Preclinical Study of the Mn(II) complex with Glucaric Acid as an Oncotropic Paramagnetic contrast Agent for MR Imaging of Malignant Tumors

Purpose: Since currently there are no selective drugs for paramagnetic contrast enhancement (PMC) in MRI in the oncology clinic as such, we tried to obtain a selective oncotropic paramagnetic contrast agent (PMCA) – Mn(II) manganese compound with glucaric acid (used in combination with ^99mTc for breast cancer (breast cancer), and to evaluate on the basis of animal studies the possibility of using Mn(II)-glucarate (Glucaromang) as an oncotropic PMCA in breast cancer.

Material and methods: The synthesis of glucaric acid was carried out by a modified method by oxidation of D-glucose with strong nitric acid. A solution of D-glucaric acid was used to produce manganese glucarate by combining with manganese oxide or carbonate with an excess of glucarate in solution, since one manganese atom forms a complex with two glucaric acid molecules. The injection solution of the obtained Mn(II)-glucarate was adjusted to pH = 6.4–7.2 and sterilized by microfiltration through Millipore filters with a pore size of 0.22 μm. The toxicity indices LD₁₀, LD₅₀, LD₉₀ (ml/kg) were determined in laboratory white mice. An in vivo MRI study of the tumor accumulation of Mn(II)-glucarate was performed in veterinary patients – cats (n = 9) with diagnosed breast cancer, who underwent body MRI to clarify the diagnosis and assess the extent of breast cancer, and 4 cats with malignant tumors of the neck and submandibular region (salivary glands). Scanning was performed using Toshiba Titan Vantage (Canon Medical) and Magnetom Open (Siemens Medical), with subsequent processing by Radiant (https://www.radiantviewer.com ).

Results: In the injection solution of Mn(II)-glucarate 0.5 M, free manganese was absent in detectable amounts, the excess of glucaric acid (has an antineoproliferative effect) was up to 2–2.5 %. Osmolality 1550±39 mOsmol/(kg H₂O), viscosity 2.85±0.15 MPa·s, at 37 °C. When stored for 6 months, there was no release of manganese from the complex. The thermodynamic stability constant was 17.6–17.9. For the injection drug «Mn(II)-glucarate, 0.5M, aqueous solution”, the mortality rates for single administration in mice were, respectively: LD₁₀ = 6.8 ± 5.0 ml/kg, LD₅₀=15.1 ± 4.7 ml/kg, LD₉₀=37.5 ± 23.8 ml/kg . When administered Mn(II)-glucarate as laboratory mice and cats with breast cancer did not show significant changes in the blood pattern and any side effects. The drug accumulated intensively in the primary tumor and metastases. The index of enhancement for T₁-WI was 1.78 ± 0.082 (p < 0.02) for the primary tumor and 1.49 ± 0.09 (p < 0.05) for lymphogenic metastases.

Conclusion: Mn-glucarate is an original paramagnetic contrast agent, highly stable, non-toxic, providing in vivo intensive MRI imaging of tumor structures, in particular in breast cancer.