Targeted theranostic microbubble vectors for transcription factor decoy delivery

用于转录因子诱饵递送的靶向治疗诊断微泡载体

• 批准号: 8281002
• 负责人: Flordeliza S Villanueva
• 金额: $ 16.58万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-10 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8281002
• 关键词: Acids; Acoustics; Address; Adoption; Animal Cancer Model; Biodistribution; Biological Assay; Biomedical Engineering; Carrying Capacities; Cell Membrane Permeability; Cell membrane; Cells; Chemical Engineering; Clinical; Clinical Oncology; Detection; Development; Diagnostic; Disease; Endocytosis; Foundations; Gases; Gene Silencing; Gene Targeting; Genes; Goals; Growth; Head and neck structure; Image; Imagery; In Vitro; Injection of therapeutic agent; Knowledge; Ligands; Malignant Epithelial Cell; Malignant Neoplasms; Measures; Mediating; Methods; Microbubbles; Modeling; Molecular; Molecular Biology; Molecular Target; Morbidity - disease rate; Mus; Nucleic Acids; Oligonucleotides; Oncogenes; Outcome; Pathway interactions; Patients; Physics; Proteins; Research; Rupture; Safety; Scheme; Signal Transduction; Site; Squamous cell carcinoma; Stat3 protein; System; Techniques; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Time; Translations; Ultrasonography; Western Blotting; Work; base; cancer therapy; design; design and construction; imaging modality; in vivo; innovation; macromolecule; minimally invasive; mortality; multidisciplinary; novel; novel strategies; portability; targeted delivery; theranostics; therapeutic target; transcription factor; tumor; tumor growth; tumorigenesis; user-friendly; vector; vibration

DESCRIPTION (provided by applicant): Expanding knowledge of pathways and proteins involved in oncogenesis has led to the development of targeted molecular therapeutics, including the use of small nucleic acid constructs designed to act as transcription factor decoys. Despite the plethora of small nucleic acid-based therapeutics of potential clinical value, no available method is capable of targeted, safe, minimally invasive, and repeated delivery of therapeutic quantities of these agents to cancers. As a result, clinical translation of small nuclec acid-based therapeutics has been slow. Accordingly, in this proposal, a unique multi-disciplinary team embodying expertise in chemical and biomedical engineering, acoustic physics, basic and clinical oncology, molecular biology, and imaging, will develop a new approach for targeted delivery of transcription factor decoys that capitalizes on unique bioeffects ensuing from ultrasound-induced vibrations of microbubbles (MBs). These bioeffects include enhanced cell membrane permeability to macromolecules, such as transcription factor decoys, which can be loaded on MBs and released solely at the target site upon induction of MB rupture by an ultrasound beam directed at the site. Because ultrasound also confers imaging capability, the project team will innovate a theranostic ultrasound- MB delivery system that combines ultrasound imaging with nucleic acid carrying capacity, which together may overcome current barriers to therapeutic transcription factor decoy delivery, while allowing real time visualization of the tumor and distribution of the decoy. We will test the overall hypothesis that MB can be loaded with a therapeutic nucleic acid (transcription factor decoy), that ultrasound-mediated delivery of the therapeutic will cause oncogene silencing and reduce tumor growth, and that the use of tumor-specific targeting moieties will enhance the therapeutic effect and simultaneously allow specific tumor detection. We will utilize the STAT3 decoy as a test therapeutic, as this small nucleic acid is known to have therapeutic potential and safety in animal cancer models. First, we will expose cultured carcinoma cells to STAT3 decoy- loaded MBs under varying ultrasound conditions, assay the resulting expression of downstream target genes, and determine the ultrasound and MB features which are critical for successful delivery of this particular agent. Then, to determine if the ultrasound-MB delivery platform induces STAT3 signal silencing and tumor growth suppression in vivo, we will intravenously deliver STAT3 decoy-loaded MBs and administer ultrasound to mice bearing squamous cell carcinomas, assay expression of STAT responsive genes, and ultrasonically track tumor growth over time. These studies will culminate in an efficient, non-invasive, targeted transcription factor decoy delivery strategy that should facilitate clinical implementation. Importantly, while our proposed delivery strategy targets a specific oncogene in this project, this work will establish general principles fr an image- guided ultrasound-MB therapeutic delivery platform that can be extended to other diseases for which small nucleic acid delivery represents a therapeutic approach. PUBLIC HEALTH RELEVANCE: Clinical adoption of molecular therapeutics for targeted silencing of abnormal genes involved in diseases such as cancer, including the use of small nucleic acid constructs designed to act as transcription factor decoys, is limited by the lack of strategies for targeted, safe, minimally invasive, and repeated delivery of these constructs. In this proposal, a unique multi-disciplinary team will develop a bedside ultrasound-microbubble diagnostic and delivery system that combines real time ultrasound imaging with transcription factor decoy-loaded microbubbles for ultrasound-induced decoy delivery specifically to tumors. The delivery platform developed in this project should facilitate the clinical translation of approaches using transcription factor decoys for treatment of cancer, ultimately leading to better outcome in patients afflicted with cancer. This platform can also be applied to molecular therapy of other diseases for which targeted gene silencing represents a treatment option.

描述（由申请人提供）：对肿瘤发生过程中涉及的途径和蛋白质的不断扩展的知识导致了靶向分子治疗的发展，包括使用设计作为转录因子诱饵的小核酸结构。尽管有大量具有潜在临床价值的基于核酸的小分子治疗方法，但没有一种可用的方法能够靶向、安全、微创和重复地向癌症输送治疗量的这些药物。因此，基于小核酸的治疗方法的临床转化一直很慢。因此，在本提案中，一个独特的多学科团队体现了化学和生物医学工程，声学物理学，基础和临床肿瘤学，分子生物学和成像方面的专业知识，将开发一种靶向递送转录因子诱饵的新方法，该方法利用超声诱导微泡（mb）振动产生的独特生物效应。这些生物效应包括增强细胞膜对大分子的渗透性，如转录因子诱饵，它可以装载在MB上，并在靶向部位的超声束诱导MB破裂时仅在靶部位释放。由于超声还具有成像能力，因此项目团队将创新一种治疗性超声- MB传输系统，该系统将超声成像与核酸携带能力相结合，可以克服目前治疗性转录因子诱饵传输的障碍，同时实现实时可视化