Stimuli-responsive mucin1-specific nanoparticles for efficacious combinatorial chemotherapy of pancreatic ductal adenocarcinoma

摘要 摘要胰腺导管腺癌是一种侵袭性和破坏性的外分泌恶性疾病。 胰腺的特点是侵袭性、早期转移和对治疗的严重抵抗。PDAC 是美国癌症相关死亡的第四大原因，约有60,430例新病例 预计2021年将有48,220人死亡。不幸的是，尽管有巨大的科学努力，但令人震惊的是 值得注意的是，PDAC的预后最差，5年存活率为10%，但没有明显改善 在过去的40年里。此外，预计未来十年PDAC的负担将会增加，预计 到2030年成为癌症相关死亡的第二大原因。高死亡率和糟糕的预后 PDAC可以归因于多因素的原因，如其固有的和获得性的抵抗行为，早期 肿瘤中的微转移扩散、促结缔组织增生效应和异质性，使电流 治疗相当无效。开发可靠的有效治疗PDAC的方法将具有重要的意义 对这种致命疾病的临床结局的影响。我们设计、合成并表征了一种 靶向性刺激反应MSN平台用于顺铂(Cispt)和吉西他滨的控释 (GEM)(TAB004-Gem-cispt-MSNS)，具有最佳药物比例。我们的初步数据表明，这 递送系统有效靶向肿瘤相关MUC1(TMUC1)，提高治疗效率 在过表达tMUC1的同基因和自发小鼠模型中都降低了毒性。在这个项目中， 我们建议开发基于MSN的新型序贯给药系统，以有效治疗PDAC。 这一提议背后的假设是，通过开发一种基于纳米颗粒的序贯疗法， 初级纳米平台以肿瘤间质为靶点传递ShH抑制物；次级纳米载体， HTAB004-Gem-cispt-MSNS，用于向PDAC细胞释放化疗药物，PDAC的治疗将是 有了显著改善。本项目的主要目标将通过完成三个目标来实现：1) HTAB004-Gem-cispt-MSNS对宝石生物稳定性的影响及其对DNA的作用机制研究 2)研究CYP-MSN的药代动力学、生物分布和安全性。 HTAB004-Gem-cispt-MSNS及序贯疗法在异种移植中的治疗效果 (3)评价其靶向性、治疗效果和抗肿瘤转移的有效性。 CYP-MSNS和hTAB004-Gem-cispt-MSNS在转基因自发性PDA.MUC1中的序贯治疗 小鼠模型。这些数据将为该平台成功的从台面到床边的平移提供概念验证。

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and devastating malignant disease of the exocrine pancreas which is characterized by invasiveness, early metastasis and profound resistance to therapies. PDAC is the fourth-leading cause of cancer-related mortality in the United States, with approximately 60,430 new cases and 48,220 deaths anticipated in 2021. Unfortunately, despite the tremendous scientific efforts, it is shocking to note that PDAC has the worst prognosis with 5-year survival rate of 10% which has not significantly improved from the past 40 years. Further, the PDAC burden is projected to increase in the next decade and is anticipated to be the second-leading cause of cancer-related deaths by 2030. The high mortality and awful prognosis of PDAC can be attributed to multifactorial reasons like its intrinsic and acquired resistant behavior, early micrometastatic dissemination, desmoplastic effect and heterogeneities in tumors, rendering the current treatments rather ineffective. Developing reliable methods for the effective treatment of PDAC will have a major impact on the clinical outcome for this deadly disease. We have designed, synthesized and characterized a target-specific, stimuli-responsive MSN platform for the controlled delivery of cisplatin (cisPt) and gemcitabine (Gem) (TAB004-Gem-cisPt-MSNs) with an optimal drug ratio. Our preliminary data demonstrates that this delivery system effectively targets tumor associated MUC1 (tMUC1), increases therapeutic efficiency with reduced toxicity in both a syngeneic and a spontaneous mouse model that overexpressed tMUC1. In this project, we are proposing to develop novel MSN-based sequential delivery systems for the effective treatment of PDAC. The hypothesis underlying this proposal is that by developing a sequential nanoparticle-based regimen where the primary nanoplatform targets the tumor stroma to deliver a SHh inhibitor; and the secondary nanocarrier, hTAB004-Gem-cisPt-MSNs, is used to release chemotherapeutics to PDAC cells, the treatment of PDAC will be dramatically improved. The main goal of this project will be accomplished by the completion of three Aims: 1) Study the effect of hTAB004-Gem-cisPt-MSNs on the biological stability of Gem and its mechanistic role on DNA damage repair in PDAC cells; 2) Investigate the pharmacokinetics, biodistribution and safety of CyP-MSNs and hTAB004-Gem-cisPt-MSNs; and the therapeutic efficacy of the sequential therapy in patient derived xenograft (PDX) mice; and 3) Evaluate the targeting, therapeutic efficacy and effectiveness against tumor metastasis of the sequential therapy CyP-MSNs and hTAB004-Gem-cisPt-MSNs in a transgenic spontaneous PDA.MUC1 mice model. This data will be the proof of concept for successful bench to bedside translation of this platform.