Injectable reporters to image tumors and guide resection

可注射报告基因对肿瘤进行成像并指导切除

• 批准号: 8238907
• 负责人: ROGER Y TSIEN
• 金额: $ 64.02万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-16 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8238907
• 关键词: Adhesives; Adjuvant Therapy; Aminolevulinate; Animals; Antibodies; Avidity; Beds; Biochemical; Bioluminescence; Blood Vessels; Caliber; Cell Count; Cell Line; Cells; Cleaved cell; Clinical; Contrast Media; Dendrimers; Detection; Development; Diagnostic Neoplasm Staging; Early Diagnosis; Ensure; Equilibrium; Evaluation; Excision; Firefly Luciferases; Fluorescence; Gadolinium; Gelatinase A; Genetic; Goals; Gold; Histology; Image; Imaging Techniques; Immunoglobulin Fragments; Implant; Indolent; Injectable; Integrins; Label; Light; Literature; Luciferases; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Neoplasms; Matrix Metalloproteinases; Measurement; Measures; Membrane; Molecular; Monitor; Monitoring for Recurrence; Mus; Normal tissue morphology; Operative Surgical Procedures; Organ; Outcome; Peptide Hydrolases; Peptides; Performance; Photochemotherapy; Positron-Emission Tomography; Postoperative Period; Preparation; Primary Neoplasm; Procedures; Proteins; ROC Curve; Receiver Operating Characteristics; Recurrence; Reporter; Residual Tumors; Resolution; Signal Transduction; Solid Neoplasm; Specificity; Staging; Surgeon; Techniques; Testing; Thymidine Kinase; TimeLine; Tumor stage; Variant; Viral; Weight; aqueous; fluorophore; gadolinium oxide; imaging modality; improved; interest; killings; link protein; molecular imaging; mouse model; nanoparticle; neoplastic cell; novel; red fluorescent protein; response; success; tumor; tumor specificity; whole body imaging

DESCRIPTION (provided by applicant): Early detection with clinically translatable molecular imaging agents: Novel clinically translatable molecular imaging contrast agents for detecting tumors by T1-weighted magnetic resonance imaging (MRI) or positron emission tomography (PET) will be developed, optimized, and quantitatively characterized. The MRI agents are activatable cell penetrating peptides (ACPPs) conjugated to dendrimers bearing gadolinium chelates. The ACPPs' selectivity for matrix metalloproteinases and the stability of the gadolinium chelates will be optimized. The PET reporters will be reduced-size antibodies bearing novel near-infrared (NIR) fluorophores incorporating 18F-fluoborates. Both MRI and PET agents will be tested in mice on tumors stably expressing genetic reporters for fluorescence (FL), bioluminescence (BL), and positron emission tomography (PET), combining best available versions of far-red fluorescent protein, firefly luciferase, and thymidine kinase, expressed as separate but genetically linked proteins separated by self-cleaving viral 2A sequences. These tests will quantify how reliably can such injectable agents detect solid tumors of different sizes and stages of progression, under what circumstances false positive and negative signals are obtained, when is either combination of probe and imaging modality superior to the other, and whether indolent vs. highly malignant and invasive tumors can be distinguished. Evaluation and improvement of FL-guided surgical resection and adjuvant therapies: Intraoperative FL guidance from injectable agents such as ACPPs conjugated to fluorescent dendrimers, reduced-size antibodies labeled with NIR fluorophores, or 5-aminolevulinate will be compared with FL guidance from the fluorescent protein representing perfect tumor-specific labeling. These comparisons will show which injectable agent performs best under what circumstances, and whether completeness of fluorescence-guided resection is limited more by imperfect biochemical specificity of current contrast agents, or by inability to resolve and manually remove scattered or disseminated tumor cells. Photodynamic therapy (PDT) to kill off residual tumor cells in the surgical field before closure will also be tested. Completeness of initial tumor removal and any recurrence will be assessed postoperatively using the genetic reporters. Comparison with signals from injectable contrast agents and traditional survival measures should quantify how surgical outcomes depend on the thoroughness of tumor cell removal, how much improvement results from current injectable contrast agents vs. genetically perfectly labeling, whether PDT helps, how well can current injectable agents monitor recurrence, and what materials or procedures most need improvement. PUBLIC HEALTH RELEVANCE: This project aims to develop, optimize, and characterize the performance of novel injectable, clinically translatable contrast agents for early detection of tumors, distinction between indolent and aggressive cancers, molecular fluorescence-guided surgery, and postoperative monitoring. The long-term goal is to improve detection of aggressive tumors while they are still small and localized, and to help surgeons remove those tumors accurately completely while sparing as much normal tissue as possible.

描述(申请人提供)：临床可翻译分子显像剂的早期检测：将开发、优化和定量表征用于通过T1加权磁共振成像(MRI)或正电子发射断层扫描(PET)检测肿瘤的新型临床可翻译分子成像造影剂。核磁共振试剂是可激活的细胞穿透肽(ACPPs)，连接到含有Gd螯合物的树状大分子上。ACPP对基质金属蛋白酶的选择性和Gd络合物的稳定性将得到优化。PET记者将是携带含有18F-氟硼酸盐的新型近红外(NIR)荧光团的减小尺寸的抗体。MRI和PET试剂都将在小鼠的肿瘤上进行测试，稳定表达荧光(FL)、生物发光(BL)和正电子发射断层扫描(PET)的遗传报告，结合远红荧光蛋白、萤火虫荧光素酶和胸苷激酶的最佳可用版本，这些蛋白通过自我切割的病毒2A序列表达为单独但基因相连的蛋白。这些测试将量化这些可注射试剂检测不同大小和进展阶段的实体肿瘤的可靠性，在什么情况下获得假阳性和阴性信号，何时探针和成像方式的组合优于另一种，以及是否可以区分惰性肿瘤和高度恶性和侵袭性肿瘤。评估和改进FL引导的手术切除和辅助治疗：术中FL引导将与来自代表完美肿瘤特异性标记的荧光蛋白的荧光蛋白的FL引导进行比较。这些比较将显示哪种注射剂在什么情况下表现最好，以及荧光引导切除的完整性是否更多地受到当前造影剂不完善的生物化学特异性的限制，或者是无法分辨和手动去除散布或播散的肿瘤细胞。还将测试光动力疗法(PDT)，以在关闭前杀死外科领域中残留的肿瘤细胞。首次肿瘤切除的完成性和任何复发将在术后使用基因报告进行评估。与可注射造影剂和传统生存测量的信号进行比较，应该量化手术结果如何取决于肿瘤细胞去除的彻底性，目前的可注射造影剂与基因完美标记相比有多大改善，PDT是否有帮助，目前的可注射造影剂监测复发的效果如何，以及哪些材料或程序最需要改进。 公共卫生相关性：该项目旨在开发、优化和表征新型可注射、临床可翻译的造影剂的性能，用于肿瘤的早期检测、惰性癌症和侵袭性癌症的区分、分子荧光引导的手术和术后监测。长期目标是在侵袭性肿瘤仍然很小和局部的情况下提高对它们的检测，并帮助外科医生准确地完全切除这些肿瘤，同时尽可能多地保留正常组织。