Optimization and in vitro toxicity evaluation of G4 PAMAM dendrimer–risperidone complexes

• Published in: European journal of medicinal chemistry 2011-03, Vol.46 (3), p.845-850
• Main Authors: Prieto, María Jimena, Temprana, Carlos Facundo, del Río Zabala, Nahuel Eduardo, Marotta, Cristian Hernán, Alonso, Silvia del Valle
• Format: Article
• Language: English
• Subjects: Animals; Antipsychotic Agents - administration & dosage; Antipsychotic Agents - chemistry; Antipsychotic Agents - toxicity; Biological and medical sciences; Cell Line; Cell Survival - drug effects; Cytotoxicity; Dendrimers - chemistry; Dendrimers - toxicity; Drug Carriers - chemistry; Drug Carriers - toxicity; Erythrocytes - drug effects; General pharmacology; Hemolysis - drug effects; Humans; Medical sciences; Mice; Nylons - chemistry; Nylons - toxicity; PAMAM G4; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Poly(amidoamine) dendrimers; Risperidone; Risperidone - administration & dosage; Risperidone - chemistry; Risperidone - toxicity; Solubility
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2010.12.021

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%). As new strategies to improve treatments efficiency are needed, we have studied cationic G4 PAMAM dendrimers’ performance to act as efficient nanocarriers for this therapeutic drug. In this respect, we explored dendrimer–risperidone complexation dependence on solvent, temperature, pH and salt concentration, as well as in vitro cytotoxicity measured on L929 cell line and human red blood cells. The best dendrimer–risperidone incorporation was achieved when a mixture of 70:30 and 90:10 v/v chloroform:methanol was used, obtaining 17 and 32 risperidone molecules per dendrimer, respectively. No cytotoxicity on L929 cells was found when dendrimer concentration was below 3 × 10−2 μM and risperidone concentration below 5.1 μM. Also, no significant hemolysis or morphological changes were observed on human red blood cells. Finally, attempting to obtain an efficient drug delivery system for risperidone, incorporation in G4 PAMAM dendrimers was optimized, improving drug solubility with low cytotoxicity. [Display omitted] ► Incorporation of Risp molecules into DG4 was studied. ► The best conditions encountered for drug incorporation were: low solvent polarity mixture, pH c.a. 7, room temperature and low ionic strength. ► DG4–Risp showed no cell viability reduction at concentrations below 3 × 10−2 μM DG4 and 5.1 μM Risp. ► No significant hemolysis or morphological changes were observed on red blood cells. ► Complex resulted structurally stable for a period of 106 h in buffer.