Targeted therapy of peritoneal carcinomatosis using theranostic nanoparticles

 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使用新型纳米技术生物标志物分析和腹膜内（即，（第30页）受体靶向治疗诊断纳米颗粒的递送，用于有效治疗患有大面积腹膜转移或腹膜癌病（PC）的癌症患者。大多数PC患者不仅具有不可切除的肿瘤，而且还产生腹水积聚，并且被认为是不可治愈的。为了解决这一未满足的临床挑战，我们建议开发一种新的，有针对性的治疗PC的治疗策略。首先，我们将开发用于检测以下水平的体外测定： 细胞受体靶向和评估对腹膜肿瘤细胞中受体靶向治疗诊断纳米颗粒的治疗反应，以选择将从靶向癌症治疗中获益最多的PC患者。我们的初步研究结果表明，i。尿激酶纤溶酶原激活物受体（uPAR）靶向治疗诊断磁性氧化铁纳米颗粒（IONP）的p.递送具有高效率的纳米颗粒递送到原位胰腺肿瘤中，并具有深入肿瘤中心的优异穿透性，这是由于其靶向肿瘤细胞和介导肿瘤基质屏障破坏的肿瘤基质内皮细胞、成纤维细胞和巨噬细胞的能力。I. p.递送受体靶向的治疗诊断性IONP导致i.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上可行的和新的精确的基于纳米医学的治疗方法，该方法将生物标志物分析和腹膜液中肿瘤细胞的治疗反应评估与i. p.递送携带有效药物组合的生物标志物靶向治疗诊断IONP以增强耐药性i.肿瘤，并因此改善治疗的结果。在目标1中，将开发用于检测在腹膜肿瘤中高度表达的四种生物标志物（uPAR、IGF1R、EGFR和HER2）的体外伴随诊断试剂盒。该系统包括用于捕获肿瘤细胞的EpCAM抗体包被的IONP（30 nm核尺寸）和针对上述指定生物标志物的抗体或肽配体缀合的量子点（QD）。将在从荷瘤小鼠或人PC患者获得的腹水样品中评价生物标志物检测的分离效率和特异性。将检查富集的肿瘤细胞对受体靶向治疗诊断IONP的敏感性。目的2中的研究将开发负载有多柔比星（Dox）并与融合有细菌毒素（PE 38KDEL）的uPAR靶向ATF配体缀合的双药剂治疗诊断IONP，并确定i.在裸鼠的转移性胰腺或卵巢肿瘤异种移植物模型中的腹膜内递送。同时将有效毒素和Dox递送到肿瘤细胞中具有克服化学抗性的潜力。最后，在目标3中，将在正常和i. p.荷瘤小鼠。

 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.