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

• 批准号: 9032253
• 负责人: Hui Mao
• 金额: $ 42.53万
• 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: 2015-12-04 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9032253
• 关键词: Address; Animal Model; Antibodies; Antineoplastic Agents; Ascites; Bacterial Toxins; Biodistribution; Biological Assay; Biological Markers; Cancer Patient; Cancer cell line; Carcinomatosis; Chimeric Proteins; Clinical; Colon; Detection; Development; Dose; Doxorubicin; Drug Carriers; Drug Combinations; Drug Delivery Systems; Drug Kinetics; Drug resistance; Dyes; ERBB2 gene; Endothelial Cells; Epidermal Growth Factor Receptor; Epithelial Cells; Evaluation; Fibroblasts; Goals; Greater sac of peritoneum; Human; Image; In Vitro; 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; 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; Staging; 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; improved; improved outcome; in vitro Assay; in vitro testing; industry partner; intraperitoneal; intraperitoneal therapy; iron oxide; macrophage; mouse model; nanomedicine; nanoparticle; neoplastic cell; new therapeutic target; 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; treatment response; tumor; tumor xenograft

 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（由申请人提供）：该学术和工业合作研究项目的转化目标是开发一种精准肿瘤学方案，结合新型纳米技术生物标志物分析和腹膜内（i.p.）递送靶向受体的治疗纳米颗粒，以有效治疗患有大量腹膜转移或腹膜癌病（PC）的癌症患者。大多数PC患者不仅肿瘤无法切除，而且会出现腹水积聚，被认为无法治愈。为了解决这一未满足的临床挑战，我们建议开发一种新颖的、有针对性的治疗策略来治疗 PC。首先，我们将开发体外检测方法来检测 细胞受体靶标并评估腹膜肿瘤细胞中受体靶向治疗纳米粒子的治疗反应，以选择将从靶向癌症治疗中受益最大的 PC 患者。我们的初步研究结果表明，i。 p。尿激酶纤溶酶原激活剂受体 (uPAR) 靶向治疗诊断磁性氧化铁纳米粒子 (IONP) 的纳米粒子递送效率很高，能够高效地递送到原位胰腺肿瘤中，并且能够出色地深入肿瘤中心，因为它能够靶向肿瘤细胞和介导肿瘤破裂的肿瘤基质内皮细胞、成纤维细胞和巨噬细胞 基质屏障。 I. p.靶向治疗诊断 IONP 的受体递送导致 i 中腹膜肿瘤和腹水量显着减少。 p。转移性胰腺癌和卵巢癌小鼠模型。我们的项目旨在开发一种临床可行的新型精密纳米医学治疗方法，将腹膜液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。递送生物标志物靶向治疗诊断IONP，其携带有效的药物组合，以增强耐药性i的治疗反应。 p。肿瘤，从而改善治疗效果。在目标1中，将开发一种体外伴随诊断试剂盒，用于检测在腹膜肿瘤中高表达的四种生物标志物（uPAR、IGF1R、EGFR和HER2）。该系统包括用于捕获肿瘤细胞的 EpCAM 抗体包被的 IONP（30 nm 核心尺寸）以及针对上述指定生物标志物的抗体或肽配体缀合量子点 (QD)。生物标志物检测的分离效率和特异性将在从荷瘤小鼠或人类 PC 患者获得的腹水样本中进行评估。将检查富集的肿瘤细胞对受体靶向治疗诊断 IONP 的敏感性。目标 2 中的研究将开发一种双药治疗诊断 IONP，负载阿霉素 (Dox)，并与 uPAR 靶向 ATF 配体结合，并与细菌毒素融合 (PE38KDEL)，并确定 i 的治疗效果。 p。在裸鼠转移性胰腺或卵巢肿瘤异种移植模型中进行递送。同时将强效毒素和阿霉素递送至肿瘤细胞内有可能克服化疗耐药性。最后，在目标 3 中，生物分布、全身毒性、剂量反应和药代动力学 (PK)/药效学 (PD) 的临床前研究将在正常和 i 状态下进行。 p。荷瘤小鼠。