Multifunctional nanoparticles for combinational therapy of pancreatic cancer

描述（由申请人提供）：本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，能够克服化疗和基质耐药性，以改善胰腺导管腺癌（PDAC）治疗的最终结局。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年生存率约为6%。PDAC可怕的预后是诊断晚和肿瘤对当前药物治疗的难治性行为的结果。介孔二氧化硅纳米颗粒（MSNs）作为下一代纳米医学具有相当大的前景，可以早期检测疾病，同时监测和治疗，以及毒性最小的靶向治疗。该建议的基础假设是，通过使用MSNs作为支架，我们可以联合收割机不同的治疗，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。该提案的主要目标是开发基于MSN的多模式治疗策略，其具有克服化疗和间质抵抗的能力，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）开发用于PDAC的组合化疗和靶向治疗的新型MSN方法; 2）评估目标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;和3）开发基于MSN的递送平台，其将联合收割机化疗和靶向治疗与基质消耗剂结合作为改善PDAC治疗的新策略。这项工作的结果将导致几个平台的发展，克服化疗和基质耐药性的能力，以改善PDAC的治疗。此外，从独特的三重转基因PDAC小鼠模型获得的体内结果将提供概念证明，以证明这些平台在临床研究中的评价是合理的。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.