ABAKUMOVA Tatiana Serbsky Scientific Center for Social and Forensic Psychiatry

Synthesis and Comparison of Targeted T1-contrast Agents based on DOTA and DTPA Complexes

Co-authors ABAKUMOV Maxim, BYCHKOV Dmitry, KABANOV Alexander,NUKOLOVA Natalia, CHEKHONIN Vladimir

Permeability of blood brain barrier (BBB) plays a key role in drug delivery to the brain tissues. Many brain abnormalities such as tumors, demyelination, necrosis, inflammation are accompanied with enhanced penetration of BBB. Based on this fact we proposed the targeted polymer-based contrast agents for MRI visualization of brain tumors. The goal of our study was to synthesize macromolecular multi-chelate complexes of gadolinium with further conjugation with specific monoclonal antibodies. For this purpose poly-L-lysine (PLL) was modified with chelating agents - DTPA or DOTA - using carbodiimide chemistry and conjugated with monoclonal antibodies to connexin 43 (mAb Cx43). Afterwards these conjugates were loaded with Gd(III) ions. Cytotoxicity of targeted agents was analyzed by MTT-test on human embryonic kidney (HEK293) and glioma C6 cell lines. T1-relaxivity was measured on 7T MR-tomograph ClinScan (Bruker). During synthesis the immunochemical activity of conjugated mAbs was preserved up to 85%. Maximal non-toxic concentration of contrast agents was 0.6 mg/ml. Important, that obtained contrast agents had higher T1-relaxivity values (6.5 and 8 mM-1s-1 for DTPA and DOTA chelating motif) in comparison with commercial available agent Magnevist (3.4 mM-1s-1). T1-contrast agent based on PLL and specific monoclonal antibody was successfully synthesized and characterized. These agents had a high relaxivity and high affinity to Cx43. This work supported by grant №11G34.31.0004, RFBR grant №13-04-01383, program «UMNIC» of Foundation for Assistance to Small Innovative Enterprises and financial support by agreement № 182-MRA between Lomonosov Moscow State University, Skolkovo Institute for science and technology and Massachusetts Institute of Technology