Adenosine released during myocardial ischemia is cardioprotective. Potent multivalent A3 adenosine receptor agonists, in which modified adenosine was chain-functionalized at the C2 or N6 position and coupled to poly(amidoamine) (PAMAM) dendrimers, were highly cardioprotective.
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.