Use of nanogels to target delivery of siRNA to cancer cells in mice

使用纳米凝胶将 siRNA 靶向递送至小鼠癌细胞

• 批准号: 8300828
• 负责人: John F McDonald
• 金额: $ 24.77万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8300828
• 关键词: Alanine Transaminase; Alkaline Phosphatase; Animal Model; Animals; Ascites; Aspartate Transaminase; Biochemical Markers; Biodistribution; Bioluminescence; Blood; Blood Urea Nitrogen; Blood specimen; Brain Neoplasms; Cancer Etiology; Cause of Death; Cells; Characteristics; Cloning; Creatinine; Development; Diagnostic; Disease Resistance; Dose; Drug resistance; Engineering; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor Receptor; Epithelial; Evaluation; Genes; Giemsa stain; Growth; Heart; Hematoxylin and Eosin Staining Method; Hepatotoxicity; Human; Image; Immunocompromised Host; In Vitro; Inflammatory; Interferon Type I; Interferons; Interleukin-6; Interleukins; Investigation; Kidney; Label; Laboratory Organism; Life; Liver; Longitudinal Studies; Luc Gene; Malignant Female Reproductive System Neoplasm; Malignant neoplasm of ovary; Messenger RNA; Metabolic Marker; Modeling; Monitor; Mus; NanoGel; Nanotechnology; Nude Mice; Oncogenes; Operative Surgical Procedures; Ovarian; Peritoneal; Phenotype; Physiological; Process; Proteins; RNA; Resistance; Sampling; Serum; Small Interfering RNA; Specificity; Spleen; Staining method; Stains; Surface; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Tissue Embedding; Tissue Extracts; Tissue Sample; Tissue Stains; Tissues; Toxic effect; Tumor Burden; Tumor Debulking; Tumor Necrosis Factor-alpha; Woman; Xenograft procedure; c-erbB-1 Proto-Oncogenes; cancer cell; cancer therapy; chemotherapeutic agent; chemotherapy; clinical application; clinical practice; clinically significant; cytokine; design; fluorescence imaging; implantation; in vivo; intraperitoneal; mouse model; nanoparticle; nephrotoxicity; new technology; non-invasive monitor; parallel processing; receptor expression; response; targeted delivery; tissue processing; tumor

DESCRIPTION (provided by applicant): Ovarian cancer is the leading cause of death from gynecologic cancer. Despite high initial tumor response rates of 80% to surgical debulking and chemotherapy, most women with advanced ovarian cancer will eventually develop drug-resistant disease. Because second-line chemotherapeutic agents provide a response rate of only 15-25%, there is clearly a need to develop better therapeutic strategies. Small interfering RNAs (siRNAs) are a class of RNA molecules that previously have been demonstrated to be highly effective in inactivating cancer-causing genes (oncogenes) in cancer cells grown in culture. However, the development of siRNAs as clinically significant therapeutic agents has been hampered by the fact that siRNAs are extremely unstable at physiological conditions. In addition, there has been no effective way to target these potentially therapeutic molecules specifically to cancer cells. We have recently demonstrated that gelatinous-like nanoparticles called nanogels can be easily loaded with siRNAs and targeted to deliver their potentially therapeutic payload to ovarian cancer cells grown in culture. Nanogels protect the siRNA molecules from degradation until released into the cancer cells. The proposed studies seek to demonstrate that these non-toxic nanogels can be used to effectively target siRNAs to cancer cells in living organisms (experimental mice) as well. Such studies are pre-requisite to the potential clinical application of the technology for the treatment of cancer in humans. Specifically, siRNAs directed against the EGFR (epidermal growth factor receptor) gene will be loaded into nanogels engineered to specifically target proteins expressed on the surface of ovarian cancer cells. The EGFR gene is highly expressed in ovarian and most other types of cancer cells and is known to induce cells to rapidly divide and become resistant to most commonly used chemotherapy agents. Thus, the inactivation of EGFR in cancer cells has great therapeutic value. Demonstration that nanogels can be an effective vehicle for the delivery of therapeutic siRNAs to cancer cells in mice will open the door to the development of this exciting new technology of clinical application in humans.

描述（由申请人提供）：卵巢癌是妇科癌症死亡的主要原因。尽管手术切除和化疗的初始肿瘤应答率高达80%，但大多数晚期卵巢癌妇女最终会发展为耐药疾病。由于二线化疗药物的反应率仅为15-25%，因此显然需要开发更好的治疗策略。小干扰RNA （sirna）是一类RNA分子，先前已被证明在培养的癌细胞中对灭活致癌基因（癌基因）非常有效。然而，sirna作为具有临床意义的治疗药物的发展一直受到sirna在生理条件下极不稳定这一事实的阻碍。此外，目前还没有有效的方法将这些潜在的治疗分子特异性地靶向于癌细胞。我们最近已经证明，凝胶状的纳米颗粒（称为纳米凝胶）可以很容易地装载sirna，并靶向将其潜在的治疗有效载荷传递给培养的卵巢癌细胞。纳米凝胶保护siRNA分子不被降解，直到释放到癌细胞中。所提出的研究旨在证明这些无毒纳米凝胶也可以用于有效地将sirna靶向活生物体（实验小鼠）中的癌细胞。这些研究是该技术用于治疗人类癌症的潜在临床应用的先决条件。具体来说，针对表皮生长因子受体（EGFR）基因的sirna将被装载到纳米凝胶中，以特异性靶向卵巢癌细胞表面表达的蛋白质。EGFR基因在卵巢癌和大多数其他类型的癌细胞中高度表达，已知它能诱导细胞快速分裂，并对大多数常用的化疗药物产生耐药性。因此，肿瘤细胞中EGFR的失活具有很大的治疗价值。证明纳米凝胶可以作为一种有效的载体，将治疗性sirna输送到小鼠的癌细胞中，将为这项令人兴奋的新技术在人类临床应用的发展打开大门。

项目成果

Targeted in vivo delivery of EGFR siRNA inhibits ovarian cancer growth and enhances drug sensitivity.

• DOI: 10.1038/srep36518
• 发表时间: 2016-11-07
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Satpathy M;Mezencev R;Wang L;McDonald JF
• 通讯作者: McDonald JF