Targeting orthotopic gliomas with renal-clearable luminescent gold nanoparticles

Abstract

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.

Dendrimer size effects on the selective brain tumor targeting in orthotopic tumor models upon systemic administration

“…Compared to other types of dendrimers injected via tail vein in flank tumor models, our hydroxyl‐terminated PAMAM dendrimer results exhibit similar levels of tumor accumulation despite needing to overcome physical transport barriers in orthotopic brain tumors that flank tumors lack 49‐51 . Compared to other types of nanoparticles explored in orthotopic brain tumors, G6 shows a ~100‐fold greater in tumor accumulation than liposomal 52 nanoparticles and ~10‐fold greater than G4 and reported tumor levels of gold 53,54 and PEGylated iron oxide 55 nanoparticles. Studies based on traditional polymeric nanoparticles with ~135 nm size showed only a 50% improvement in the delivery of temozolomide in a rat brain tumor model 56 .…”

Renal Clearable Luminescent Gold Nanoparticles: From the Bench to the Clinic

“…In 2013, through a comprehensive comparison of the passive tumor targeting of renal‐clearable NIR‐emitting GS‐AuNPs and a renal clearable organic dye, IRDye 800CW, we found that the EPR effect can still be retained in renal clearable GS‐AuNPs, which exhibited a much longer tumor retention time and faster normal tissue clearance than IRDye 800CW . Through the EPR effect, renal clearable GS‐AuNPs can target different types of cancers, including breast, prostate, and brain cancers (Figure and Table S8).…”

“…Reproduced with permission from Ref. . Copyright 2017, Tsinghua University Press and Springer‐Verlag Berlin Heidelberg.…”

Renal Clearable Luminescent Gold Nanoparticles: From the Bench to the Clinic

“…Minireviews and ar enal clearable organic dye,I RDye 800CW,w ef ound that the EPR effect can still be retained in renal clearable GS-AuNPs,which exhibited amuch longer tumor retention time and faster normal tissue clearance than IRDye 800CW. [35] Through the EPR effect, renal clearable GS-AuNPs can target different types of cancers,i ncluding breast, [35,[37][38]47] prostate, [57] and brain cancers [73] (Figure 10 and Table S8).…”

“…Reproducedw ith permission from Ref. [73].C opyright 2017, Tsinghua UniversityP ress and Springer-Verlag Berlin Heidelberg. D) The linear relationship between tumor-targeting efficiencies of gold clusters in xenograft model of MCF-7 at 24 hp.i.…”