Endosomal pH-Responsive Polymer-Based Dual-Ligand-Modified Micellar Nanoparticles for Tumor Targeted Delivery and Facilitated Intracellular Release of Paclitaxel.

purposeThe purpose of the present study was to design and fabricate endosomal pH-sensitive dual-ligand-modified micellar nanoparticles to achieve enhanced drug delivery to tumor cells and facilitated intracellular drug release.

methodsEnd-group-carboxylated poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) and cyclic Arg-Gly-Asp-Tyr-Lys- and anti-prostate specific membrane antigen antibody-modified diblock copolymer poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) were synthesized and characterized by (1)H NMR and gel permeation chromatography, and self-assembled into micelles. Paclitaxel-loaded dual-ligand-modified micelles were prepared by thin-film hydration method, and characterized by dynamic light scattering, transmission electron microscope, pH-dependent in vitro release and stability. Intracellular paclitaxel delivery was measured by flow cytometry and imaged by confocal microscopy. In vitro cytotoxicity was studied in the 22Rv1 xenograft prostate tumor cell lines.

resultsThe prepared dual-ligand-modified micelles with about 30 nm in diameter and rapid intracellular drug release behavior at endo/lysosomal pH were very effective in enhancing the cytotoxicity of paclitaxel against 22Rv1 cells by increasing the cellular uptake, which was verified the correlation with the expression of integrin αvβ3 and prostate specific membrane antigen in tumor cells by flow cytometric analysis and confocal microscopy, compared with single ligand-modified micelles.

conclusionThese findings provided valuable information that the application of combining of dual-ligand modifications with pH-sensitivity to polymeric micelles may be a promising approach in the efficient delivery of anticancer drugs for treatment of integrin αvβ3 and prostate specific membrane antigen expressing prostate cancers.