RGD-peptides modifying dexamethasone: to enhance the anti-inflammatory efficacy and limit the risk of osteoporosis

Abstract

Dexamethasone (Dex) is one of the most effective anti-inflammatory glucocorticoids, while the side effect, osteoporosis seriously limits its clinical use. Cell adhesion is involved in the onset of inflammation and osteoporosis, and RGD-peptides are well known as anti-adhesion peptides. To enhance the anti-inflammatory efficacy and limit the osteoporotic risk of Dex three novel conjugates of RGDV, RGDS and RGDF covalently modified Dex were presented here. On xylene-induced ear edema model the ear edema of the mice treated with the conjugates was significantly lower than that of the mice treated with Dex. Receiving 15day therapy the total volumetric bone mineral density, the peripheral quantitative CT and the femur weight of the mice treated with the conjugates were significantly higher than those of the mice treated with Dex. Therefore covalently modifying Dex with RGDV, RGDS and RGDF not only increased the anti-inflammation activity but also decreased the osteoporotic risk of Dex. Besides, the enhanced anti-inflammation activity was collated with the downregulated DNA expression of the conjugates.

Design, synthesis, and evaluation of cystargolide-based β-lactones as potent proteasome inhibitors

“…The dipeptide fragments 11a-t were assembled by esterification of L-amino acids with aliphatic or aromatic alcohols followed by coupling with either N -Boc or Fmoc protected amino acids under standard conditions [40–43]. Assembly of the final compounds was then carried out by cleavage of the protective groups on both the dipeptides 11a-t and the β-lactones 9a-e , followed by coupling using EDCI/HOBt [40] (Scheme 2, see supplementary information).…”

A Supramolecular Shear‐Thinning Anti‐Inflammatory Steroid Hydrogel

“…Here, we present shear‐thinning and self‐healing hydrogels based on steroid drugs (anti‐inflammatory glucocorticoid receptor agonists) such as dexamethasone, betamethasone, and hydrocortisone that can be formed in seconds by simple coordination reactions. In clinical practice, glucocorticoid receptor agonists are widely used as anti‐inflammatory agents to treat arthritis, asthma, and many other conditions.…”

RGD(F/S/V)-Dex: towards the development of novel, effective, and safe glucocorticoids

“…RGDF, RGDV, and RGDS, the so called RGD-peptides, are antiadhesive peptides and have been widely used to modify various drugs, of which motif-like action with integrins can potentially enhance the therapeutic efficacy and reduce the coagulation and osteoporosis risks of drugs. 26 , 30 Aimed at this, the present study examines the development profile of covalent conjugates of RGD-peptides and Dex (RGDV-Dex, RGDS-Dex, and RGDF-Dex) as new drugs. In vitro and in vivo, the activities of the conjugates are significantly higher than Dex itself and induce no coagulation risk.…”

“… 31 , 32 Figure 7 shows that RGDF-Dex, RGDS-Dex, and RGDV-Dex, but not Dex itself, prolong the tail bleeding time of the mice. Taking RGDF-Dex, RGDS-Dex, and RGDV-Dex, but not Dex itself, inducing no osteoporosis into account, 26 RGD-peptide modification leads to the complete relief of side effects of Dex. The safety of RGDF-Dex, RGDS-Dex, and RGDV-Dex was further evaluated with acute toxicity assay.…”

“…In a mouse model, the conjugates are superior to Dex in inhibiting inflammatory and osteoporotic actions. 26 However, whether they are worthy of development remains unclear. In this context, the nanostructures, immunosuppressive activities, thrombosis risks, and toxicities of these three conjugates were investigated.…”