The effect of efflux pump inhibitors on in vitro and in vivo efficacy of solid lipid nanoparticles containing SN38

Abstract

7-ethyl-10-hydroxy camptothecin (SN38) is poorly soluble in water and pharmaceutical solvents. Oral administration of SN38 was restricted due to poor solubility. Many ways such as encapsulation in carriers are used for solving this restriction. Solid lipid nanoparticles (SLNs) are able to encapsulate lipophilic drugs and improve oral bioavailability. In addition, concomitant use of the efflux pump inhibitors can improve the performance of the encapsulated drug. In the present study, SN38 was loaded in SLNs. Nanoparticle size, zeta potential and drug encapsulation efficacy were investigated. The drug release from nanoparticles was also determined in the simulated intestinal fluid (SIF) and simulated gastric fluid (SGF). Cytotoxicity of nanoparticles after 24 and 48 h were measured in C26 and Caco-2 cell lines. The cellular uptake of the drug was determined. Tumor growth inhibition and survival were evaluated in animal model. The results showed that the drug-loaded SLNs were about 172.3 ± 3.3 nm in size. The encapsulation efficacy was 61% ± 7. In cellular studies, higher toxicity of the drug-loaded nanoparticles with the two substances piperine and quercetin were achieved in the Caco-2 cell line. It was observed that drug uptake of nanoparticles containing SN38 with or without piperine and quercetin by C26 and Caco-2 cell line was significantly higher than free SN38 in 2 and 4 h. According to in vivo studies, the use of piperine and quercetin with SLN containing SN38 has produced a favorable synergistic effect as increasing the survival time in animal model.