Ischemic tolerance and neuronal protection can be obtained by activation of adenosine A1 membrane receptors. Several A1 selective ligands have been synthesised in order to reproduce these effects and, currently, N6-cyclopentyladenosine (CPA) is identified as a potent and selective A1 agonist. On the other hand, A1 receptors are ubiquitous in the body and their general activation causes unwanted effects which do not allow the clinical use of A1 agonists. Moreover, the adenosine derivatives appear poorly adsorbed into the brain and can be quickly degraded in whole blood or in vivo. Several approaches are currently under examination in the aim to increase stability and diffusion through lipid barriers of A1 ligands. As an example, 5’-esters of CPA were proposed as pro-drugs and, among them, the lipophilic 5’-octanoyl-CPA (Oct-CPA) homologue was found able to be hydrolysed in whole blood only by plasma esterases. Moreover, it has been previously demonstrated that CPA encapsulation in poly(lactic acid) microparticles allows to sensibly increase its stability in human whole blood. In order to obtain sustained release systems for CPA which can be injected in vivo, we report here a preliminary study about the encapsulation of CPA and its pro-drug Oct-CPA in poly(lactic acid) nanospheres. The effects of the release systems have been evaluated on the stability in human whole blood of the pro-drug Oct-CPA and on the interaction between CPA and human A1 receptor expressed by CHO cells.
Controlled release studies of antiischemic agents encapsulated in poly(lactic acid) nanoparticles.
DALPIAZ, Alessandro;PAVAN, Barbara;BORTOLOTTI, Fabrizio;SCATTURIN, Angelo;MANFREDINI, Stefano;BIONDI, Carla;
2004
Abstract
Ischemic tolerance and neuronal protection can be obtained by activation of adenosine A1 membrane receptors. Several A1 selective ligands have been synthesised in order to reproduce these effects and, currently, N6-cyclopentyladenosine (CPA) is identified as a potent and selective A1 agonist. On the other hand, A1 receptors are ubiquitous in the body and their general activation causes unwanted effects which do not allow the clinical use of A1 agonists. Moreover, the adenosine derivatives appear poorly adsorbed into the brain and can be quickly degraded in whole blood or in vivo. Several approaches are currently under examination in the aim to increase stability and diffusion through lipid barriers of A1 ligands. As an example, 5’-esters of CPA were proposed as pro-drugs and, among them, the lipophilic 5’-octanoyl-CPA (Oct-CPA) homologue was found able to be hydrolysed in whole blood only by plasma esterases. Moreover, it has been previously demonstrated that CPA encapsulation in poly(lactic acid) microparticles allows to sensibly increase its stability in human whole blood. In order to obtain sustained release systems for CPA which can be injected in vivo, we report here a preliminary study about the encapsulation of CPA and its pro-drug Oct-CPA in poly(lactic acid) nanospheres. The effects of the release systems have been evaluated on the stability in human whole blood of the pro-drug Oct-CPA and on the interaction between CPA and human A1 receptor expressed by CHO cells.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
