Theranostic approach of cancers using ECDG

Objectives Phosphorylation of uridine 5'-diphosphate (UDP)-N-acetylated glucosamine (GlcNAc) is involved in cell activity. Ethylenedicysteine-N-acetylglucosamine (ECDG) has structural similarity to GlcNAc. ECDG can be converted to a theranostic perform in diagnosis and treatment of cancer. The study was aimed to demonstrate the feasibility of a theranostic approach in cancers using ECDG.

Methods ECDG was labeled with In-111 chloride for radiotheranostic studies. Breast tumor-bearing Fischer rats (induced by 13762 cells) were imaged at 0.5-24 hrs and rad absorbed dose was estimated. Re-187 ECDG was synthesized for theranostic studies. Twelve diffuse large B-cell lymphoma (DLBCL) cells were incubated (0-10 µM) and TUNEL assay was performed. To ascertain the mechanism of the anticancer properties of Re-187 ECDG, DLBCL-LY10 cells were treated for 48 hrs and immunoblotting were then performed on nuclear extracts (50 µg).

Results Tumor-to-muscle count density ratios for In-111-ECDG were 5.43±0.45 to 7.80±0.05 whereas In-111 EC had 3.24±0.32 to 4.64±0.16 at 0.5-24 hrs. Rad exposure of In-111-ECDG to whole body, blood-forming organs, gonads, and effective dose equivalent for a single dose at 5 mCi was below the limits of 3 rad annually and 5 rad total. The absorbed dose in all other organs was well below the rad annually and rad total doses. Re-187 ECDG enters the nucleus and causes DNA damage that leads to DLBCL apoptosis. Inhibition of cell proliferation of aggressive dividing lymphoma cells, but was less effective at the dose given for slow growing lymphoma cells. Re-187 ECDG showed significant tumorcidal activity compared to normal B-lymphocyte activity at doses >0.17 umol. Exhibit a decrease expression of HIF-1 alpha under normoxic conditions in DLBCL-LY10 cells.

Conclusions In-111-ECDG has favorable dosimetry which provides an opportunity for imaging (Tc-99m, Ga-68) or to treat cancers. Moreover, Re-187-ECDG could inhibit HIF-1alpha expression which is an attractive anticancer agent as well