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 胃肠道肿瘤（GIST）是胃肠道中最常见的间充质肿瘤， 主要是从stallch和小肠子中原来的，但从食道到直肠的任何地方。 原发性肿瘤患者的GIST患者的护理标准是手术，旨在宏观完成 分切除，负微观边缘。在大多数本地性要点，可以完全切除， 但是仅通过手术，只有大约一半的五年或更长时间才能复发。此外， 大约30％的恶性GIST表现出转移和浸润，很难使用常规 内窥镜评估和CT扫描。 GIST经常以酪氨酸 - 蛋白酶激酶（试剂盒）和血小板衍生的过表达为特征 生长因子受体α（PDGFRA）基因突变。伊马替尼梅赛酸盐（STI571; Gleevec，Novartis）是一个 选择性酪氨酸激酶抑制剂的靶标/PDGFRA靶向并抑制多个信号通路。伊马替尼 最初用于转移性或不可切除的GIST，患者显示出多达80％的临床反应 病例，当前FDA批准的治疗包括在调整设置中使用伊马替尼 完全切除套件阳性肿瘤，以防止复发。用一个完整切除肿瘤 完整的假胶囊和负显微镜缘可改善患者的预后。但是，大多数 GIST手术仍然“盲目”进行，而没有任何有效的术中图像指南 边缘，没有理想的手术领域其他隐匿转移酶的验证。 我们的假设是，针对GIST的近红外纳米探针将为外科医生提供敏感的， 单次术前注射后的特定和实时术中图像指导。最近，我们有 开发了用于诊断，分期和治疗癌症的肾脏可透明有机纳米颗粒（H点）（Kang 等。 ADV。母校。 2016）。通过将伊马替尼结合在H-DOT纳米探针的腔中，我们可以实现 通过全身循环和快速分布以及肾脏排泄的特定特定特定分娩 靶向肿瘤部位，而无需非特异性摄取。我们还可以通过实时术中分辨出GIST 手术场中准确的肿瘤边缘指南。 在此提案中，我们建议使用这些有针对性的纳米探针进行主动治疗特殊的特殊性和特征。 基因工程的要点动物模型。实时术中成像系统将使我们看到 屏幕上的要点“发光”，从而允许用清晰手术的小肿瘤切除图像引导 利润。此外，要点特异性抗癌药物伊马替尼将抑制在细胞水平的套件表达 小且无法检测到的转移性肿瘤。这项研究的目的是对疗法H点的临床翻译 图像引导的手术和GIST的治疗。这种新颖的方法有可能改变 癌症和纳米医学治疗干预措施的发展。