Injectable reporters to image tumors and guide resection

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ACPP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 在什么情况下，药物表现最好，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 还将测试闭合前手术区域中的细胞。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。

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.