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（由适用提供）：本项目旨在解决该U01计划中确定的几个主要领域。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，同类尺寸最小，可增强肿瘤渗透和保留率，并且是药物负荷的每单位表面积最大。它的新型T1/T2双对比度可切换，具体取决于其隔室化，例如分散在血管中，并自组装在肿瘤中，这可以通过MRI报告全身药物递送过程。开发的UIONP与新开发的抗污染“隐形”涂料技术以及针对肿瘤微环境（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的递送机制及其对热反应的影响。更重要的是，携带抗癌剂的靶向疗法UIONP可以克服当前疗法在治疗胰腺癌方面的挑战和失败，通过打破肿瘤在基质中的物理屏障并破坏肿瘤微环境，从而改善了癌症分子靶向和靶向药物的递送。拟议的调查和开发破坏基质的疗法UIONP平台将在将药物输送到纤维化的人类癌症中，尤其是胰腺癌，这是由于严重的纤维性肿瘤肿瘤肿瘤的肿瘤肿瘤和外细胞外肿瘤含量而导致药物递送最差的癌症类型时，将对当前的纳米材料的效率较差。 With our new understanding of pancreatic cancer biology and expert 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）和IGF-1同时靶向两个细胞受体UPAR和IGF-1，在肿瘤细胞和相关的肿瘤成纤维细胞和巨噬细胞中共表达。 AIM 2将研究并确定体内ATFMMP-iGF-uionp的靶向递送的基质破裂能力和效率。与较大的IONP相比，开发的ATFMMP-IGF-UIONP（单独或使用药物）应能够轻松，更快地从漏水的肿瘤血管中外出，破坏细胞外基质并破坏基质细胞以进入癌细胞，然后进行细胞受体介导的内在化。我们将研究使用MR和MRM成像和光学成像在体内，多光（Multiphoton Microspopicy exe ex ex ex ex ex ex ex e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e e ex and Mytivo ex exipary of In Videmotics In Imagy of Flidotial and的转基因小鼠胰腺肿瘤模型）和转基因小鼠胰腺肿瘤模型的靶向输送和肿瘤内分布的效率。在AIM 3中，我们将首先首先确定MRI引导递送的质基质疗法UIONP的治疗效果和能力的改善，然后首先携带顺铂，然后与SN38结合使用，SN38是一种camptothecin Ableogue，这是一种在人类Pancreatic Cancer Cancer Cancer PDX模型中对耐药性的组合治疗。

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