| 19785401 |
Kim Y, Hechler B, Gao ZG, Gachet C, Jacobson KA: PEGylated Dendritic Unimolecular Micelles as Versatile Carriers for Ligands of G Protein-Coupled Receptors. Bioconjug Chem. 2009 Sep 28.
Despite its widespread application in nanomedicine, poly (ethylene glycol) (PEG) is seldom used for covalent modification of ligands for G protein-coupled receptors (GPCRs) due to potential steric complications. In order to study the influence of PEG chains on the biological activity of GPCR ligands bound to a common macromolecular carrier, we prepared a series of G3 polyamidoamine (PAMAM) dendrimers derivatized with Alexa Fluor 488, varying numbers of PEG (550)/PEG (750)/PEG (2000), and nucleoside moieties derived from the A (2A) adenosine receptor (AR) agonist CGS21680 (2-[4-(2-carboxylethyl) phenylethylamino]-5'-N-ethylcarboxamidoadenosine). These dendrimer conjugates were purified by size exclusion chromatography and characterized by (1) H NMR and MALDI MS. In radioligand binding assays, some PAMAM-PEG conjugates showed enhanced subtype-selectivity at the human A (2A) AR compared to monomeric ligands of comparable affinity. The functional potency was measured in the A (2A) AR-mediated activation of adenylate cyclase and inhibition of ADP-induced platelet aggregation. Interestingly, the dendrimer conjugate 10c bearing 11 PEG (750) chains (out of theoretical 32 amino end groups) and 14 nucleoside moieties was 5-fold more potent in A (2A) AR-mediated stimulation of cyclic AMP formation than 10d with 4 PEG (2000) chains and 21 nucleosides, although the binding affinities of these 2 compounds were similar. Thus, a relatively small (ligand 10c modified for water solubility maintained high potency and displayed increased A (2A) AR binding selectivity over the monomeric nucleosides. The current study demonstrates the feasibility of using short PEG chains in the design of carriers that target ligand-receptor interactions. |
82(1,1,1,2) |