PEGylation and Zwitterionization: Pros and Cons in the Renal Clearance and Tumor Targeting of Near‐IR‐Emitting Gold Nanoparticles

PEGylation is the most common and successful surface-chemistry strategy for reducing nonspecific accumulation and prolonging blood circulation of inorganic nanoparticles (NPs), so that the NPs can effectively target tumors through well-known “enhanced permeability and retention (EPR)” effect.[1] These strengths fundamentally arise from the fact that poly(ethylene glycol) (PEG) moiety on the particle surface creates steric hindrance for the serum protein (opsonin) adsorption and slows down the NP uptake by the reticuloendothelial system (RES) organs (liver, spleen etc.).[2] However, the majority of PEGylated NPs still end up in RES organs after the circulation,[3] resulting in low targeting specificity (defined as the amount of NPs in tumor vs that in liver).[4] For instance, even though PEGylated AuNPs with a 2 nm core size can circulate in the body at a high concentration, they were found to severely accumulate in the liver (78 %ID/g) and spleen (15.2 %ID/g) at 24 h post-injection (p.i.).[5] Such long-term severe accumulation in RES potentially induces health hazards, hampering their clinical translation. Therefore, developing PEGylated inorganic NPs that not only can retain strong EPR effect but also can be eliminated from the urinary system like clinically used small molecular contrast agents[6] is highly desired but remains a big challenge.