Tumor vasculature-targeted nanotherapeutics for DNA damage response

 描述(申请人提供)：肿瘤转移到远处器官是乳腺癌死亡的主要原因。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损伤反应通路和组织特异性治疗药物来有效治疗。因此，靶向治疗是通过肿瘤组织靶向输送靶向治疗药物来实现的。我们最近开发了一种用于siRNA传递的聚阳离子功能化纳米多孔硅(PCPS)技术平台。该平台具有很高的负载能力，并保护siRNA不被血浆和组织酶降解。此外，它还保持了治疗性siRNA纳米颗粒的持续释放，这些纳米颗粒是在纳米多孔硅降解过程中原位形成的，以有效摄取肿瘤细胞。我们还发现，肿瘤血管内皮细胞表达高水平的E-选择素，并且E-选择素硫代核苷酸(ESTA)与肿瘤血管具有高度的亲和力和特异性。在这一应用中，我们将利用肿瘤血管靶向部分对PCPS颗粒的表面进行功能化，以实现肿瘤特异性siRNA的传递。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是乳腺癌治疗成功率最低的亚型。化疗/放射治疗引起基因组损伤，引起DNA损伤反应，而DNA损伤反应的主要调节因子是ATM激酶。ATM激酶的下调增强了癌细胞的敏感性。目的：1.研制肿瘤血管靶向的高容量siRNA载体，研究治疗性siRNA向肿瘤细胞的转运；2.检测ATM表达抑制与化疗对人TNBC细胞杀伤的协同作用；3.评价肿瘤血管靶向ATM siRNA对人TNBC骨转移异种移植模型和乳腺癌肺转移PDX模型的治疗效果。

 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.