Improved Tumor Rediotherapy by MORF Pretargeting

肿瘤的预靶向正在成为一种成熟的、合理地被充分理解的和成功的成像模式。 预靶向的优势通常不在于更高的绝对肿瘤积累，而在于更高的肿瘤累积。 肿瘤/正常组织比率迅速达到。该实验室正在探索几种新的方法， 预靶向，每一种都共同使用寡聚物代替链霉亲和素/生物素或双特异性寡聚物。 抗体的在研究用于“常规”预靶向的寡聚体的过程中，显而易见的是， 这些令人感兴趣的分子对于该应用具有许多有用的性质。除了常规 这些研究导致了三个新的调查子领域的发展，我们称之为 “扩增预靶向”、“用寡聚体增强亲和力预靶向”以及最近的“光学预靶向”。 预先瞄准”。由于在放射性药物设计中使用低聚物的新奇，特别是 为了实现MORFs的预靶向应用，我们需要开发用99 mTc标记MORFs的方法 和188 Re，开发将抗体和聚合物与MORF缀合的新方法， 合成具有不同间距的二价MORFs，最近，探索了细胞内 荧光团缀合的MORF。此外，有必要校准我们的肿瘤小鼠模型，以更好地 了解其关于预靶向的特性，以便肿瘤和正常组织的积累可以 根据变量的变化进行准确预测。这些和其他发展已成功地 我们已完成的工作已记录在我们的印刷出版物、印刷出版物、已提交的出版物和正在编写的出版物中。我们打算 通过强调我们传统的临床前研究， 用188 Re-MORF进行的预靶向放射治疗研究（补充资金） 2）通过继续我们的MORF扩增和MORF亲和力来改善预靶向 增强肿瘤的预靶向。我们还将继续我们的MORF预靶向研究与光学 侦测我们的多学科UMMS团队由化学家，辐射物理学家和分子 生物学家在调查的每个阶段都有经验。拟议的研究将建立在我们的 过去的结果，以实现我们的目标，大大改善传统的分子靶向肿瘤， 改善癌症诊断，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.