Drug delivery into the central nervous system (CNS) appears currently as one of the most important hindrance in development of therapies for brain diseases. Several strategies have been proposed to overcome this problem, such as the pro-drug approach or the nanoparticle technology. Recently, it has been suggested that membrane transporters of native compounds can also take part in drug transport in the cerebral tissue. According to this point of view, it is to underline that a new class of Na+-dependent ascorbic acid (AA) transporters, SVCT2, localized in the choroid plexus, has been recently discovered and characterized. Taking this into account, we have hypothesized that drugs able to interact with the SVCT2 transporter can potentially be transported into the brain. Preliminary studies by us performed indicated the human retinal pigment epithelium (HRPE) cells as a valuable model for a selective in vitro analysis of SVCT2-mediated transport. The AA uptake in these cells was saturable according to a constant transport value (Kt) of 36 microM and a VMAX value of 4.3 nmol/106 cells/60 min. Moreover, 6-Br-ascorbic acid (Br-AA) showed better affinity for SVCT2 transporters than AA itself (Kt = 5.1 microM; VMAX = 4.0 nmol/106 cells/60 min). The present study is performed with the aim to analyse the interaction properties between pro-drugs obtained by conjugation with AA and Br-AA and the SVCT2 transporter selectively expressed by HRPE cells. Nipecotic (nipec) and kynurenic (kynur) acids, selected as anticonvulsant drugs that do not enter into the brain, have been selected for this approach. The in vivo central effects of these compounds and the related conjugates have been also evaluated.
Neuroactive molecules and their pro-drugs obtained by conjugation with vitamin c: studies of delivery into the brain.
DALPIAZ, Alessandro;PAVAN, Barbara;BORTOLOTTI, Fabrizio;BIONDI, Carla;SCATTURIN, Angelo;FERRARO, Luca Nicola;TANGANELLI, Sergio;MANFREDINI, Stefano
2004
Abstract
Drug delivery into the central nervous system (CNS) appears currently as one of the most important hindrance in development of therapies for brain diseases. Several strategies have been proposed to overcome this problem, such as the pro-drug approach or the nanoparticle technology. Recently, it has been suggested that membrane transporters of native compounds can also take part in drug transport in the cerebral tissue. According to this point of view, it is to underline that a new class of Na+-dependent ascorbic acid (AA) transporters, SVCT2, localized in the choroid plexus, has been recently discovered and characterized. Taking this into account, we have hypothesized that drugs able to interact with the SVCT2 transporter can potentially be transported into the brain. Preliminary studies by us performed indicated the human retinal pigment epithelium (HRPE) cells as a valuable model for a selective in vitro analysis of SVCT2-mediated transport. The AA uptake in these cells was saturable according to a constant transport value (Kt) of 36 microM and a VMAX value of 4.3 nmol/106 cells/60 min. Moreover, 6-Br-ascorbic acid (Br-AA) showed better affinity for SVCT2 transporters than AA itself (Kt = 5.1 microM; VMAX = 4.0 nmol/106 cells/60 min). The present study is performed with the aim to analyse the interaction properties between pro-drugs obtained by conjugation with AA and Br-AA and the SVCT2 transporter selectively expressed by HRPE cells. Nipecotic (nipec) and kynurenic (kynur) acids, selected as anticonvulsant drugs that do not enter into the brain, have been selected for this approach. The in vivo central effects of these compounds and the related conjugates have been also evaluated.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
