Multivalent nanoparticles for personalized theranostics based on tumor receptor distribution behaviorElectronic supplementary information (ESI) available: Characterization of PRn by NMR and FTIR; in vitro stability and drug release of Fe-PRn; simulation calculation on the size of the ligand cluster PRn; bio-distribution of Fe-PRn in the KB tumor-bearing mice; body weight of mice in the KB and H22 tumor groups; pathological staining of organs. See DOI: 10.1039/c8nr09347d

It is acknowledged that the targeting ability of multivalent ligand-modified nanoparticles (MLNs) strongly depends on the ligand spatial presentation determined by ligand valency. However, the receptor overexpression level varies between different types or stages of tumors. Thus, it is essential to explore the influence of ligand valency on the targeting ability of MLNs to tumors with different levels of receptor overexpression. In this study, a dual-acting agent raltitrexed was used as a ligand to target the folate receptor (FR). Different copies of the raltitrexed-modified multivalent dendritic polyethyleneimine ligand cluster PR n ( n = 2, 4, and 8) were conjugated onto magnetic nanoparticles to form multivalent magnetic NPs (MMNs) with different valences. The in vitro studies demonstrated that Fe-PR 4 was the most effective valency in the treatment of high FR overexpressing KB cells with a decentralized receptor distribution, owing to the fact that Fe-PR 2 was negative in statistical rebinding and Fe-PR 8 could induce steric hindrance in the limited binding area. Instead, in moderate FR overexpressing HeLa cells with clustered receptor display, the extra ligands on Fe-PR 8 would facilitate statistical rebinding more beneficially. Furthermore, in in vivo tumor inhibition and targeted magnetic resonance imaging (MRI) of KB tumors and another moderate FR expressing H22 tumor, similar results were obtained with the cell experiments. Overall, the optimizable treatment effect of Fe-PR n by modulating the ligand valency based on the overexpressing tumor receptor distribution behavior supports the potential of Fe-PR n as a nanomedicine for personalized theranostics. The distribution behaviour of folate receptors associated with the receptor overexpression level affects the best matching ligand valency of multivalent nanoparticles.