Anti-ischemic effects of multivalent dendrimeric A3 adenosine receptor agonists in cultured cardiomyocytes and in the isolated rat heart

Abstract

Adenosine released during myocardial ischemia mediates cardioprotective preconditioning. Multivalent drugs covalently bound to nanocarriers may differ greatly in chemical and biological properties from the corresponding monomeric agents. Here, we conjugated chemically functionalized nucleosides to poly(amidoamine) (PAMAM) dendrimeric polymers and investigated their effects in rat primary cardiac cell cultures and in the isolated heart. Three conjugates of A3 adenosine receptor (AR) agonists, chain-functionalized at the C2 or N6 position, were cardioprotective, with greater potency than monomeric agonist Cl-IB-MECA. Multivalent amide-linked MRS5216 was selective for A1 and A3ARs, and triazole-linked MRS5246 and MRS5539 (optionally containing fluorescent label) were A3AR-selective. The conjugates protected ischemic rat cardiomyocytes, an effect blocked by an A3AR antagonist MRS1523, and isolated hearts with significantly improved infarct size, rate of pressure product, and rate of contraction and relaxation. Thus, strategically derivatized nucleosides tethered to biocompatible polymeric carriers display enhanced cardioprotective potency via activation of A3AR on the cardiomyocyte surface.

The A3Adenosine Receptor: History and Perspectives

“…These findings have also been confirmed in A 3 AR-overexpressing mice, where infarct size was smaller than in wild-type mice after in vivo regional IR (Shneyvays et al, 2004). Similarly, antiischemic effects have been found with positive allosteric modulators as well as with dendrimeric A 3 AR agonists (Wan et al, 2011;Du et al, 2012;Chanyshev et al, 2012).…”

“…Interestingly, it has been demonstrated that the PAMAM dendrimer conjugate specifically activates A 3 ARs to improve postischemic/reperfusion function in isolated mouse hearts (Wan et al, 2011). Similar results were confirmed in rat primary cardiac cell cultures and in the isolated heart where these strategically derivatized nucleosides display enhanced cardioprotective potency (Chanyshev et al, 2012). In vivo testing will now be needed to explore the effects on pharmacokinetics and tissue targeting.…”

“…Although there is low A 3 AR expression in myocardial tissue, a number of works demonstrated that acute treatment with agonists induces protective "antiischemic" effects (Auchampach et al, 1997;Tracey et al, 1997;Thourani et al, 1999a,b;Ge et al, 2006Ge et al, , 2010Xu et al, 2006;Chanyshev et al, 2012). These findings have also been confirmed in A 3 AR-overexpressing mice, where infarct size was smaller than in wild-type mice after in vivo regional IR (Shneyvays et al, 2004).…”

The Potential for Nanotechnology to Improve Delivery of Therapy to the Acute Ischemic Heart

“…The effects of three different receptor agonist-modified dendrimers in hypoxic cardiomyocytes, cardiomyocytes treated with H 2 O 2 , and ex vivo hearts subjected to ischemia-reperfusion were investigated. [60,61] Adenosine has also been encapsulated in liposomes (130 nm). [62] Compared to free adenosine, administration of the liposomal formulation prior to reperfusion in rats prolonged time in circulation and delayed degradation, showed greater accumulation in infarcted myocardium, and decreased effects on hemodynamic parameters.…”

Targeting G Protein‐Coupled Receptors with Magnetic Carbon Nanotubes: The Case of the A3 Adenosine Receptor

“…Whereas on one hand A 3 AR stimulation has been found to inhibit prostate carcinoma cells proliferation and induce cell death in myeloid and lymphoid cell lines, [10,11] it has been shown on the other dendrimers displaying multiple AR ligands. [21][22][23][24][25][26] In particular, when an A 3 ligand was conjugated to a G4 PAMAM dendrimeric core, a dramatic enhancement of both selectivity and affinity was achieved when compared to the ligand alone. [25] Gold nanoparticles were also used as platforms to modulate adenosine receptors by conjugation with both agonists and antagonists.…”