Targeted therapy of peritoneal carcinomatosis using theranostic nanoparticles

 描述(由申请人提供)：这一学术和产业伙伴关系研究项目的翻译目标是开发一种结合使用新的纳米技术生物标记物分析和腹膜内(I.P.)的精确肿瘤学方案。提供受体靶向的治疗纳米粒子，用于有效治疗腹膜转移或腹膜癌(PC)的癌症患者。大多数PC患者不仅有无法切除的肿瘤，还会出现腹水积聚，并被认为是无法治愈的。为了解决这一尚未满足的临床挑战，我们建议开发一种新的、有针对性的治疗策略来治疗PC。首先，我们将开发体外检测方法，以检测 细胞受体靶点和对腹膜肿瘤细胞中受体靶向治疗纳米颗粒的治疗反应的评估，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，腹腔注射靶向抗癌磁性氧化铁纳米粒(IONPs)的尿激酶型纤溶酶原激活剂受体(UPAR)可高效地将纳米粒输送到原位胰腺肿瘤中，并具有良好的深入肿瘤中心的能力，这是因为它能够靶向肿瘤细胞和介导肿瘤间质屏障破裂的肿瘤间质内皮细胞、成纤维细胞和巨噬细胞。腹腔注射靶向治疗的受体IONPs可显著减少腹腔内转移性胰腺癌和卵巢癌小鼠模型的腹膜肿瘤和腹水量。我们的项目旨在开发一种临床上可行的新型精密纳米药物治疗方法，将腹腔液中肿瘤细胞的生物标记物分析和治疗反应评估与携带有效药物组合的生物标记物靶向治疗IONPs的注射相结合，以增强对耐药的I.P.肿瘤的治疗反应，从而改善治疗结果。在目标1中，将开发一种体外配套诊断试剂盒，用于检测腹膜肿瘤中高表达的四个生物标记物(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IONPs(核心尺寸为30 nm)和针对上述指定生物标记物的抗体或多肽配体共轭量子点(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患者的腹水样本中进行评估。将检测肿瘤细胞对受体靶向治疗性IONPs的敏感性。AIM 2的研究将开发一种负载阿霉素(Dox)并与uPAR靶向ATF配体融合细菌毒素(PE38KDEL)偶联的双剂治疗IONP，并确定ip给药对裸鼠转移性胰腺癌或卵巢癌移植瘤模型的治疗效果。同时将一种有效的毒素和Dox输送到肿瘤细胞中有可能克服化疗耐药性。最后，在目标3中，将在正常和I.P.荷瘤小鼠中进行关于生物分布、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。

 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.