Stroma Breaking Theranostic Nanoparticle for Targeted Pancreatic Cancer Therapy

用于靶向胰腺癌治疗的基质破坏治疗诊断纳米颗粒

• 批准号: 9750645
• 负责人: Hui Mao
• 金额: $ 46.97万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-28 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750645
• 关键词: Address; Animals; Antineoplastic Agents; Area; Biodistribution; Biological Availability; Biology; Blood; Camptothecin Analogue; Camptothecin-11; Cancer Biology; Catalytic Domain; Cells; Chemicals; Cisplatin; Collagen Fiber; Combined Modality Therapy; Data; Development; Drug Delivery Systems; Drug Targeting; Drug resistance; Endothelial Cells; Engineering; Extracellular Matrix; Failure; Fibroblasts; Generations; Goals; Growth Factor Receptors; Half-Life; Histologic; Human; Image; Image Enhancement; Imaging technology; In Vitro; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Investigation; Ligands; MMP14 gene; Magnetic Resonance; Magnetic Resonance Imaging; Magnetic nanoparticles; Magnetism; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Modeling; Molecular Target; Monitor; Mus; Neoplasms in Vascular Tissue; Pancreas; Patients; Penetration; Peptide Hydrolases; Peptides; Permeability; Pharmaceutical Preparations; Physiological; Polymers; Process; Proteins; Receptor Cell; Reporting; Research; Research Project Grants; Residual Tumors; Stromal Cells; Stromal Neoplasm; Surface; System; Technology; Testing; Therapeutic Effect; Tissues; Transgenic Mice; Tumor Tissue; Tumor-Derived; Ultrafine; Urokinase Plasminogen Activator Receptor; Xenograft Model; Xenograft procedure; cancer cell; cancer imaging; cancer therapy; cancer type; cellular targeting; chemotherapy; contrast imaging; design; drug distribution; effective therapy; image guided; image guided therapy; imaging modality; improved; in vivo; in vivo imaging; iron oxide nanoparticle; macrophage; molecular drug target; multiphoton microscopy; nanomaterials; nanomedicine; nanoparticle; nanoparticle delivery; nanoparticle drug; neoplastic cell; next generation; novel; novel strategies; optical imaging; overexpression; pancreatic cancer model; pancreatic cancer patients; programs; public health relevance; receptor; response; systemic toxicity; targeted delivery; targeted treatment; theranostics; tool; treatment response; tumor; tumor growth; tumor microenvironment; tumor xenograft

 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.

 描述（由申请人提供）：该项目旨在解决这个U 01计划中确定的几个主要领域。所提出的高度稳定的3 nm超细氧化铁纳米颗粒（uIONP）平台是下一代磁性纳米颗粒，具有最小的尺寸，用于增强肿瘤渗透和保留，以及最大的单位载药表面积。其新颖的T1/T2双对比度可根据其划分进行切换，例如，分散在血管中并在肿瘤中自组装，这使得能够通过MRI报告全身药物递送过程。开发的uIONP与新开发的防污“隐形”涂层技术和靶向肿瘤微环境（基质）和癌细胞的新策略的组合将使我们能够研究纳米颗粒递送机制及其对治疗反应的影响。更重要的是，携带抗癌剂的靶向治疗诊断uIONP可以通过打破肿瘤在基质中的生理屏障并破坏肿瘤微环境来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递送。所提出的基质破坏治疗诊断uIONP平台的研究和开发将深刻改变当前纳米材料在将药物递送到纤维化人类癌症中时的低效率，特别是胰腺癌，由于高含量的致密纤维化肿瘤基质和细胞外基质，胰腺癌是药物递送的最差癌症类型。随着我们对胰腺癌生物学的新理解和图像引导治疗诊断IONP递送系统的专业知识，在目标1中，我们将开发和表征具有“隐形”涂层（uIONP）的双对比治疗诊断uIONP，该涂层（uIONP）用含有uPA的氨基末端片段和MMP 14的催化结构域（ATFmmp）的融合肽的新uPAR靶向配体官能化，和IGF-1同时靶向两种细胞受体uPAR和IGF-1 R，它们在肿瘤细胞和肿瘤相关的成纤维细胞和巨噬细胞中共表达。目的2研究和确定ATFmmp-IGF-uIONP体内靶向递送的基质破坏能力和效率。开发的ATFmmp-IGF-uIONP（单独或与药物一起）应该能够比较大的IONP更容易和更快地从渗漏的肿瘤血管外渗，破坏细胞外基质并破坏基质细胞以到达癌细胞，随后是细胞受体介导的内化。我们将使用体内MR和光学成像、离体多光子显微术以及体外组织学和化学分析来检查uIONP在原位人胰腺癌患者组织来源的异种移植物（PDX）和转基因小鼠胰腺肿瘤模型中的靶向递送和肿瘤内分布的效率。在目的3中，我们将确定MRI引导递送的基质破坏治疗诊断性uIONP的治疗效果和能力的改善，所述uIONP首先单独携带顺铂，然后与SN 38（其是喜树碱类似物）组合，作为针对人胰腺癌PDX模型中的耐药性的组合疗法。

项目成果

Inhibition of NADPH Oxidase-ROS Signal using Hyaluronic Acid Nanoparticles for Overcoming Radioresistance in Cancer Therapy.

• DOI: 10.1021/acsnano.2c07440
• 发表时间: 2022-11-22
• 期刊: ACS nano
• 影响因子: 17.1
• 作者: Zhu L;Zhao Y;Liu T;Chen M;Qian WP;Jiang B;Barwick BG;Zhang L;Styblo TM;Li X;Yang L
• 通讯作者: Yang L