Connexin 43-targeted T1 contrast agent for MRI diagnosis of glioma.
Glioblastoma multiforme is the most aggressive form of brain tumor. Early and accurate diagnosis of glioma and its borders is an important step for its successful treatment. One of the promising targets for selective visualization of glioma and its margins is connexin 43 (Cx43), which is highly expressed in reactive astrocytes and migrating glioma cells. The purpose of this study was to synthesize a Gd-based contrast agent conjugated with specific antibodies to Cx43 for efficient visualization of glioma C6 in vivo. We have prepared stable nontoxic conjugates of monoclonal antibody to Cx43 and polylysine-DTPA ligands complexed with Gd(III), which are characterized by higher T1 relaxivity (6.5 mM(-1) s(-1) at 7 T) than the commercial agent Magnevist® (3.4 mM(-1) s(-1)). Cellular uptake of Cx43-specific T1 contrast agent in glioma C6 cells was more than four times higher than the nonspecific IgG-contrast agent, as detected by flow cytometry and confocal analysis. MRI experiments showed that the obtained agents could markedly enhance visualization of glioma C6 in vivo after their intravenous administration. Significant accumulation of Cx43-targeted contrast agents in glioma and the peritumoral zone led not only to enhanced contrast but also to improved detection of the tumor periphery. Fluorescence imaging confirmed notable accumulation of Cx43-specific conjugates in the peritumoral zone compared with nonspecific IgG conjugates at 24 h after intravenous injection. All these features of Cx43-targeted contrast agents might be useful for more precise diagnosis of glioma and its borders by MRI.
Department of Fundamental and Applied Neurobiology, Serbsky National Research Center for Social and Forensic Psychiatry, Moscow, Russia.
Tatiana
T
Abakumova
Department of Medical Nanobiotechnology, Pirogov Russian National Research Medical University, Moscow, Russia.
Maxim
M
Abakumov
Department of Fundamental and Applied Neurobiology, Serbsky National Research Center for Social and Forensic Psychiatry, Moscow, Russia.
Sergey
S
Shein
Laboratory of Synthesis of Peptides and Polymer Microspheres, Institute of Macromolecular Compounds, Russian Academy of Sciences, St Petersburg, Russia.
Pavel
P
Chelushkin
Department of Geology, Lomonosov Moscow State University, Moscow, Russia.
Dmitry
D
Bychkov
Department of Medical Nanobiotechnology, Pirogov Russian National Research Medical University, Moscow, Russia.
Vladimir
V
Mukhin
Department of Fundamental and Applied Neurobiology, Serbsky National Research Center for Social and Forensic Psychiatry, Moscow, Russia.
Gaukhar
G
Yusubalieva
Department of Fundamental and Applied Neurobiology, Serbsky National Research Center for Social and Forensic Psychiatry, Moscow, Russia.
Nadezhda
N
Grinenko
Department of Chemistry, Laboratory Chemical Design of Bionanomaterials, Lomonosov Moscow State University, Moscow, Russia.|Center for Nanotechnology in Drug Delivery and Division of Molecular Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Alexander
A
Kabanov
Department of Fundamental and Applied Neurobiology, Serbsky National Research Center for Social and Forensic Psychiatry, Moscow, Russia.|Department of Chemistry, Laboratory Chemical Design of Bionanomaterials, Lomonosov Moscow State University, Moscow, Russia.
Natalia
N
Nukolova
Department of Fundamental and Applied Neurobiology, Serbsky National Research Center for Social and Forensic Psychiatry, Moscow, Russia.|Department of Medical Nanobiotechnology, Pirogov Russian National Research Medical University, Moscow, Russia.
Vladimir
V
Chekhonin
D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D003287:Contrast Media; D019786:Gadolinium DTPA / Q000008:administration & dosage; D005910:Glioma / Q000000981:diagnostic imaging* / Q000235:genetics / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D011107:Polylysine / Q000008:administration & dosage / Q000031:analogs & derivatives; D011859:Radiography; D051381:Rats
D018031:Connexin 43; D003287:Contrast Media; C068674:polylysine-(Gd-DTPA); D011107:Polylysine; D019786:Gadolinium DTPA
MRI; T1 contrast agent; cellular targeting; connexin 43; glioma; targeted imaging