Targeted Imaging as a Biomarker for Pt Therapeutics

拟议的项目将使用成像来开发和测试分子靶标的原理证明。 心理治疗。我们将合成五种放射性示踪剂，能够检验分子靶向的假设 治疗剂可以比非靶向制剂产生更大的肿瘤积聚，而且成像可以 用来指导设计。其结果将是一种具有更高治疗指数的新制剂； 贡献将是对使用分子成像来指导设计的设计范式的确认 化疗药物。 第一组实验将在荷瘤小鼠身上比较非靶向AP5346聚合物标记的 带有维生素B12的LN-111靶向AP5346聚合物具有相同的放射性标记。如果目标聚合物具有 在选定的时间，较大的肿瘤与肌肉(TMR)比率，聚合物将被标记F-18或BR-76 视乎通行证的大小减半。如果目标聚合物具有较差的TMR比率，则维生素B12摩尔% 将增加并重新评估。下一个关键实验将是评估最优的靶向 体内化合物将DNA中的Ft与使用PET和Plane测量的肿瘤放射性进行比较 成像。最终的特定目标将在一项治疗试验中研究最佳靶向和非靶向聚合物。 老鼠。治疗方案的设计将遵循用于研究原始聚合物AP5346的方案。 该方案利用含有10%靶向剂的聚合物来增加对肿瘤的亲和力。 与已经显示出作为有效化疗药物的非靶向聚合物相比。这 亲和力的增加应该会导致靶标浓度的增加，从而增加对 化疗引起的变化。我们包括了改变摩尔百分比的应急计划，因为文献 表明结合亲和力(亲和力)不是摩尔百分比负载量之间的直接线性关系 和聚合物的局部化。最佳亲和力的阐明将是一个重要的结果。确认 这一假说将为分子靶向癌症治疗的概念和 将最佳聚合物转化为癌症临床的动机。 如果这个项目成功，其意义将是：(1)我们将有证据表明，一种靶向化疗 药物可以将更大的有效载荷输送到治疗作用部位，即肿瘤的DNA；(2)我们将 证明成像报告器可用于外部监测铂向DNA的传递；以及 (3)我们将生产一套带有成像记者的化疗药物，准备用于GMP级 合成和FDA的批准程序。一种显像剂可以被开发为 个体化治疗的生物标记物将是一个重大进步。在本提案中，基线 化合物是一种很有前途的化疗药物。这增加了此类研究的潜在影响，因为 假设靶向聚合物会比非靶向聚合物表现更好。

The proposed project will employ imaging to develop and test a proof-of-principle for molecular-targeted therapy. We will synthesize five radiotracers capable of testing the hypothesis that a molecular targeted therapeutic agent can produce greater tumor accumulation than a non-targeted agent and that imaging can be used to guide the design. The consequence will be a new agent with a higher therapeutic index; the contribution will be a confirmation of the design paradigm that uses molecular imaging to guide the design of chemotherapeutic agents. The first set of experiments will compare in tumor-bearing mice the non-targeted AP5346 polymer labeled with ln-111 with a Vitamin B12 targeted AP5346 polymer with the same radiolabels. If the target-polymer has a larger tumor-to-muscle (TMR) ratio at selected times, the polymer will be labeled with either F-18 or Br-76 depending on the clearance half times. If the targeted polymer has an inferior TMR ratio, the Vit B12 mol% will be increased and re-evaluated. The next key experiment will be to evaluate the optimal targeted compounds in vivo to compare Ft in DNA with tumor radioactivity measurements using PET and planar imaging. The final Specific Aim will study the optimal targeted and non-targeted polymer in a therapy trial in mice. The design of the therapy protocol will follow the protocol used to study the original polymer AP5346. The proposal makes use of a polymer with 10 mol% of targeting agent to increase avidity for the tumor compared to a non-targeted polymer that has already shown promise as a potent chemotherapeutic. This increase in avidity should lead to increased target concentration and thereby increase the sensitivity to changes due to chemotherapy. We included contingency plans to vary the mol% because the literature shows that the binding affinity (avidity) is not a straightforward linear relationship between the mol% loading and polymer localization. The elucidation of the optimal avidity will be an important outcome. Confirmation of this hypothesis will provide proof-of-principle for the concept of molecular targeted cancer therapy and the motivation to translate the optimal polymer into the cancer clinic. If this project is successful the significance will be: (1) we will have proof that a targeted chemotherapeutic agent can deliver a greater payload to the therapeutic site of action, the tumor's DNA; (2) we will demonstrate that an imaging reporter can be used to externally monitor the delivery of Platinum to DNA; and (3) we will produce a set of chemotherapeutic agents with imaging reporters that will be ready for GMPgrade synthesis and the FDA approval process. The possibility that an imaging agent can be developed as a biomarker for individualized therapy would be a significant advance. In this proposal, the baseline compound is a promising chemotherapeutic. This increases the potential impact of such a study given that the hypothesis is a targeted polymer will outperform a non-targeted polymer.