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（请参阅说明）：恶性神经胶质瘤（MG）代表了中枢神经的最普遍和致命的原发性癌症系统。尽管手术切除和攻击性治疗方案，诊断为诊断为最高级MG，IV级胶质母细胞瘤（GBM）的患者仅在诊断后9-12个月生存。使用辐射和结合化疗（Temozolamlde）的多模式方法导致患者的生存期限仅增加14.6个月。复发几乎是普遍的，这种进展的挽救疗法仍然无效。对分类的遗传畸变如何决定该疾病的表型标志，尤其是强烈的治疗（凋亡）耐药性，但植物内肿瘤内坏死作用，与高度治疗的抗药性癌症干细胞种群（脑肿瘤干细胞，BTSC，BTSC，BTSC）相结合，是一种使gbm高度良好的gbms and gbm，一种不完整的理解。这项赠款提案解决了多个层面上的神经胶质瘤领域面临的关键挑战：（i）要克服毒性，不足的特异性和靶向疗法的交付（例如（R）TK抑制剂），我们的努力专注于使用新型的小型小型RNA（sirna） - 结合的金纳米纳米类枝（RNA-apa）（RNA-APA）。与传统的分子RNAi以及其他聚合物和纳米结构相比，这种替代性且高度有希望的新药物表现出增强的细胞/组织吸收，降低的Offarget效应以及提高的生物稳定性和兼容性。（ii）这种单个rnai纳米含量将靶向同时激活的RTK和BCL2L12作为GBM签名病变，并在功能验证的治疗性耐药性调节剂和神经学上衰弱的坏死剂。 (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小鼠模型评估RNA-AU NP在完整免疫系统和生理上更相关的肿瘤微环境中的功效。