Prieto Maria Jimena, del Rio Zabala Nahuel Eduardo, Marotta Cristian Hernán, Carreño Gutierrez Hector, Arévalo Arévalo Rosario, Chiaramoni Nadia Silvia, del Valle Alonso Silvia
Biomembrane Laboratory, Department of Science and Technology, National University of Quilmes, Buenos Aires, Argentina ; IMBICE-CONICET, CCT La Plata, Argentina.
Department of Cell Biology and Pathology, Institute of Neuroscience of Castilla y Leon, School of Medicine, University of Salamanca, Salamanca, Spain.
PLoS One. 2014 Feb 28;9(2):e90393. doi: 10.1371/journal.pone.0090393. eCollection 2014.
Risperidone is an approved antipsychotic drug belonging to the chemical class of benzisoxazole. This drug has low solubility in aqueous medium and poor bioavailability due to extensive first-pass metabolism and high protein binding (>90%). Since new strategies to improve efficient treatments are needed, we studied the efficiency of anionic G4.5 PAMAM dendrimers as nanocarriers for this therapeutic drug. To this end, we explored dendrimer-risperidone complexation dependence on solvent concentration, pH and molar relationship. The best dendrimer-risperidone incorporation (46 risperidone molecules per dendrimer) was achieved with a mixture of chloroform:methanol 50∶50 v/v solution pH 3. In addition, to explore the possible effects of this complex, in vivo studies were carried out in the zebrafish model. Changes in the development of dopaminergic neurons and motoneurons were studied using tyrosine hydroxylase and calretinin, respectively. Physiological changes were studied through histological sections stained with hematoxylin-eosin to observe possible morphological brain changes. The most significant changes were observed when larvae were treated with free risperidone, and no changes were observed when larvae were treated with the complex.
利培酮是一种已获批准的抗精神病药物，属于苯并异恶唑化学类别。由于广泛的首过代谢和高蛋白结合率（>90%），该药物在水性介质中的溶解度较低且生物利用度较差。由于需要新的策略来改善有效治疗方法，我们研究了阴离子型G4.5聚酰胺-胺（PAMAM）树枝状大分子作为这种治疗药物纳米载体的效率。为此，我们探讨了树枝状大分子与利培酮的络合对溶剂浓度、pH值和摩尔比的依赖性。在pH值为3的氯仿：甲醇50∶50 v/v混合溶液中，实现了最佳的树枝状大分子与利培酮结合（每个树枝状大分子结合46个利培酮分子）。此外，为了探究这种络合物的可能影响，我们在斑马鱼模型中进行了体内研究。分别使用酪氨酸羟化酶和钙视网膜蛋白研究了多巴胺能神经元和运动神经元发育的变化。通过苏木精-伊红染色的组织切片研究生理变化，以观察可能的脑形态学变化。在用游离利培酮处理幼虫时观察到了最显著的变化，而在用络合物处理幼虫时未观察到变化。
