Novel alendronate-CGS21680 conjugate reduces bone resorption and induces new bone formation in post-menopausal osteoporosis and inflammatory osteolysis mouse models

Abstract

Loss of bone is a common medical problem and, while it can be treated with available therapies, some of these therapies have critical side effects. We have previously demonstrated that CGS21680, a selective A2A adenosine receptor agonist, prevents bone loss, but its on-target toxicities (hypotension, tachycardia) and frequent dosing requirements make it unusable in the clinic. We therefore generated a novel alendronate-CGS21680 conjugate (MRS7216), to target the agonist to bone where it remains for long periods thereby diminishing the frequency of administration and curtailing side effects. MRS7216 was synthesized from CGS21680 by sequential activation of the carboxylic acid moiety and reacting with an appropriate amino acid (PEG, alendronic acid) under basic conditions. MRS7216 was tested on C57BL/6J (WT) mice with established osteoporosis (OP) and WT or A2A KO mice with wear particle-induced inflammatory osteolysis (OL). Mice were treated weekly with MRS7216 (10mg/kg). Bone formation was studied after in vivo labeling with calcein/Alizarin Red, and μCT and histology analyses were performed. In addition, human primary osteoblasts and osteoclasts were cultured using bone marrow discarded after hip replacement. Receptor binding studies demonstrate that MRS7216 efficiently binds the A2A adenosine receptor. MRS7216-treated OP and OL mice had significant new bone formation and reduced bone loss compared to vehicle or alendronate-treated mice. Histological analysis showed that MRS7216 treatment significantly reduced osteoclast number and increased osteoblast number in murine models. Interestingly, cultured human osteoclast differentiation was inhibited, and osteoblast differentiation was stimulated by the compound indicating that MRS7216 conjugates represent a novel therapeutic approach to treat osteoporosis and osteolysis.

Protective role of the CD73-A2AR axis in cirrhotic cardiomyopathy through negative feedback regulation of the NF-κB pathway

“…To investigate the biological function of A2AR in CCM, mice were administered CGS 21680 (a specific agonist of A2AR, 1mg/kg) via intraperitoneal injection to increase the expression of A2AR in the heart ( 17 ). Protein immunoblot analysis indicated that compared to the BDL group, the BDL + CGS 21680 group had increased expression of A2AR, and reduced expression of the apoptosis-related protein cleaved Caspase3 and a decreased Bax/Bcl-2 ratio, along with a significant reduction in the ratio of phosphorylated IκB to IκB (p-IκB/IκB) and phosphorylated P65 to P65 (p-p65/P65) ( Figures 7A, B ).…”

Package delivered: folate receptor-mediated transporters in cancer therapy and diagnosis

“…115 Alendronate, a member of the N-containing bisphosphonate, can be conjugated to TPGS, providing additional functionalities such as targeting bone tissue 115 or inhibiting osteoclast activity. 116 The results demonstrated a superior alendronatemediated binding affinity for hydroxyapatite in the bone matrix using Rho-labelled NPs. An elevated level of cellular uptake of drug payload via FR-targeting to FR(+) 4T1 cells was reported compared to FR(−) A549 cells.…”