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

摘要 胰腺导管腺癌（PDAC）是一种侵袭性和破坏性的外分泌系统恶性疾病 胰腺癌的特征在于侵袭性、早期转移和对治疗的严重抗性。PDAC 是美国癌症相关死亡的第四大原因，约有60，430例新发病例 预计2021年将有48,220人死亡。不幸的是，尽管科学界付出了巨大的努力， 值得注意的是，PDAC的预后最差，5年生存率为10%，没有显著改善 过去40年的记录此外，预计PDAC负担将在未来十年增加， 到2030年将成为癌症相关死亡的第二大原因。死亡率高，预后差， PDAC可归因于多因素的原因，如其内在和获得性耐药行为， 微转移性播散、促结缔组织增生作用和肿瘤异质性，使目前的 治疗相当无效。开发有效治疗PDAC的可靠方法将是一个重大的挑战。 对这种致命疾病的临床结果的影响。我们设计、合成并表征了 用于顺铂（cisPt）和吉西他滨的受控递送的靶向特异性、刺激响应性MSN平台 (Gem)（TAB 004-Gem-cisPt-MSNs），具有最佳药物比例。我们的初步数据表明， 递送系统有效地靶向肿瘤相关MUC 1（tMUC 1）， 在过表达tMUC 1的同基因和自发小鼠模型中降低毒性。在这个项目中， 我们建议开发新的基于MSN的序贯给药系统，用于PDAC的有效治疗。 这一提议的假设是，通过开发一种基于纳米颗粒的连续方案， 初级纳米平台靶向肿瘤基质以递送SHh抑制剂;和次级纳米载体， hTAB 004-Gem-cisPt-MSNs用于将化疗剂释放至PDAC细胞，PDAC的治疗将是有效的。 戏剧性的改善。该项目的主要目标将通过完成三个目标来实现：1） 研究hTAB 004-Gem-cisPt-MSNs对Gem生物稳定性的影响及其对DNA的作用机制 2）研究CyP-MSN的药代动力学、生物分布和安全性， hTAB 004-Gem-cisPt-MSNs;以及序贯疗法在患者来源的异种移植物中的治疗功效 (PDX)3）评估抗肿瘤转移的靶向、治疗功效和有效性， 转基因自发PDA.MUC1中CyP-MSNs和hTAB 004-Gem-cisPt-MSNs的序贯治疗 小鼠模型该数据将成为该平台从实验室到床旁成功转化的概念证明。

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.