Diethylentriaminepentaacetic Acid-deoxyglucoseamine (DTPA-DG):

Novel Nanosized Anti-Wilson's Disease Cell Model

Mehdi Shafiee Ardestani^{1, 3*}, Bita Mehravi⁴

¹ Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

² Department of Clinical Pharmacy (Pharmacotherapy), Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

³ Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran

⁴ Medical Physics and Biomedical Engineering and Nanomedicine Department, Faculty of Medicine, Shahid Beheshti Medical University, Tehran, Iran

^x These authors are contributed equally to the experiments (Considered as 'First Author')

^*Corresponding author:

Dr. Mehdi Shafiee Ardestani

Department of Hepatitis and AIDS

Pasteur Institute of Iran and Department of Medicinal Chemistry

Faculty of Pharmacy Tehran University of Medical Sciences

Tehran, Iran

Tel/Fax: +98-2166953311

Email: shafieeardestani@gmail.com

Abstract

       Wilson disease (WD) is an autosomal recessive disorder well recognized by the copper progressive accumulation. Copper accumulation in various organs and tissues causes toxic effects in various tissues including liver, brain, kidneys and eyes. Chelation therapy is the mainstay of treatment for patients with Wilson's disease. Chelators are naturally occurring or chemically designed molecules that bind to specific toxins in the body and promote excretion of them. Diethylenetriamine penta-acetic acid (DTPA) is one of the well-known Chelators which is used in WD treatment but it’s main defect is that it cannot enter into the intracellular space. When an amine such as D-glucosamine (DG) was conjugated to DTPA, the resulting compound obtains the ability to enter cells and may be used to treat the intracellular metal overload. Based on the hypothesis, A new compound consisting of D-glucose (1.1 nm) conjugated DTPA, was synthesized and evaluated on HepG2 WD cell model in vitro. Our results revealed that that the copper accumulation significantly P<0.05 decreased in the HepG2 WD cells by DTPA-DG as compared with D-penicillamine (as gold standard treatment) compared with the D-penicillamine (gold standard). Interestingly, no toxicological findings were seen in HepG2 WD cell. Based on our findings, administration of DTPA-DG could be significantly decrease the copper accumulation in HepG2 WD cell model without any toxicity and seems to have a very good prognosis for treatment of WD in the future.

Keywords: DTPA-DG, copper overload, Wilson's disease, chelator, cell uptake.

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