Ascorbic and 6-Br-ascorbic acid conjugates as a tool to increase the therapeutic effects of potentially central active drugs

Alessandro Dalpiaz, Barbara Pavan, Silvia Vertuani, Federica Vitali, Martina Scaglianti, Fabrizio Bortolotti, Carla Biondi, Angelo Scatturin, Sergio Tanganelli, Luca Ferraro, Giuliano Marzola, Puttur Prasad, Stefano Manfredini

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Ascorbic acid (AA) or 6-Br-ascorbate (BrAA) conjugation has been investigated as a tool to improve brain drug delivery by the Vitamin C transporter SVCT2. To this aim, the effects of AA- or BrAA-conjugation on drug affinity and uptake have been assessed in vitro, by using human retinal pigment epithelium (HRPE) cells, and compared in vivo on mice. Nipecotic, kynurenic and diclofenamic acids were chosen as model drugs. Kinetic and inhibition experiments referred to [14C]AA uptake into HRPE cells showed that nipecotic and kynurenic acids became able to interact with SVCT2, as competitive inhibitors, only when conjugated to AA or BrAA. Surprisingly, diclofenamic acid itself appeared able to interact with SVCT2, with an affinity that was significantly increased or decreased by AA or BrAA conjugation, respectively. HPLC analysis, performed on HRPE cells, confirmed the SVCT2 mediated transport for the BrAA-conjugate of nipecotic acid, whereas kynurenic acids conjugates although interacting with the transporter did not enter the cells. In accordance, only the nipecotic acid conjugates showed anticonvulsant activity after systemic injection in mice.

Original languageEnglish (US)
Pages (from-to)259-269
Number of pages11
JournalEuropean Journal of Pharmaceutical Sciences
Volume24
Issue number4
DOIs
StatePublished - Mar 2005

Keywords

  • Brain delivery
  • Drug targeting
  • HRPE cells
  • SVCT2 transporter
  • Vitamin C

ASJC Scopus subject areas

  • Pharmaceutical Science

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