权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
8898737
负责人：
Quyen Nguyen
金额：
$ 63.94万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-16 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8898737
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 PUVA Photochemotherapy Peptide Hydrolases Peptides Performance 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 cancer imaging fluorophore gadolinium oxide imaging agent 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

项目摘要

Project Summary 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.

项目摘要用临床可翻译的分子成像剂进行早期检测：新的临床可翻译的用于通过T1加权磁共振成像（MRI）检测肿瘤的分子成像造影剂，或正电子发射断层扫描（PET）将被开发、优化和定量表征。的MRI 试剂是与带有钆的树枝状聚合物缀合的可活化的细胞穿透肽（ACPP 螯合物。ACPPs对基质金属蛋白酶的选择性和钆螯合物的稳定性将优化。PET报告者将是携带新型近红外（NIR）掺入18F-氟硼酸盐的荧光团。MRI和PET试剂都将在小鼠肿瘤上进行测试，表达用于荧光（FL）、生物发光（BL）和正电子发射断层扫描的遗传报告基因 (PET)结合了远红荧光蛋白、萤火虫荧光素酶和胸苷激酶的最佳可用版本，表达为通过自切割病毒2A序列分离的单独但遗传连接的蛋白质。这些测试将量化这种可注射剂检测不同大小和不同阶段的实体瘤的可靠性。进展，在什么情况下获得假阳性和阴性信号，什么时候探头和成像方式的组合上级其他方式，以及惰性与高度恶性并且可以区分侵袭性肿瘤。 FL引导下手术切除及辅助治疗的评价与改进：术中FL 来自可注射剂的指导，例如与荧光树枝状聚合物缀合的ACPP，尺寸减小用NIR荧光团或5-氨基乙酰丙酸标记的抗体将与来自荧光蛋白代表完美的肿瘤特异性标记。这些比较将显示哪些注射剂试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限于当前造影剂的不完善的生化特异性，或者受限于不能分辨，手动去除分散或播散的肿瘤细胞。光动力学疗法（PDT）杀死残余肿瘤还将对关闭前手术野中的细胞进行测试。初次肿瘤切除的完整性和任何术后将使用基因报告物评估复发。与信号的比较可注射造影剂和传统的生存测量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带来了多大的改善 vs.基因完美标记，PDT是否有帮助，目前的注射剂监测效果如何复发，以及哪些材料或程序最需要改进。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize.

DOI：
10.1038/ncomms13019
发表时间：
2016-10-04
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Adams, Stephen R.;Yang, Howard C.;Savariar, Elamprakash N.;Aguilera, Joe;Crisp, Jessica L.;Jones, Karra A.;Whitney, Michael A.;Lippman, Scott M.;Cohen, Ezra E. W.;Tsien, Roger Y.;Advani, Sunil J.
通讯作者：
Advani, Sunil J.

Dual targeting of integrin αvβ3 and matrix metalloproteinase-2 for optical imaging of tumors and chemotherapeutic delivery.

整合素αvβ3和基质金属蛋白酶-2的双重靶向，用于肿瘤光学成像和化疗药物输送。