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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Radiation Therapeutics and Biology Study Section (RTB)
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Prasanna, Pat G
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University of Massachusetts Medical School Worcester
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Dou, Shuping; Virostko, John; Greiner, Dale L et al. (2015) A feasible approach to evaluate the relative reactivity of NHS-ester activated group with primary amine-derivatized DNA analogue and non-derivatized impurity. Nucleosides Nucleotides Nucleic Acids 34:69-78
Dou, Shuping; Virostko, John; Greiner, Dale L et al. (2015) Quantitative Correlation of in Vivo Properties with in Vitro Assay Results: The in Vitro Binding of a Biotin-DNA Analogue Modifier with Streptavidin Predicts the in Vivo Avidin-Induced Clearability of the Analogue-Modified Antibody. Mol Pharm 12:3097-103
Dou, Shuping; Wang, Yuzhen; Barton, Bruce et al. (2014) Comparison between two labeled agents in mice using a coinjection-ratio approach in contrast to a conventional group approach. Nucl Med Biol 41:127-31
Liu, Guozheng (2013) Rules of thumb for maximum percent tumor accumulation. Nucl Med Biol 40:865-7
Dou, Shuping; Smith, Miles; Wang, Yuzhen et al. (2013) Intraperitoneal injection is not always a suitable alternative to intravenous injection for radiotherapy. Cancer Biother Radiopharm 28:335-42
Liu, Guozheng; Dou, Shuping; Akalin, Ali et al. (2012) Pretargeting vs. direct targeting of human betalox5 islet cells subcutaneously implanted in mice using an anti-human islet cell antibody. Nucl Med Biol 39:645-51
Liu, Guozheng; Dou, Shuping; Cheng, Dengfeng et al. (2011) Human islet cell MORF/cMORF pretargeting in a xenogeneic murine transplant model. Mol Pharm 8:767-73
Liu, Xinrong; Wang, Yi; Hnatowich, Donald J (2011) A nanoparticle for tumor targeted delivery of oligomers. Methods Mol Biol 764:91-105
Liu, Guozheng; Dou, Shuping; Liu, Yuxia et al. (2011) Unexpected side products in the conjugation of an amine-derivatized morpholino oligomer with p-isothiocyanate benzyl DTPA and their removal. Nucl Med Biol 38:159-63
Liu, Guozheng; Dou, Shuping; Liu, Yuxia et al. (2011) 90Y labeled phosphorodiamidate morpholino oligomer for pretargeting radiotherapy. Bioconjug Chem 22:2539-45

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