Targeted Imaging as a Biomarker for Pt Therapeutics

拟议的项目将采用成像技术来开发和测试分子靶向的原理证明。 疗法我们将合成五种放射性示踪剂，以验证一种分子靶向 治疗剂可以比非靶向剂产生更大的肿瘤积聚，成像可以 用于指导设计。结果将是具有更高治疗指数的新药剂; 的贡献将是一个确认的设计范式，使用分子成像，以指导设计 化疗剂。 第一组实验将在荷瘤小鼠中比较非靶向的AP 5346标记的聚合物 与ln-111和具有相同放射性标记的维生素B12靶向AP 5346聚合物。如果目标聚合物具有 在选定的时间具有较大的肿瘤-肌肉（TMR）比，则聚合物将用F-18或Br-76标记 取决于间隙的一半时间。如果目标聚合物具有较差的TMR比率，则维生素B12摩尔% 将被重新评估和评估。下一个关键实验将是评估最佳靶向 在体内化合物，比较Ft在DNA与肿瘤放射性测量使用PET和平面 显像最后的具体目标将研究在治疗试验中的最佳靶向和非靶向聚合物， 小鼠治疗方案的设计将遵循用于研究原始聚合物AP 5346的方案。 该提案利用具有10摩尔%靶向剂的聚合物来增加对肿瘤的亲合力 与已经显示出作为有效化疗剂的前景的非靶向聚合物相比。这 亲合力的增加应导致靶浓度的增加，从而增加对 化疗引起的变化。我们纳入了改变mol%的应急计划，因为文献 表明结合亲和力（亲合力）不是摩尔%负载量之间的直接线性关系 和聚合物定位。最佳亲合力的阐明将是一个重要的结果。确认 这一假设将为分子靶向癌症治疗的概念提供原理证明， 将最佳聚合物转化为癌症临床的动机。 如果这个项目是成功的意义将是：（1）我们将有证据表明，有针对性的化疗药物， 药物可以将更大的有效载荷递送到作用的治疗部位，即肿瘤的DNA;（2）我们将 证明成像报告物可用于外部监测铂向DNA的递送;以及 (3)我们将生产一套具有成像报告的化疗药物， 合成和FDA批准程序。成像剂可以被开发为 用于个体化治疗的生物标志物将是一个重大进步。在本提案中， 化合物是一种有前途的化疗药物。这增加了这种研究的潜在影响，因为 假设靶向聚合物将优于非靶向聚合物。

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.