Drug-free therapeutic copolymer for the treatment of diabetes

Introduction

Cell adhesion molecules on the surface of vascular endothelial cells play a critical role in leukocytes infiltration into the inflamed tissues. E-selectin (CD62E) is an adhesion molecule which is overly expressed on inflamed vasculature compering to physiological conditions. The increased expression of E-selectin has been identified in several acute and chronic inflammation processes, including insulin-dependent diabetes mellitus¹. Our group has described the development of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer displaying the high-affinity E-selectin binding peptide (Esbp, primary sequence DITWDQLWDLMK) as a ligand for targeting E-selectin on tumor vascular endothelium². More recently we demonstrated that an E-selectin-targeted “drug-free” copolymer, without any therapeutic cargo, effectively targets inflamed atherosclerotic lesions, reverses the growth of atherosclerotic lesions and prevents adverse cardiac remodeling and dysfunction in ApoE^(-/-) mice³. These results indicate that the “drug-free” copolymer P-Esbp can be utilized to block the cell adhesion molecules interaction with leukocytes and by this inhibit their infiltration into the inflamed tissue. In this study, we further investigated the anti-inflammatory effects of P-Esbp in streptozotocin (STZ)-induced diabetes. STZ has been extensively used to induce diabetes in various animal species and to help screen for hypoglycemic drugs⁴.

Results and discussion

C57BL/6 mice underwent multiple low dose STZ induction of 50 mg/kg i.p. for 5 consecutive days, and then were treated with a “drug-free” polymer-bound Esbp (P-Esbp) (i.p. injection of 1mg P-Esbp on days 1, 4, 7, 10). Although the difference between the two intervention groups (STZ+P-Esbp and just STZ) was not statistically significant, a trend towards an effect was seen (throughout the experiment blood glucose of STZ+P-Esbp group was lower than STZ group). In future experiments, we plan to treat mice with different STZ induction protocols and dosage regimens of P-Esbp.

Refrences

1. Impellizzeri, D. al., Expert Opin. Ther. Targets, 18.1 (2014): 55-67.
2. Shamay, Y. et al., Control. Release, 217 (2015): 102-112.
3. Tsoref, O. et al., Circulation, (2016); A14013-A14013.
4. Goyal, SN. et al., Biol. Interact, 244 (2016): 49-63.