Preclinical Validation of Polyvalent siRNA Gold Nanoparticle Conjugates as anti-G

多价 siRNA 金纳米粒子缀合物作为抗 G 的临床前验证

• 批准号: 8710086
• 负责人: Alexander H. Stegh
• 金额: $ 0.54万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8710086
• 关键词: Acute; Address; Aftercare; Anchorage-Independent Growth; Animals; Apoptosis; Apoptotic; Applications Grants; Automobile Driving; Biochemical; Biocompatible; Biological; Biological Models; Brain Neoplasms; Cancer Diagnostics; Caspase; Cataloging; Catalogs; Cell Culture Techniques; Cell Death Signaling Process; Cell Line; Cells; Clinical; Complement; DNA Damage; Data; Dependence; Development; Diagnosis; Disease; Dose; Doxorubicin; Drug Kinetics; Employee Strikes; Epidermal Growth Factor Receptor; Excision; Exhibits; Gene Silencing; Genetic; Genetically Engineered Mouse; Genomics; Genotype; Glioblastoma; Glioma; Gliomagenesis; Gold; Growth; Heterogeneity; Histologic; Human; Immune; Immune system; Individual; Induction of Apoptosis; Injection of therapeutic agent; Instruction; Lesion; Life; MAP Kinase Gene; Malignant - descriptor; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of central nervous system; Modeling; Molecular; Molecular Abnormality; Monitor; Mus; Necrosis; New Agents; Oligonucleotides; Oncogene Proteins; Operative Surgical Procedures; Pathway interactions; Patients; Pattern; Pharmacologic Substance; Phenotype; Polymers; Primary Neoplasm; Proteins; Proteomics; RNA; RNA Interference; Radiation; Radiation therapy; Reagent; Receptor Protein-Tyrosine Kinases; Recruitment Activity; Recurrence; Research; Resistance; SCID Mice; Safety; Salvage Therapy; Sampling; Signal Pathway; Signal Transduction; Small Interfering RNA; Soft Agar Assay; Specificity; Staurosporine; Stem cells; Stimulus; Therapeutic; Time; Tissues; Toxic effect; Treatment Protocols; Tumor Stem Cells; Tyrosine Kinase Inhibitor; Validation; Western Blotting; Xenograft Model; Xenograft procedure; base; brain tissue; cancer stem cell; chemotherapy; dosage; drug development; flexibility; functional genomics; glioma cell line; improved; in vivo; indexing; inhibitor/antagonist; irradiation; mouse model; mutant; nano; nanomaterials; nanoparticle; neoplastic cell; novel; pre-clinical; programs; randomized trial; receptor; stem cell population; success; targeted delivery; therapy resistant; tumor; tumor microenvironment; uptake

PROJECT SUIVIMARY (See instructions): Malignant glioma (MG) represent the most prevalent and lethal primary cancer of the central nervous system. Patients diagnosed with the highest grade MG, grade IV glioblastoma multiforme (GBM), survive for only 9-12 months after diagnosis despite surgical resection and aggressive treatment regimens. Multimodal approaches using radiation with conjunctive chemotherapy (temozolamlde) resulted in only margina increase in patients' survival up to 14.6 months; recurrence is nearly universal and salvage therapies for such progression remain ineffective. An incomplete understanding of how catalogued genetic aberrations dictate phenotypic hallmarks of the disease, particularly intense therapy (apoptosis) resistance, yet florid intratumoral necrogenesis, combined with a highly therapy-resistant cancer stem cell population (brain tumor stem cells, BTSC) as the putative cell-of-origin conspired to make GBM a highly enigmatic and incurable disease. This grant proposal addresses the critical challenges facing the glioma field on multiple levels: (i) To overcome toxicity, insufficient specificity and delivery of targeted therapies (e.g. (R)TK inhibitors), our efforts focus on gene silencing using novel small interfering RNA (siRNA)-conjugated gold nanoparticles (RNA-Au NPs). This alternative and highly promising new agent exhibits enhanced cellular/tissue uptake, reduced offtarget effects and improved biostability and compatibility compared to conventional molecular RNAi and other polymer and nanoconstructs. (ii) This single-entity RNAi nano-reagent will target concomitantly activated RTKs and Bcl2L12 as GBM signature lesions and functionally validated modulators of therapeutic resistance and neurologically debilitating necrogenesis. (iii) We will pre-clinically validate RTK- and Bcl2L12- targeting NPs (RTK-, L12-RNA-Au NPs) in physiologically highly relevant BTSC and derived orthotopic explant model systems, (iv) We will extend our pre-clinical validation efforts from orthotopic xenograft models to studies of tumor regression in a refined, acute onset, highly penetrant GBM mouse model to assess efficacy of RNA-Au NPs in the setting of an intact immune system and a physiologically more relevant tumor microenvironment.

项目随附资料（见说明）： 恶性胶质瘤（malignant glioma，MG）是中枢神经系统最常见、最致命的原发性恶性肿瘤 系统诊断为最高级别MG，IV级多形性胶质母细胞瘤（GBM）的患者在诊断后仅存活9-12个月，尽管手术切除和积极的治疗方案。使用放射联合化疗（替莫唑胺）的多模式方法仅使患者的生存期增加了14.6个月;复发几乎是普遍的，并且对这种进展的挽救治疗仍然无效。不完全理解如何编目遗传畸变决定疾病的表型特征，特别是强烈的治疗（凋亡）抗性，但华丽的瘤内坏死，结合高度治疗抗性的癌症干细胞群体（脑肿瘤干细胞，BTSC）作为假定的细胞起源合谋使GBM成为一种高度神秘和不可治愈的疾病。该拨款提案解决了胶质瘤领域在多个层面上面临的关键挑战：（i）为了克服毒性，特异性不足和靶向治疗（例如（R）TK抑制剂）的递送，我们的努力集中在使用新型小干扰RNA（siRNA）缀合的金纳米颗粒（RNA-Au NPs）进行基因沉默。与传统的分子RNAi和其他聚合物和纳米结构相比，这种替代的和非常有前途的新试剂表现出增强的细胞/组织摄取，减少的脱靶效应和改善的生物稳定性和相容性。(ii)这种单一实体RNA干扰纳米试剂将靶向同时激活的RTK和Bcl 2L 12，作为GBM标志性病变以及功能上经过验证的治疗耐药性和神经衰弱性坏死发生的调节剂。(iii)我们将在临床前验证RTK和Bcl 2L 12靶向NP（RTK-，L12-RNA-Au NP）在生理学上高度相关的BTSC和衍生的原位外植体模型系统中的应用。（iv）我们将从原位异种移植模型将我们的临床前验证工作扩展到在精细的急性发作中的肿瘤消退的研究，在一个实施方案中，使用高度渗透的GBM小鼠模型来评估RNA-Au NP在完整免疫系统和生理学上更相关的肿瘤微环境的设置中的功效。