Attenuated polyethylene glycol immunogenicity and overcoming accelerated blood clearance of a fully PEGylated dendrimer.

Polyethylene glycol (PEG) is a popular biocompatible polymer and PEGylated nanoparticles passively accumulate in tumor tissues because of their enhanced permeability and retention effects. Recently, the anti-PEG immunity of PEGylated nanoparticles has become an issue that needs to be solved for their clinical applications. Dendrimers are highly branched and well-defined polymers with many terminal groups, which act as potent drug carriers. In this study, we examined the pharmacokinetics, biodistribution, anti-PEG immunity, and tumor accumulation of a fully PEGylated polyamidoamine (PAMAM) dendrimer after the first and second injections and compared them to those of a PEGylated liposome with the same lipid component as Doxil®. The PEGylated dendrimer showed greater blood circulation than that of the PEGylated liposome after the first and second injections in rats. In mice injected with the PEGylated dendrimer, much less anti-PEG immunoglobulin M (IgM) was generated than that in mice injected with the PEGylated liposome. The PEGylated dendrimer accumulated in the tumor after both the first and second injections. Our results indicated that the PEGylated dendrimer with a small size and high PEG density showed attenuated anti-PEG immunity and overcame the accelerated blood clearance phenomenon, which is useful for drug delivery systems for cancer treatment.

Different hydration states and passive tumor targeting ability of polyethylene glycol-modified dendrimers with high and low PEG density.

It has been reported that the amount of intermediate water, defined as water molecules loosely bound to a material, is a useful index of the material's bio-inert properties. Polyethylene glycol (PEG) is a well-known biocompatible polymer with a large amount of intermediate water. Many researchers have showed that PEGylated nanoparticles are passively accumulated in tumor tissues owing to their enhanced permeability and retention (EPR) effects. Dendrimers are regularly branched polymers with highly controllable size and structure, which can be exploited as potent drug carriers. In this study, we investigated the tripartite relationship among the PEG density, the hydration state, and the passive tumor targeting property, using PEGylated dendrimers. The fully PEGylated dendrimer, PEG64-den, showed similar hydration behavior to PEG and a passive tumor targeting property. In contrast, the hydration state of the partly PEGylated dendrimer, PEG5-den, was different from that of PEG64-den, and the passive tumor targeting property was not observed. This is the first report to show the hydration state of a drug carrier as well as discuss a relationship between the hydration state and biodistribution.