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

基本信息

批准号：
7983875
负责人：
Alexander H. Stegh
金额：
$ 21.43万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7983875
关键词：
Acute Address Aftercare Anchorage-Independent Growth Animals Apoptosis Apoptotic Applications Grants Automobile Driving Biochemical Biocompatible Biological Biological Models Brain Neoplasms 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 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 TP53 gene 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 nanoparticle neoplastic cell novel pre-clinical programs randomized trial receptor stem cell population success targeted delivery therapy resistant tumor uptake

项目摘要

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.

SUIVIMARY 项目（参见说明）：恶性神经胶质瘤 (MG) 是中枢神经最常见和最致命的原发性癌症系统。诊断为最高级别 MG、IV 级多形性胶质母细胞瘤 (GBM) 的患者，尽管进行了手术切除和积极的治疗方案，但诊断后仅存活 9-12 个月。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略有增加，最多 14.6 个月；复发几乎是普遍的，并且针对这种进展的挽救疗法仍然无效。对编目遗传畸变如何决定疾病的表型特征的理解不完全，特别是强烈的治疗（细胞凋亡）抵抗，但华丽的瘤内坏死发生，结合高度治疗抵抗的癌症干细胞群（脑肿瘤干细胞，BTSC）作为假定的起源细胞共同使 GBM 成为一种高度神秘且无法治愈的疾病。该拨款提案在多个层面上解决了神经胶质瘤领域面临的关键挑战：(i) 为了克服毒性、特异性不足和靶向治疗（例如 (R)TK 抑制剂）的传递，我们的工作重点是使用新型小干扰 RNA 进行基因沉默（ siRNA）-缀合金纳米颗粒（RNA-Au NP）。与传统的分子 RNAi 和其他聚合物和纳米结构相比，这种替代性且非常有前途的新药物表现出增强的细胞/组织吸收、减少脱靶效应以及改善的生物稳定性和相容性。 (ii) 这种单实体 RNAi 纳米试剂将靶向同时激活的 RTK 和 Bcl2L12，作为 GBM 标志性病变以及治疗耐药性和神经衰弱性坏死发生的功能验证调节剂。 (iii) 我们将在生理上高度相关的 BTSC 和衍生的原位外植体模型系统中对 RTK 和 Bcl2L12 靶向 NP（RTK-、L12-RNA-Au NP）进行临床前验证，(iv) 我们将扩展我们的临床前验证从原位异种移植模型到在精致的、急性发作的、高渗透性 GBM 小鼠模型中研究肿瘤消退的努力，以评估 RNA-Au NP 的功效在完整的免疫系统和生理上更相关的肿瘤微环境的环境中。