Multifunctional cytotoxic stealth nanoparticles. A model approach with potential for cancer therapy

Here we report on a highly versatile nanoparticle-based core/shell drug delivery system consisting of cytotoxic stealth carrier particles. Their multifunctional shells, mandatory for addressing different diagnostic/treatment requirements, are constructed using a single assembly process in which various different functionalities are incorporated in a modular fashion. More specifically, we discuss a robust electrostatic and covalent layer-by-layer (LBL) assembly strategy as engineering approach toward nanoparticles with multilayer shells that combine all of the following properties: (i) a small size distribution of the nanoparticle carrier, (ii) a high stability in physiological media, (iii) attachment of a pro-drug in covalent form and thus a low toxicity of the carrier system, (iv) the triggered release and activation of the drug only after endocytosis and enzymatic cleavage, and (v) "stealthiness" and thus protection against uptake by macrophages. The fact that we employ small nanoparticles as carriers is predicted to enhance the accumulation of active drug in the tumor tissue (i.e., enhanced permeability and retention of tumor tissues, EPR). To establish this system as a proof of concept, we use the smallest nanoparticles within the interesting size range of about 25-100 nm for EPR targeting since these are the most difficult to functionalize and because they possess the highest surface area. On the basis of gold nanoparticle cores, our system allows for precise control of particle size and size distribution and also for easy monitoring of the dispersion stability by the naked eye.