Injectable reporters to image tumors and guide resection

项目摘要 临床可翻译的分子显像剂早期检测：新的临床可翻译的 分子成像造影剂用于T1加权磁共振成像(MRI)或 正电子发射断层扫描(PET)将得到发展、优化和定量表征。核磁共振 试剂是连接到含Gd的树枝状大分子上的可激活细胞穿透肽(ACPP) 络合物。ACPPS对基质金属蛋白酶的选择性及其Gd络合物的稳定性 进行优化。PET记者将是携带新型近红外(NIR)的缩小尺寸抗体 含有18F-氟硼酸盐的荧光团。MRI和PET试剂都将在小鼠肿瘤上进行稳定测试 表达荧光(FL)、生物发光(BL)和正电子发射断层扫描的遗传报告 (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， 表达为分离的但基因相连的蛋白，由自裂解的病毒2A序列分隔。这些 测试将量化这些可注射试剂检测不同大小和不同阶段的实体肿瘤的可靠性 进展，在什么情况下获得假阳性和假阴性信号，在什么时候 探头和成像方式的组合优于另一种方式，无论是惰性还是高度恶性 侵袭性肿瘤可以被区分开来。 术中FL引导下手术切除及辅助治疗的评价与改进 来自可注射剂的指导，如连接到荧光树枝状大分子的ACPP，缩小尺寸 用近红外荧光团或5-氨基酮戊酸标记的抗体将与来自 代表完美的肿瘤特异性标记的荧光蛋白。这些比较将显示哪种注射剂 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 更多的限制是由于目前造影剂不完善的生化特异性，或者是无法分辨和 手动清除散布或播散的肿瘤细胞。光动力疗法(PDT)杀死残留肿瘤 关闭前外科领域的细胞也将进行测试。初始肿瘤切除的完整性和任何 术后将使用基因记录仪评估复发情况。与来自 注射造影剂和传统的生存测量应该量化手术结果如何依赖于 肿瘤细胞清除的彻底性，目前可注射造影剂有多大改善 与遗传上完美的标记相比，光动力疗法是否有帮助，目前的注射药物监测情况如何 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.