项目总结/摘要 脂质体药物包封最近作为治疗递送方式获得了显著的吸引力， 特别是作为增强局部药物释放或在癌组织中直接递送的手段， 药物副作用。大多数“靶向”脂质体技术的特征在于囊泡展示配体或配体受体。 结合靶细胞上特异性细胞表面部分的结合蛋白， 附件.如果没有这些系统的任何进一步的机械调节，脂质体注定要释放 内容物进入靶细胞附近的细胞外空间或通过内体途径进入靶细胞， 限制了可以递送的药物类型以及细胞质递送的效率。少量脂质体 存在以蛋白质或脂质体化学为特征的技术，其能够使膜融合， 药物有效载荷直接进入胞质溶胶或内体逃逸。然而，这些方法非常 由于它们不能同时靶向预定义的感兴趣的受体， 特异性递送至异质组织或器官中的其他细胞类型，同时能够直接进入胞质 通过脂质体和靶细胞之间的膜融合。在这项工作中，我们建议开发一个 模块化、超选择性脂质体递送平台技术，其利用重定向病毒融合系统 结合感兴趣的靶受体以直接触发细胞表面的膜融合并使 细胞溶质有效载荷递送，同时使脱靶递送最小化。作为概念验证，我们将采用此系统 以表达依赖性方式将有效载荷递送至HER 2阳性细胞， 递送至异质培养物中的乳腺癌细胞。