Image-Guided Drug Delivery and Treatment for GIST

图像引导胃肠道间质瘤的药物输送和治疗

基本信息

批准号：
9792375
负责人：
Hak Soo Choi
金额：
$ 17.77万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-25 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9792375
关键词：
3-Dimensional Adjuvant Affinity Animal Model Animals Antineoplastic Agents Binding Biodistribution Biological Biological Assay Bladder Blood Circulation C-KIT Gene Cancer Intervention Cancerous Cell Line Charge Chemotherapy-Oncologic Procedure Clinical Complex Contrast Media Cryoultramicrotomy Culture Media Data Diagnosis Dose Drug Kinetics Endoscopy Ensure Equilibrium Esophagus Excision Excretory function Exhibits Extinction (Psychology)FDA approved Fluorescence Fluorescence Microscopy Foundations Gastrointestinal Stromal Tumors Gastrointestinal tract structure Gene Mutation Genetic Engineering Gleevec Goals Histology Image Image-Guided Surgery Imaging Techniques Imatinib Imatinib mesylate Immunohistochemistry In Vitro Infiltration Injections Intravenous Kidney Knock-in Mouse Malignant - descriptor Malignant Neoplasms Measurement Measures Mesenchymal Cell Neoplasm Microscopic Microscopy Monitor Mus Mutate Near-infrared optical imaging Neoplasm Metastasis Operative Surgical Procedures Optics Patients Pharmaceutical Preparations Pharmacotherapy Platelet-Derived Growth Factor alpha Receptor Play Primary Neoplasm Procedures Property Protein Tyrosine Kinase Proto-Oncogene Protein c-kit Rectum Recurrence Renal clearance function Resected Resistance Role STI571 Serum Signal Pathway Site Small Intestines Specificity Staging Stomach Surface Surgeon Surgical margins Therapeutic Therapeutic Intervention Therapeutic Studies Time Tissues Toxic effect Transgenic Animals Travel Treatment Efficacy Tumor Suppression Tumor Volume Tumor-Associated Process Tyrosine Kinase Inhibitor Unresectable Urine X-Ray Computed Tomography Xenograft procedure active method anti-cancer biocompatible polymer cancer surgery cancer therapy clinical translation cytotoxicity design fluorophore image guided image guided intervention image-guided drug delivery imaging system improved in vivo nanocarrier nanomedicine nanoparticle nanoprobe novel strategies outcome forecast overexpression prevent quantum real time monitoring response standard of care targeted delivery targeted imaging technique development theranostics therapeutic development tumor tumor xenograft uptake

项目摘要

PROJECT SUMMARY/ABSTRACT Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor in the gastrointestinal tract, mostly originated from the stomach and small intestine, but anywhere from the esophagus to the rectum. The standard of care for GIST patients with a primary tumor is surgery, aiming for a macroscopically complete resection with negative microscopic margins. Complete resection is possible in the majority of localized GISTs, but only approximately one-half remain recurrence-free for five or more years with surgery alone. Additionally, about 30% of malignant GISTs exhibit metastasis and infiltration, which are difficult to find using conventional endoscopic assessments and CT scanning. GIST is frequently characterized by the overexpression of tyrosine-protein kinase (KIT) and platelet-derived growth factor receptor alpha (PDGFRA) gene mutations. Imatinib mesylate (STI571; Gleevec, Novartis) is a selective tyrosine kinase inhibitor that targets of KIT/PDGFRA and inhibits multiple signaling pathways. Imatinib was originally used for metastatic or unresectable GISTs with patients showing clinical responses in up to 80% of cases, and the current FDA-approved treatments include the use of imatinib in the adjuvant setting following complete gross resection of KIT-positive tumors to prevent recurrence. The complete resection of tumors with an intact pseudocapsule and negative microscopic margin improves the prognosis of the patients. However, most GIST surgeries are still performed “blindly” without any efficient of intraoperative image guidance for tumor margin and without an ideal verification of other occult metastases in the surgical field. Our hypothesis is that near-infrared nanoprobes targeted to GISTs will provide surgeons with sensitive, specific, and real-time intraoperative image-guidance after a single preoperative injection. Recently, we have developed renal clearable organic nanoparticles (H-Dots) for diagnosis, staging, and treatment of cancers (Kang et al. Adv. Mater. 2016). By combining imatinib in the cavity of H-dot nanoprobes, we could achieve GIST-specific delivery via systemic circulation and rapid distribution as well as renal excretion after complete targeting to the tumor site without nonspecific uptake. We could also resect GISTs with real-time intraoperative guidance for accurate tumor margin in the surgical field. In this proposal, we propose to use these targeted nanoprobes for active treatment of GIST in xenograft and genetically engineered GIST animal models. The real-time intraoperative imaging system will allow us to see the GIST “glowing” on the screen, thus permitting image-guided resection of small tumors with clear surgical margins. Furthermore, GIST-specific anticancer drug imatinib will inhibit KIT expression at the cellular level in small and undetectable metastatic tumors. The goal of this study is clinical translation of theranostic H-dots for image-guided surgery and treatment of GIST. This novel approach has the potential to revolutionize the development of therapeutic interventions of cancer and nanomedicine.

项目概要/摘要胃肠道间质瘤（GIST）是胃肠道最常见的间叶质肿瘤，大多数起源于胃和小肠，但也有从食道到直肠的任何地方。患有原发性肿瘤的 GIST 患者的护理标准是手术，旨在获得宏观完整的治疗大多数局部 GIST 均可实现显微切缘阴性的切除。但只有大约一半的患者仅通过手术就能在五年或更长时间内保持无复发。约30%的恶性GIST存在转移和浸润，使用常规方法很难发现内窥镜评估和 CT 扫描。 GIST 的常见特征是酪氨酸蛋白激酶 (KIT) 和血小板衍生的过度表达生长因子受体α（PDGFRA）基因突变甲磺酸伊马替尼（STI571；格列卫，诺华）是一种。选择性酪氨酸激酶抑制剂，靶向 KIT/PDGFRA 并抑制多种信号通路。最初用于治疗转移性或不可切除的 GIST，患者的临床缓解率高达 80% 病例，目前 FDA 批准的治疗方法包括在以下辅助治疗中使用伊马替尼完全切除 KIT 阳性肿瘤以防止复发。完整的假包膜和阴性的显微镜边缘改善了患者的预后。 GIST手术仍处于“盲目”状态，缺乏有效的肿瘤术中影像引导切缘且没有对手术野中其他隐匿性转移进行理想的验证。我们的假设是，针对胃肠道间质瘤的近红外纳米探针将为外科医生提供敏感、最近，我们在单次术前注射后进行了具体的实时术中图像引导。肾开发出可清除的有机纳米颗粒（H-Dots），用于癌症的诊断、分期和治疗（Kang 等人，Adv.2016）。通过体循环和快速分布以及完成后的肾脏排泄进行 GIST 特异性递送我们还可以在术中实时切除 GIST。为手术区域准确的肿瘤切缘提供指导。在本提案中，我们建议使用这些靶向纳米探针来积极治疗异种移植中的胃肠道间质瘤（GIST）和基因工程胃肠道间质瘤动物模型实时术中成像系统将使我们能够看到胃肠道间质瘤在屏幕上“发光”，从而可以通过清晰的手术在图像引导下切除小肿瘤此外，GIST特异性抗癌药物伊马替尼会在细胞水平上抑制KIT表达。本研究的目标是治疗诊断 H 点的临床转化。这种新颖的方法有可能彻底改变胃肠道间质瘤的图像引导手术和治疗。癌症和纳米医学治疗干预措施的发展。