Preparation and evaluation of peptide amphiphile-modified lipid nanoparticles for targeted docetaxel delivery

Abstract

The aim of this study is to develop and evaluate peptide amphiphile (PA)-modified lipid nanoparticles for targeted docetaxel (DTX) delivery. DTX-loaded PA-modified lipid nanoparticles (DTX-PANPs) were prepared by nanotemplate engineering technique. The physicochemical properties of DTX-PANPs were evaluated by dynamic light scattering (DLS), transmission electron microscopy (TEM) and differential scanning calorimetry (DSC). In vitro release study was performed in matrix metalloproteinase-2 (MMP-2) containing media to ensure enzyme-specific DTX release from PANPs. In vitro cytotoxicity of DTX-PANPs was evaluated by cell viability assay against MCF-7 and MDA-MB-231 cell lines. The cellular binding and uptake of DTX-PANPs were determined by confocal laser scanning microscopy (CLSM) using coumarin 6 as a fluorescent marker for nanoparticles. The targeting ability of DTX-PANPs was evaluated by a RGDS competitive inhibition assay after pretreatment with free RGDS. The average particle size of DTX-PANPs was 94.1 ± 1.3 nm with polydispersity index (PDI) of 0.145 ± 0.011. TEM images showed that DTX-PANPs are uniform and spherical in shape. The results of DSC thermograms showed that DTX from PANPs was present in amorphous state. The drug release profiles from DTX-NPs and DTX-PANPs was evaluated in PBS (pH 7.4) containing MMP-2 solution at 37°C. Following 12 hours, DTX amount released from DTX-PANPs in presence of MMP-2 solution was markedly increased as compared with the other NPs. DTX-PANPs also showed a triggered drug release through biodegradation of MMP-2-specific sequence in PA. In vitro cytotoxicity against MCF-7 and MDA-MB-231 cell lines was assessed by MTT assay. IC50 values of Taxotere®, DTX-NPs, and DTX-PANPs against MDA-MB-231 were 29.10 ± 0.80, 11.5 ± 1.30 and 6.1 ± 0.43 respectively. In a RGDS competitive inhibition assay, cell viability was decreased up to 20% in MDA-MB-231 when treated with DTX-PANPs without treatment of free RGDs. These results showed that DTX-PANPs displayed more cellular uptake in MDA-MB-231 cell lines in comparison with Taxotere® and DTX-NPs. The targeting efficiency of DTX-PANPs was confirmed by in vitro cytotoxicity, cellular uptake and competitive inhibition assay in MCF-7 and MDA-MB-231 cell lines. In conclusion, PANPs are potential tumor-specific delivery systems for DTX with MMP-2-sensitive drug release and active targeting.