Connexin 43‐targeted T₁ contrast agent for MRI diagnosis of glioma

Abstract

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 T 1 relaxivity (6.5 mM À1 s À1 at 7 T) than the commercial agent Magnevist® (3.4 mM À1 s À1 ). Cellular uptake of Cx43-specific T 1 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.

Connexins and Pannexins: Important Players in Tumorigenesis, Metastasis and Potential Therapeutics

“…Intriguingly, a combination of this Cx43 antibody with TMZ completely abolishes the antitumor effect of this antibody while combination treatment with γ-irradiation greatly inhibits tumour development and prolongs survival median to 60 days versus 38 days [ 172 ]. Recently, a magnetic resonance imaging (MRI) study further shows that uptake of Gd-based contrast agent with the same monoclonal Cx43 antibody is more than 4 times higher than nonspecific IgG-contrast agent and this Cx43 antibody conjugated agent markedly enhances visualization of glioma in vivo [ 173 ]. Although the specific molecular mechanism of this antibody is unknown, this Cx43-targeting monoclonal antibody could be developed as a potential drug and/or diagnostic agent for glioma therapies.…”

Complex role of connexin 43 in astrocytic tumors and possible promotion of glioma-associated epileptic discharge

“…The value of Cx43 in glioma diagnosis and therapy is beginning to be recognized. Abakumova (103) demonstrated that the Cx43-targeted T1 contrast agent may efficiently visualize glioma C6 and its borders in vitro and in vivo. MAbE2Cx43 s was covalently associated with the Phthalosens derivative photosensitizer delivery of fluorescent agents to the glioma tissue.…”

Peptide‐based building blocks as structural elements for supramolecular Gd‐containing MRI contrast agents

“…Concerning tumor targeting, after the seminal papers in which conjugates of poly‐ L ‐lysine with DTPA‐Gd chelates (PLL‐DTPA‐Gd) were used for tumor diagnosis of mammary adenocarcinoma and glioma in rodent models, further improvements of MRI diagnosis of tumor were pursued through active targeting. An example is represented by the system proposed by Abakumova et al who synthesized a conjugate of the monoclonal antibody (mAb) to Cx43 and poly‐lysine‐DTPAmonoamide‐Gd(III) (see Figure B) for the efficient in vivo visualization of glioma C6. The total Gd(III) loading was about 520 ions per mAb, and the molecular weight of the targeted CA was about 850 kDa.…”