Stroma Breaking Theranostic Nanoparticle for Targeted Pancreatic Cancer Therapy

 描述(由申请者提供)：该项目旨在解决该U01计划中确定的几个主要领域。拟建的高度稳定的3纳米超细氧化铁纳米颗粒(UIONP)平台是下一代磁性纳米颗粒，具有同类产品中最小的尺寸，可增强肿瘤的穿透性和保持性，并具有最大的单位药物装载表面积。其新颖的T1/T2双对比可根据其分区而切换，例如，分散在血管中和在肿瘤中自组装，这使得通过MRI报告全身给药过程成为可能。将开发的uIONPs与最新开发的防污染“隐形”涂层技术和针对肿瘤微环境(间质)和癌细胞的新策略相结合，将使我们能够研究纳米颗粒的传递机制及其对治疗反应的影响。更重要的是，携带抗癌药物的靶向治疗uIONPs可以打破肿瘤间质中的生理障碍，扰乱肿瘤微环境，从而克服目前治疗胰腺癌的挑战和失败，从而改善癌症分子靶向和靶向药物输送。研究和开发打破基质的uIONP平台将深刻改变目前纳米材料在给药到纤维性肿瘤，特别是胰腺癌方面的低效率，胰腺癌是最糟糕的给药癌症类型，因为致密的纤维肿瘤间质和细胞外基质含量高。随着我们对胰腺癌生物学的新理解以及在图像引导下的消融IONP递送系统方面的专业知识，在目标1中，我们将开发和表征具有“隐形”防污涂层(UIONP)的双对比消融uIONPs，该uIONP通过包含uPA氨基末端片段与MMP14催化结构域(ATFmmp)的融合肽的新型uPAR靶向配体和IGF-1来同时靶向在肿瘤细胞、肿瘤相关成纤维细胞和巨噬细胞中共同表达的两种细胞受体uPAR和IGF-1R。目的研究和测定ATFmMP-IGF-uIONP体内靶向给药对基质的破坏能力和效率。开发的ATFmMP-IGF-uIONP(单独或与药物联合使用)应该能够比较大的IONP更容易和更快地从泄漏的肿瘤血管渗出，破坏细胞外基质和破坏基质细胞到达癌细胞，然后通过细胞受体介导的内化。我们将利用体内磁共振和光学成像、体外多光子显微镜和体外组织学和化学分析等方法，检测uIONP在人胰腺癌患者组织源异种移植(PDX)和转基因小鼠胰腺肿瘤模型中的靶向传递和瘤内分布的效率。在目的3中，我们将首先确定MRI引导下单独携带顺铂的间质破裂型uIOPS的治疗效果和能力的改善，然后再联合喜树碱类似物SN38作为联合治疗对人胰腺癌PDX模型的耐药。

 DESCRIPTION (provided by applicant): This project seeks to address several major areas identified in this U01 program. The proposed, highly stable 3-nm ultra-fine iron oxide nanoparticle (uIONP) platform is the next generation of magnetic nanoparticles with the smallest size of its kind for enhanced tumor penetration and retention and the largest per unit surface areas for drug loading. Its novel T1/T2 dual-contrast is switchable depending on its compartmentalization, e.g., dispersed in vessels and self-assembled in tumors, which enables report of the systemic drug delivery process via MRI. The combination of developed uIONPs with the newly developed anti-fouling "stealth" coating technology and new strategy of targeting both the tumor microenvironment (stroma) and cancer cells will allow us to investigate nanoparticle delivery mechanisms and their implications on therapeutic responses. More importantly targeted theranostic uIONPs carrying anti-cancer agents can overcome the challenge and failure of current therapies in treating pancreatic cancer by breaking the tumor's physiological barriers in stroma and disrupt the tumor microenvironment, leading to improved cancer molecular targeting and targeted drug delivery. The proposed investigation and development of a stroma-breaking theranostic uIONP platform will profoundly change the current nanomaterials' poor efficiency when delivering drugs into fibrotic human cancers, especially pancreatic cancer which is the worst cancer type for drug delivery due to a high content of dense fibrotic tumor stromal and extracellular matrix. With our new understanding of pancreatic cancer biology and expertise in image-guided theranostic IONP delivery systems, in Aim 1 we will develop and characterize dual contrast theranostic uIONPs with "stealth" antifouling coating (uIONP) that is functionalized with a new uPAR targeting ligand containing the fused peptide of the amino terminal fragment of uPA and the catalytic domain of MMP14 (ATFmmp), and IGF-1 to simultaneously target two cellular receptors, uPAR and IGF- 1R, co-expressed in tumor cells and tumor associated fibroblasts and macrophages. Aim 2 will investigate and determine the stroma breaking ability and efficiency of targeted delivery of ATFmmp-IGF-uIONP in vivo. Developed ATFmmp-IGF-uIONP (alone or with drugs) should be able to extravasate from leaky tumor blood vessels easier and faster than larger IONPs, break extracellular matrix and destroy stromal cells to reach cancer cells, followed by cell receptor-mediated internalization. We will examine the efficiency of targeted delivery and intratumoral distribution of the uIONP in orthotopic human pancreatic cancer patient tissue- derived xenograft (PDX) and transgenic mouse pancreatic tumor models using MR and optical imaging in vivo, multiphoton microscopy ex vivo, and histological and chemical analyses in vitro. In Aim 3, we will determine the improvement in the therapeutic effect and capability of MRI-guided delivery of stroma-breaking theranostic uIONPs carrying cisplatin alone first, and then combined with SN38, which is a camptothecin analogue, as a combination therapy against drug resistance in human pancreatic cancer PDX models.