Targeting orthotopic gliomas with renal-clearable luminescent gold nanoparticles

A major clinical translational challenge in nanomedicine is the potential of toxicity associated with the uptake and long-term retention of non-degradable nanoparticles （NPs） in major organs. The development of inorganic NPs that undergo renal clearance could potentially resolve this significant biosafety concern. However, it remains unclear whether inorganic NPs that can be excreted by the kidneys remain capable of targeting tumors with poor permeability. Glioblastoma multiforme, the most malignant orthotopic brain tumor, presents a unique challenge for NP delivery because of the blood-brain barrier and robust blood-tumor barrier of reactive microglia and macroglia in the tumor microenvironment. Herein, we used an orthotopic murine glioma model to investigate the passive targeting of glutathione-coated gold nanoparticles （AuNPs） of 3 nm in diameter that undergo renal clearance and 18-nm AuNPs that fail to undergo renal clearance. Remarkably, we report that 3-nm AuNPs were able to target intracranial tumor tissues with higher efficiency （2.3× relative to surrounding non-tumor normal brain tissues） and greater specificity （3.0×） than did the larger AuNPs. Pharmacokinetics studies suggested that the higher glioma targeting ability of the 3-nm AuNPs may be attributed to the longer retention time in circulation. The total accumulation of the 3-nm AuNPs in major organs was significantly less （8.4×） than that of the 18-nm AuNPs. Microscopic imaging of blood vessels and renal-clearable AuNPs showed extravasation of NPs from the leaky blood-tumor barrier into the tumor interstitium. Taken together, our results suggest that the 3-nm AuNPs, characterized by enhanced permeability and retention, are able to target brain tumors and undergo renal clearance.

Effect of glutathione on in vivo biodistribution and clearance of surface-modified small Pd nanosheets

Plasmonic Pd nanosheets have been emerging as promising materials for application in near-infrared(NIR) photothermal therapy(PTT) of cancer. However, animal in mice studies indicated that the original synthesized poly(vinylpyrrolidone)(PVP)-protected small Pd nanosheets(Pd-PVP) and some further surface-modified small Pd nanosheets such as Pd-PEG(SH) easily accumulated in reticuloendothelial system(RES) organs(liver, spleen, etc.) and were difficult to be cleared from these organs quickly. In the work, we surprisingly found that glutathione(GSH) could promote the clearance of surface-modified small Pd nanosheets(e.g. Pd-PVP, Pd-PEG(SH) and Pd-GSH) from the RES organs efficiently. The effects of GSH on the biodistribution and clearance of different surface-modified Pd nanosheets were investigated. Our results indicated that these surface-modified Pd nanosheets with or without GSH added caused no morbidity at target primary organs, and GSH can promote the clearance of different surface-modified Pd nanosheets in the order of Pd-PVP≈Pd-PEG(SH)>Pd-GSH. This study suggests that glutathione could be an attractive reagent for promoting nanomaterials eliminated from the reticuloendothelial systems(RES).