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

刺激响应性粘蛋白1特异性纳米粒子用于胰腺导管腺癌的有效联合化疗

• 批准号: 10654848
• 负责人: Juan Luis Vivero-Escoto
• 金额: $ 32.98万
• 依托单位: UNIVERSITY OF NORTH CAROLINA CHARLOTTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654848
• 关键词: Abraxane; Antibodies; Antigen Targeting; Antineoplastic Agents; Behavior; Biodistribution; Biological; Biological Availability; Biological Markers; Cancer Etiology; Cessation of life; Chemoresistance; Circulation; Cisplatin; Clinic; Clinical; Combined Modality Therapy; DNA Repair; Data; Desmoplastic; Development; Disease; Drug Delivery Systems; Drug Kinetics; Evaluation; Exocrine pancreas; Failure; Goals; Half-Life; Heterogeneity; Immunocompetent; Investigation; Malignant - descriptor; Methods; Modeling; Mucin 1 protein; Mucins; Mus; Mutation; Neoplasm Metastasis; Organ; Outcome; Outcomes Research; Paclitaxel; Pancreatic Ductal Adenocarcinoma; Patients; Performance; Pharmaceutical Preparations; Prognosis; Proteins; Public Health; Regimen; Research; Resistance; Role; SHH gene; Safety; Signal Pathway; Silicon Dioxide; Site; Stimulus; Survival Rate; System; Technology; Therapeutic; Toxic effect; Transgenic Organisms; Translations; Treatment Efficacy; United States; bench-to-bedside translation; chemotherapy; clinical effect; clinically relevant; combinatorial; cyclopamine; design; effective therapy; gemcitabine; improved; inhibitor; mortality; mouse model; nanocarrier; nanoparticle; nanoparticle delivery; nanotechnology platform; novel; overexpression; pancreatic ductal adenocarcinoma cell; patient derived xenograft model; resistance mechanism; safety outcomes; targeted treatment; therapeutic effectiveness; therapy outcome; therapy resistant; tumor; tumor heterogeneity; tumor microenvironment; tumor progression

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.

抽象的 胰腺导管腺癌（PDAC）是一种侵略性和毁灭性的外分泌疾病 胰腺的特征是侵入性，早期转移和对疗法的深刻抵抗。 PDAC 是美国与癌症相关死亡率的第四个主要原因，大约有60,430例新病例 预计2021年的48,220人死亡。不幸的是，尽管采取了巨大的科学努力，但令人震惊的是 请注意，PDAC的预后最差，5年生存率为10％，但尚未显着改善 从过去的40年开始。此外，PDAC负担预计将在未来十年内增加，并预计 到2030年成为癌症相关死亡的第二个领先原因。高死亡率和可怕的预后 PDAC可以归因于多因素原因，例如其内在和获得的抗性行为，早期 肿瘤中的微转移分散，去肿瘤作用和异质性，使电流呈现 治疗相当无效。开发可靠的PDAC有效治疗的可靠方法将具有主要 对这种致命疾病的临床结果的影响。我们设计，合成和表征了 用于控制顺铂（Cispt）和吉西他滨的靶标特异性刺激响应性MSN平台 （GEM）（TAB004-GEM-CISPT-MSN）具有最佳药物比率。我们的初步数据表明了这一点 递送系统有效靶向肿瘤相关的MUC1（TMUC1），可提高治疗效率 过表达TMUC1的同性小鼠模型和自发小鼠模型的毒性降低。在这个项目中， 我们建议开发基于新型MSN的顺序输送系统，以有效地处理PDAC。 该提议的基础假设是，通过开发一种基于纳米颗粒的方案，其中 主要的纳米植物靶向肿瘤基质以递送SHH抑制剂。和次级纳米载体， HTAB004-GEM-CISPT-MSNS用于释放化学治疗剂到PDAC细胞，PDAC的处理将是 急剧改善。该项目的主要目标将通过完成三个目标完成：1） 研究HTAB004-GEM-CISPT-MSN对GEM的生物稳定性及其在DNA上的作用的影响 PDAC细胞的损伤修复； 2）研究CYP-MSN的药代动力学，生物分布和安全性 HTAB004-GEM-CISPT-MSN；顺序治疗在患者衍生异种移植物中的治疗功效 （PDX）小鼠； 3）评估针对肿瘤转移的靶向，治疗功效和有效性 顺序治疗CYP-MSN和HTAB004-GEM-CISPT-MSN在转基因自发PDA.MUC1中 小鼠模型。这些数据将是成功的基准的概念证明该平台的床边翻译。