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Tumor vasculature-targeted nanotherapeutics for DNA damage response

针对 DNA 损伤反应的肿瘤血管靶向纳米疗法

基本信息

批准号：
9188095
负责人：
Haifa Shen
金额：
$ 36.49万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9188095
关键词：
ATM gene Achievement Affect Affinity Aftercare Animals Anthracyclines Apoptosis Binding Biological Breast Cancer Patient Breast Cancer therapy Cancer Patient Cell Death Cell surface Cells Cessation of life DNA Damage Death Rate Development Distal Distant Dose Down-Regulation E-Selectin ERBB2 gene Effectiveness Endothelial Cells Endothelium Ensure Enzymes Genome Genomic Instability Genomics Hormone Receptor Hormones Human In Situ In Vitro Liver Lung MDA MB 231 Malignant Neoplasms Metastatic Neoplasm to the Bone Metastatic Neoplasm to the Lung Metastatic breast cancer Methods Modality Molecular Biology Molecular Profiling Monitor Mus Mutagens Neoplasm Metastasis Neoplasms in Vascular Tissue Nodule Organ Pathway interactions Patient-derived xenograft models of breast cancer Patients Permeability Pharmaceutical Preparations Plasma Platinum RNA Degradation Radiation therapy Recurrence Risk Schedule Silicon Small Interfering RNA Specificity Subgroup Surface System TP53 gene Technology Testing Therapeutic Tissues Treatment Efficacy Treatment-related toxicity Tumor Tissue Vascular Endothelial Cell Woman Xenograft Model anticancer activity ataxia telangiectasia mutated protein base bone cancer cell cell killing chemical conjugate chemotherapy dosage effective therapy genome integrity improved in vivo interstitial killings malignant breast neoplasm men mortality mouse model mutational status nanoparticle nanotherapeutic neoplastic cell new technology novel novel therapeutics overexpression particle polycation pressure protein expression public health relevance repaired response standard of care success synergism targeted delivery targeted treatment treatment group triple-negative invasive breast carcinoma tumor tumor growth tumor xenograft uptake

项目摘要

DESCRIPTION (provided by applicant): Tumor metastases to distant organs cause the majority of mortality in breast cancer. There is currently no effective treatment for metastatic breast cancer. We hypothesize that metastatic breast cancer can be effectively treated through targeting the DNA damage response pathways with tissue-specific enrichment of therapeutics. Thus, targeted therapy is achieved through tumor tissue-targeted delivery of targeted therapeutics. We have recently developed a polycation-functionalized nanoporous silicon (PCPS) technology platform for siRNA delivery. This platform has a high loading capacity and protects siRNA from degradation by plasma and tissues enzymes. In addition, it maintains sustained release of therapeutic siRNA nanoparticles that are formed in situ during nanoporous silicon degradation for effective tumor cell uptake. We have also shown that the tumor vascular endothelial cells express a high level of E-selectin, and that an E-selectin thioaptamer (ESTA) binds to the tumor vasculature with high affinity and specificity. In this application, we will functionalize the surface of the PCPS particles with the tumor vasculature-targeting moiety to achieve tumor-specific delivery of siRNA. The system will be applied to treat metastatic breast cancer with focus on triple negative breast cancer (TNBC). TNBC is a sub-group of breast cancer with the lowest treatment success rate. Chemo/radiation therapy induces genome damage that evokes DNA damage response whose primary regulator is the ATM kinase. Down-regulation of ATM kinase enhances cancer cell sensitivity. We will develop an effective treatment through blocking DNA damage response by focusing these Specific Aims: Aim 1. To develop a tumor vasculature-targeted high capacity carrier for siRNA and to study transport of therapeutic siRNA to tumor cells Aim 2. To test synergy between suppression of ATM expression and chemotherapy on killing of human TNBC cells Aim 3. To evaluate therapeutic efficacy from tumor vasculature-targeted ATM siRNA in murine xenograft model of human TNBC bone metastasis and PDX model of breast cancer lung metastasis These studies will demonstrate the effectiveness of tumor tissue-enriched ATM siRNA on sensitizing chemotherapy, and will pave the way for the development of the novel siRNA therapeutics for metastatic breast cancer.

描述（由申请人提供）：肿瘤转移至远处器官导致乳腺癌的大部分死亡。目前还没有有效的治疗转移性乳腺癌的方法。我们假设转移性乳腺癌可以通过靶向DNA损伤反应途径与组织特异性富集治疗有效地治疗。因此，靶向治疗是通过靶向治疗药物的肿瘤组织靶向递送来实现的。我们最近开发了用于siRNA递送的聚阳离子官能化纳米多孔硅（PCPS）技术平台。该平台具有高负载能力，并保护siRNA免受血浆和组织酶的降解。此外，它保持治疗性siRNA纳米颗粒的持续释放，这些纳米颗粒在纳米多孔硅降解期间原位形成，用于有效的肿瘤细胞摄取。我们还表明，肿瘤血管内皮细胞表达高水平的E-选择素，并且E-选择素硫代适体（ESTA）以高亲和力和特异性结合肿瘤血管系统。在本申请中，我们将用肿瘤血管靶向部分功能化PCPS颗粒的表面，以实现siRNA的肿瘤特异性递送。该系统将用于治疗转移性乳腺癌，重点是三阴性乳腺癌（TNBC）。TNBC是治疗成功率最低的乳腺癌亚组。化疗/放疗诱导基因组损伤，引起DNA损伤反应，其主要调节因子是ATM激酶。ATM激酶的下调增强癌细胞敏感性。我们将开发一种有效的治疗方法，通过阻断DNA损伤反应，专注于这些具体目标：目标1。目的研制肿瘤血管靶向siRNA高容量载体，研究siRNA靶向肿瘤细胞的转运。为了测试ATM表达的抑制和化学疗法对杀死人TNBC细胞的协同作用。评价肿瘤血管靶向ATM siRNA在人TNBC骨转移的小鼠异种移植模型和乳腺癌肺转移的PDX模型中的治疗效果。这些研究将证明肿瘤组织富集的ATM siRNA对化疗增敏的有效性，并将为开发新的转移性乳腺癌siRNA治疗剂铺平道路。