Facilitated delivery of oligonucleotide as inhibitor of serotonin reuptake

摘要

Serotonin (5-HT) is a biogenic amine that functions as a neurotransmitter. Within the CNS, alterations in serotonergic neurotransmission are responsible for depression, headache, anxiety and feeding behavior. The major mechanism of terminatin of serotonin's action is its removal from the synapse by the serotonin transporter proteins present within the plasma membrane of the presynaptic cells. The first objective of this work was to study the 18 base oligodeoxnucleotide (5'-CTGGTAGCATATGTAAGG-3') (rSERT) corresponding to 294-311 (spanning the 1~st) transmembrane domain and the 1~(st) extracellular loop) of the rat serotonin transporter (rSERT) as an alternative for the inhibition of the reuptake of serotonin by selectively reducing the number of serotonin transporters at the plasma membrane of the RBL-2H3 cell line. The in vivo activity of antisense phosphodiester oligonucleotides has been limited due to their short biological half life caused by poor nuclease stability. The second objective of the work was to entrap the oligonucleotide in biodegradable polylactide-co-glycolide microparticles to increase its stability and delivery to the cells. Biodegradable microparticles have been demonstrated to be useful in promoting cellular uptake of drugs via endocytosis and they do not need to be removed by surgical procedures.