The antitumor effect of chemotherapeutics loaded micelles mainly depends on two aspects: the accumulation in the tumor region and the penetration into the tumor interior. These two processes have different demands on particle size. The optimal particle size for enhanced permeability and retention (EPR) is commonly believed to be around 100 nm, while much smaller size is desired for deeper penetration into the tumor interior. To address these two different requirements, we constructed size-shifting micelle nanoclusters (MNC) based on a cross-linked framework interspersed with micelles. The particle size of the micelles was 14.6 ± 0.8 nm and increased to 104.2 ± 8.1 nm after the MNC were formed, leading to an effective utilization of the EPR effect. MNC were shifted to independent micelles in lysosomes, so that a more favorable particle size for penetration could be realized. The results of antitumor growth in vivo demonstrated that size-shifting MNC were more beneficial for tumor therapy than micelles.
Keywords: deep penetration; micelle nanoclusters; pH-sensitive; polyethylenimine; size-shifting.