Improved Tumor Rediotherapy by MORF Pretargeting

肿瘤的前定位正在成为一种成熟的、相当好地理解和成功的成像方式。 前靶向治疗的优势通常不在于更高的绝对肿瘤积累量，而在于更高的肿瘤积累量 肿瘤/正常组织的比例迅速达到。这个实验室正在探索几种新的方法来 前靶向，每个都共同使用低聚物来代替链霉亲和素/生物素或双特异性 抗体。在研究“常规”预靶向齐聚物的过程中，很明显 这些有趣的分子对于这一应用具有许多有用的性质。除了常规 前置目标，这些研究导致了三个新的调查领域的发展，我们称之为 “扩增预定位”、“低聚物亲和力增强预定位”，以及最近的“光学 由于在放射性药物设计中使用低聚物的新颖性，尤其是 对于预靶向应用，我们被要求开发用99mTc标记MORF的方法 和188Re，开发了抗体和聚合物与Morf偶联的新方法，开发了 合成不同间距的二价Morf，以及最近探索细胞内积累的 荧光团共轭的MOFS。此外，有必要校准我们的肿瘤小鼠模型，以更好地 了解其与预靶向有关的属性，以便肿瘤和正常组织积聚 随着变量的变化而准确预测。这些和其他方面的发展已经成功 我们的出版物在印刷、印刷、提交和准备中都记录了这些成果。我们打算 通过强调我们传统的临床前研究来继续这些Morf前靶向的研究 188Re-Morf的预靶向放射治疗研究进入(有补充资金的)示踪剂研究 患者；2)通过继续我们的Morf扩增和Morf亲和力来改善预靶向 肿瘤的增强前定位。我们还将继续我们的Morf预定位研究， 侦测。我们的多学科UMMS团队由化学家、辐射物理学家和一个分子 生物学家对这项调查的每个阶段都有经验。拟议的研究现在将建立在我们的 过去的结果实现了我们的目标，即大大改进了传统的肿瘤分子靶向治疗 改进了癌症诊断，特别是放射治疗。

Pretargeting of tumor is becoming a mature, reasonably well understood and successful imaging modality. The advantage of pretargeting is usually not in higher absolute tumor accumulation but in higher tumor/normal tissue ratios achieved rapidly. This laboratory is exploring several novel approaches to pretargeting, each having in common the use of oligomers in place of either streptavidin/biotin or bispecific antibodies. In the course of investigating oligomers for "conventional" pretargeting, it became apparent that these interesting molecules have many useful properties for this application. In addition to conventional pretargeting, these studies have led to the development of three new subfields of investigation that we call "amplification pretargeting", "affinity enhancement pretargeting with oligomers" and,most recently, "optical pretargeting". Because of the novelty of using oligomers in radiopharmaceutical design, and in particular MORFs for pretargeting applications, we were required to develop methods of labeling MORFs with 99mTc and 188Re, develop new methods of conjugating antibodies and polymers with MORFs, develop methods of synthesizing bivalent MORFs with different spacings and,most recently, explore cellular accumulations of fluorophore conjugated MORFs. In addition, it was necessary to calibrate our tumor mouse model to better understand its properties with respect to pretargeting so that tumor and normal tissue accumulations could be accurately predicted with changes in variables. These and other developments have been successfully accomplished as documented in our publications in print, in press, submitted and in preparation. We intend to continue these investigations of MORF pretargeting by emphasizing our conventional preclinical pretargeting radiotherapy studies with 188Re-MORFs into (with supplemental funding) tracer studies in patients; 2) improving upon pretargeting by continuing our MORF amplification and MORF affinity enhancement pretargeting of tumors. We will also continue our MORF pretargeting studies with optical detection. Our multidisciplinary UMMS team consisting of chemists, radiation physicists and a molecular biologist has experience in each phase of this investigation. The proposed studies will now build upon our past results to achieve our goal of greatly improving upon conventional molecular targeting of tumor for improved cancer diagnosis and,especially, radiotherapy.