How to deliver an unselective drug selectively: Novel puromycin-loaded albumin nanoparticles for active targeting and their controllable effectiveness

Abstract

Cell specific targeting of cancer cells has been a widely investigated field in pharmaceutical nanotechnology. In this study, the active targeting properties of PEGylated albumin-based nanoparticles with covalently attached trastuzumab was investigated with regard to selective toxicity on HER2/neu-positive cell lines. For this purpose, the non-selective cytotoxic compound puromycin was successfully incorporated into albumin-based nanoparticles through covalent binding via a cathepsin B cleavable linker to the albumin matrix. It could subsequently be shown that puromycin was only released in presence of cathepsin B.

Selective cytotoxicity was assessed by a series of WST-1 assays which revealed that the puromycin-loaded nanoparticles with active targeting surface modification did lead to selective cytotoxicity on HER2/neu-positive cell lines SK-Br-3 and BT-474, while simultaneously protecting HER2/neu-negative MCF-7 from the cytotoxic effects of puromycin. This cytotoxic effect on HER2/neu-positive cells could be hindered by prior saturation of HER2/neu receptor with free trastuzumab. Controls without puromycin-loading remained non-toxic on all tested cell lines. We believe that this approach of API incorporation into protein-based nanoparticles through the concept of enzymatically cleavable linkers can be applied to a wide range of drugs. Likewise, the concept of active targeting vehicles for unselective drugs can also be employed to multiple extracellular target structures. Combining both, this nanoparticle design offers a broad spectrum of possibilities for promising therapeutic targeting concepts.