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

• 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
• 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

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.

项目摘要/摘要 胃肠道间质瘤(GIST)是胃肠道最常见的间叶性肿瘤， 大部分来自胃和小肠，但从食道到直肠的任何地方。这个 对于原发肿瘤的GIST患者的标准护理是手术，目标是宏观上的完整 显微镜下边缘阴性的切除。在大多数局限性GIST中完全切除是可能的， 但只有大约一半的人在单纯手术后五年或更长时间内没有复发。另外， 约30%的恶性胃肠道间质瘤有转移和浸润性，这是常规方法很难发现的。 内窥镜检查和CT扫描。 GIST通常以酪氨酸蛋白激酶(KIT)和血小板衍生的过度表达为特征 生长因子受体α(PDGFRA)基因突变。甲磺酸伊马替尼(STI571；诺华格列卫)是一种 选择性酪氨酸激酶抑制剂，靶向KIT/PDGFRA，抑制多条信号通路。伊马替尼 最初用于转移性或无法切除的GIST，患者在高达80%的 病例，目前FDA批准的治疗包括在以下辅助环境中使用伊马替尼 彻底切除KIT阳性肿瘤以防止复发。完全切除肿瘤的一种新方法 完整的假包膜和阴性的显微切缘改善了患者的预后。然而，大多数 GIST手术仍然“盲目”进行，术中影像引导对肿瘤没有任何效果 边缘和没有理想的其他外科领域的隐匿性转移的验证。 我们的假设是，针对GIST的近红外纳米探测器将为外科医生提供敏感的、 在单次术前注射后，进行特定的、实时的术中图像引导。最近，我们有 开发的肾可清除有机纳米粒(H-Dots)用于癌症的诊断、分期和治疗(康 等人的研究。马特上将。2016)。通过在H点纳米探针的空腔中结合伊马替尼，我们可以实现 GIST通过体循环、快速分布和完全性肾排泄的特异性递送 靶向肿瘤部位，无非特异性摄取。我们还可以在术中实时切除胃肠道间质瘤 在外科领域为准确的肿瘤边缘提供指导。 在这项建议中，我们建议使用这些靶向纳米探针来积极治疗异种移植和 转基因GIST动物模型。手术中的实时成像系统将使我们能够看到 GIST在屏幕上发光，从而使图像引导下的小肿瘤切除具有清晰的外科手术 利润率。此外，GIST特异性抗癌药物伊马替尼将在细胞水平抑制KIT的表达 微小且无法发现的转移性肿瘤。这项研究的目的是临床翻译治疗鼻咽癌的H点。 胃肠道间质瘤的影像引导手术与治疗。这种新颖的方法有可能彻底改变 癌症治疗干预和纳米医学的发展。