Multifunctional nanoparticles for combinational therapy of pancreatic cancer

描述(申请人提供)：这项研究的长期目标是开发临床相关的基于MSN的多模式治疗策略，具有克服化疗和间质耐药性的能力，以改善胰腺导管腺癌(PDAC)治疗的最终结果。PDAC是美国癌症死亡的第四大原因。这是最难治疗的疾病之一，5年存活率约为6%。PDAC的可怕预后是由于诊断较晚，以及肿瘤对当前药物治疗的顽固行为造成的。介孔二氧化硅纳米颗粒(MSN)有望成为下一代纳米药物，使疾病的早期发现、同步监测和治疗以及毒性最小的靶向治疗成为可能。这一建议背后的假设是，通过使用MSN作为支架，我们可以结合不同的治疗方法，如化疗、靶向治疗和联合治疗，以克服目前PDAC治疗中的一些主要缺陷。该建议的主要目标是开发基于MSN的多模式治疗策略，具有克服化疗和间质耐药的能力，以改善PDAC治疗的最终结果。这一目标将通过完成三个具体目标来实现：1)开发基于MSN的PDAC联合化疗和靶向治疗的新方法；2)评估Aim 1中开发的MSN材料的体内生物分布、药代动力学、靶向能力和治疗效果；以及3)开发基于MSN的给药平台，将化疗和靶向治疗与间质耗竭剂相结合，作为改进PDAC治疗的新策略。这项工作的结果将导致几个平台的开发，具有克服化疗和间质耐药的能力，以改善PDAC的治疗。此外，从一个独特的三胞胎转基因PDAC小鼠模型获得的体内结果，将为这些平台在临床研究中的评估提供概念证明。PDAC治疗的这些进展最终将影响这种致命疾病的临床护理。

DESCRIPTION (provided by applicant): The long term goal of this research is to develop clinically relevant multimodal MSN-based therapeutic strategies with the ability of overcoming chemo and stromal resistance to improve the final outcome of pancreatic ductal adenocarcinoma (PDAC) treatment. PDAC is the fourth leading cause of cancer death in the United States. This is one of the most difficult conditions to treat, with a 5-year survival at abot 6%. The horrific prognosis of PDAC is a result of late diagnosis and the tumor's refractory behavior toward current drug treatment. Mesoporous silica nanoparticles (MSNs) hold considerable promise as the next generation of nanomedicine that enables the early detection of disease, simultaneous monitoring and treatment, and targeted therapy with minimal toxicity. The hypothesis underlying this proposal is that by using MSNs as scaffold, we can combine different therapies such as chemotherapy, targeted therapy and combination therapy to overcome some of the main deficiencies in the current treatment of PDAC. The main target of this proposal is to develop multimodal MSN-based therapeutic strategies with the ability of overcoming chemo and stromal resistance to improve the final outcome of PDAC treatment. This goal will be accomplished by completion of three Specific Aims: 1) To develop novel MSN-based approaches for combinatorial chemotherapy and targeted therapy of PDAC; 2) To evaluate the in vivo biodistribution, pharmacokinetics, targeting ability and therapeutic efficacy of MSN materials developed in Aim 1; and 3) To develop MSN-based delivery platforms that combine chemotherapy and targeted therapy with stromal-depleting agents as novel strategies to improve PDAC treatment. The results of this work will lead to the development of several platforms with the ability of overcoming chemo and stromal resistance to improve the treatment of PDAC. Moreover; the in vivo results, obtained from a unique triplet transgenic PDAC mouse model, will provide the proof of concept to justify the evaluation of these platforms in clinical studies. These advancements in PDAC treatment will eventually impact the clinical care of this deadly disease.