Targeted therapy of peritoneal carcinomatosis using theranostic nanoparticles

使用治疗诊断纳米粒子靶向治疗腹膜癌病

基本信息

批准号：
9189695
负责人：
Hui Mao
金额：
$ 41.13万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-04 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9189695
关键词：
Address Animal Model Antibodies Antineoplastic Agents Ascites Bacterial Toxins Biodistribution Biological Assay Biological Markers Cancer Patient Carcinomatosis Cell Line Chimeric Proteins Clinical Colon Detection Development Dose Doxorubicin Drug Carriers Drug Combinations Drug Delivery Systems Drug Kinetics Drug Targeting Drug resistance Dyes ERBB2 gene Endothelial Cells Epidermal Growth Factor Receptor Epithelial Cells Evaluation Fibroblasts Goals Greater sac of peritoneum Human In Vitro Industrialization Insulin-Like-Growth Factor I Receptor Intravenous Label Ligands Liver Magnetic Resonance Imaging Magnetism Malignant Neoplasms Malignant neoplasm of abdomen Malignant neoplasm of ovary Malignant neoplasm of pancreas Mammary Neoplasms Maximum Tolerated Dose Mediating Molecular Target Monitor Mus Nanotechnology Neoplasm Metastasis Nude Mice Oceans Operative Surgical Procedures Organ Ovarian Ovary Pancreas Patient Selection Patients Penetration Peptides Peritoneal Peritoneal Fluid Pharmaceutical Preparations Polymers Population Protocols documentation Quantum Dots Receptor Cell Research Research Project Grants Residual Tumors Sampling Specific qualifier value Specificity Stomach Stromal Cells Stromal Neoplasm System TACSTD1 gene Testing Therapeutic Tissues Toxin Translational Research Treatment Efficacy Tumor Antibodies Tumor Debulking Universities Unresectable Urokinase Plasminogen Activator Receptor Xenograft Model absorption activating transcription factor base cellular imaging chemotherapy companion diagnostics effective therapy end stage disease gastrointestinal imaging approach improved improved outcome in vitro Assay in vitro testing industry partner intraperitoneal iron oxide macrophage mouse model nanomedicine nanoparticle neoplastic cell novel novel therapeutics optical imaging ovarian neoplasm pancreatic cancer cells pancreatic neoplasm precision oncology preclinical study public health relevance receptor response specific biomarkers success systemic toxicity targeted biomarker targeted cancer therapy targeted delivery targeted treatment theranostics therapeutic evaluation therapy outcome treatment response tumor

项目摘要

DESCRIPTION (provided by applicant): The translational goal of this Academic and Industrial Partnership research project is to develop a precision oncology protocol using a combination of novel nanotechnology biomarker profiling and intraperitoneal (i. p.) delivery of receptor-targeted theranostic nanoparticles for the effective treatment of cancer patients with massive peritoneal metastasis or peritoneal carcinomatosis (PC). The majority of PC patients not only have unresectable tumors, but also develop ascites accumulation, and are considered incurable. To address this unmet clinical challenge, we propose to develop a novel, targeted therapeutic strategy for treating PC. First, we will develop in vitro assays for the detection of the levels of cell receptor targets and evaluation of therapeutic responses to receptor targeted theranostic nanoparticles in peritoneal tumor cells for selecting PC patients who will benefit the most from the targeted cancer therapy. Results of our preliminary studies have shown that i. p. delivery of urokinase plasminogen activator receptor (uPAR) targeted theranostic magnetic iron oxide nanoparticles (IONPs) had a high efficiency of nanoparticle delivery into orthotopic pancreatic tumors with excellent penetration deep into the tumor center, due to its ability to target tumor cells and tumor stromal endothelial cells, fibroblasts, and macrophages that mediate breakage of the tumor stromal barrier. I. p. delivery of the receptor targeted theranostic IONPs led to a marked reduction of peritoneal tumors and ascites volumes in i. p. metastatic pancreatic and ovarian cancer mouse models. Our project aims to develop a clinically feasible and new precision nanomedicine based treatment that integrates biomarker profiling and treatment response evaluation of tumor cells in peritoneal fluids with i. p. delivery of the biomarker targeted theranostic IONPs carrying a potent drug combination to enhance therapeutic responses in drug resistant i. p. tumors and therefore, improve outcome of the therapy. In Aim 1, an in vitro companion diagnostic kit for the detection of four biomarkers (uPAR, IGF1R, EGFR, and HER2) that are highly expressed in peritoneal tumors will be developed. This system includes EpCAM antibody coated IONPs (30 nm core size) for capturing tumor cells and antibody or peptide ligand conjugated quantum dots (QDs) against the above specified biomarkers. Isolation efficiency and specificity of the biomarker detection will be evaluated in ascites samples obtained from tumor-bearing mice or human PC patients. Sensitivity of enriched tumor cells to receptor targeted theranostic IONPs will be examined. Studies in Aim 2 will develop a dual agent theranostic IONP loaded with doxorubicin (Dox) and conjugated with an uPAR targeting ATF ligand fused with a bacterial toxin (PE38KDEL) and determine the therapeutic efficacy of i. p. delivery in metastatic pancreatic or ovarian tumor xenograft models in nude mice. Simultaneous delivery of a potent toxin and Dox into tumor cells has the potential to overcome chemoresistance. Finally, in Aim 3, preclinical studies on biodistribution, systemic toxicity, dose-response, and pharmacokinetics (PK) /pharmcodynamics (PD) will be conducted in normal and i. p. tumor bearing mice.

