Polyelectrolyte-Doped Block Copolymer-Stabilized Nanocarriers for Continuous Tunable Surface Charge

Abstract

The surface charge of nanoparticles or nanocarriers (NCs) plays a critical role in the vehicle function, distribution, and fate in drug delivery applications. Flash NanoPrecipitation (FNP) is a platform for producing block copolymer-stabilized NCs. We show that NC charge (measured as the ζ-potential) can be continuously tuned from +40 to −40 mV by using blends of neutral poly(styrene)-block-poly(ethylene glycol) (PS-b-PEG) with polyelectrolyte block copolymers, anionic poly(styrene)-block-poly(acrylic acid) (PS-b-PAA) or cationic poly(styrene)-block-poly(N,N-dimethylaminoethyl methacrylate) (PS-b-DMAEMA), while simultaneously controlling NC diameters between 40 and 180 nm. The dense polymer brush on the surface of these FNP NCs provides a better platform to test NC surface charge effects on cellular interactions than NC systems in which charge is applied onto hydrophobic surfaces. NC charge gradually increases as more PS-b-PEG is replaced with a polyelectrolyte stabilizer, where sparsely substituted NCs (1–20 wt %) have nearly neutral (|ζ| < 5 mV) followed by a region where ζ-potential increases with increasing polyelectrolyte substitution. The protein binding to negatively charged NCs is low and equivalent to the adsorption on PEG-coated NCs, which are normally considered as the gold standard in “stealth” low protein adsorbing surfaces. In contrast, as little as 1 mol % cationic polymer produces strong protein adsorption, and cellular uptake, even though the ζ-potentials are still near zero, |ζ| < 5 mV. Binding of the NCs to Tib67, HEK293T, and HepG2 cells is distinct. While cationic NCs are taken up by all cell lines, anionic NCs are only taken up by the macrophage-like Tib67 cells. These results are discussed in terms of the protein corona differences on the NCs and the receptor differences between these cell lines. This study shows that ζ-potential alone is inadequate to predict the biological identity of an NC formed by protein corona adsorption and interactions with different types of cells.