描述（由应用程序提供）：该学术和工业伙伴研究项目的翻译目标是使用新型纳米技术生物标志物分析和腹膜内（i。p。）提供受体靶向的疗法疗法纳米颗粒的结合，以有效治疗癌症大规模胰岛胰蛋白酶或perit的癌症患者的有效治疗患者的患者，以治疗受体靶向的疗法纳米颗粒（i。p。）。大多数PC患者不仅具有不可切除的肿瘤，而且还会发展腹水，并且被认为是无法治愈的。为了应对这一未满足的临床挑战，我们建议制定一种针对性的针对性理论策略。首先，我们将开发在检测水平的体外测定细胞受体靶标和对腹膜肿瘤细胞中受体靶向疗法纳米颗粒的热反应评估，以选择将受益于靶向癌症治疗最大的PC患者。我们的初步研究的结果表明i。 p。尿激酶纤维蛋白原激活剂受体（UPAR）靶向静脉磁铁氧化铁纳米颗粒（离子）（离子）具有很高的纳米颗粒递送到原位胰腺胰腺肿瘤中，由于其能够靶向肿瘤细胞和肿瘤的肿瘤内膜细胞，并促进了肿瘤细胞，并具有出色的穿透性肿瘤中心的肿瘤中心深处。基质屏障。 I. p。受体靶向热离子的递送导致腹膜肿瘤和腹水体积显着减少。 p。转移性胰腺和卵巢癌小鼠模型。我们的项目旨在开发一种基于临床上可行和新的精度纳米医学治疗，该治疗将腹膜烟中肿瘤细胞的生物标志物分析和治疗反应评估与I相结合。 p。携带潜在药物组合的生物标志物靶向热离子的递送，以增强耐药性i的治疗反应。 p。肿瘤，因此可以改善治疗的预后。在AIM 1中，将开发出在腹膜肿瘤中高度表达的四个生物标志物（UPAR，IGF1R，EGFR和HER2）的体外伴侣诊断试剂盒。该系统包括用于捕获肿瘤细胞，抗体或肽配体共轭量子点（QD）的EPCAM抗体涂层离子（30 nm核心尺寸）针对上述指定的生物标志物。生物标志物检测的分离效率和特异性将在从肿瘤小鼠或人类PC患者中获得的腹水样品中进行评估。将检查富集的肿瘤细胞对受体靶向热离子的敏感性。 AIM 2中的研究将开发带有阿霉素（DOX）的双重剂疗法IONP，并与与细菌毒素（PE38KDEL）融合的UPAR靶向ATF配体共轭，并确定I的治疗效率。 p。裸鼠的转移性胰腺或卵巢肿瘤定位模型中的递送。同时将潜在的毒素和DOX递送到肿瘤细胞中具有克服化学抗性的潜力。最后，在AIM 3中，将以正常和i进行生物分布，全身毒性，剂量反应和药代动力学（PK） /药物动力学（PD）的临床前研究。 p。肿瘤轴承小鼠。