Interactions of Renal‐Clearable Gold Nanoparticles with Tumor Microenvironments: Vasculature and Acidity Effects

Abstract

The success of nanomedicines in the clinic depends on our comprehensive understanding of nano–bio interactions in tumor microenvironments, which are characterized by dense leaky microvasculature and acidic extracellular pH (pHe) values. Herein, we investigated the accumulation of ultrasmall renal-clearable gold NPs (AuNPs) with and without acidity targeting in xenograft mouse models of two prostate cancer types, PC-3 and LNCaP, with distinct microenvironments. Our results show that both sets of AuNPs could easily penetrate into the tumors but their uptake and retention were mainly dictated by the tumor microvasculature and the enhanced permeability and retention effect over the entire targeting process. On the other hand, increased tumor acidity indeed enhanced the uptake of AuNPs with acidity targeting, but only for a limited period of time. By making use of simple surface chemistry, these two effects can be synchronized in time for high tumor targeting, opening new possibilities to further improve the targeting efficiencies of nanomedicines.

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

“…The reason is that PEG‐AuNPs had three‐fold larger AUC than GS‐AuNPs (142.8 %ID h g −1 vs. 47.2 %ID h g −1 , 0–24 h p.i.). GC‐AuNPs targeted PC‐3 (human prostate cancer) xenograft tumors at an efficiency of 4.36 % ID g −1 , which was about two‐fold higher than that of GS‐AuNPs (2.72 %ID g −1 ), owing to larger AUC (201.6 vs. 47.5 %ID h g −1 ) . More interestingly, for sub‐nanometer gold nanoclusters, a linear relationship was found between the AUC and the tumor‐targeting efficiency in xenograft MCF‐7 model: with an increase in AUC from 49.31 to 141.55, 201.81, and 247.58 %ID h g −1 , the 24‐h tumor accumulation linearly increased from 2.28 to 4.89, 6.07, and 8.17 %ID g −1 for Au 25 , Au 18 , Au 15 , and Au 10‐11 , respectively (Figure D) .…”

“…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).…”

“…To understand the surface‐charge effect on renal clearance and PK of AuNPs, we compared two same‐sized, negatively charged zwitterionic AuNPs, GS‐AuNPs (core size of 2.1 nm, zeta potential of −48.0 mV at pH 7.4) and glutathione/cysteamine‐coated AuNPs (GC‐AuNPs, core size of 2.3 nm, zeta potential of −22.1 mV at pH 7.4). At 1 h post‐intravenous injection, liver uptake of the two types of NPs was less than 7 %ID g −1 but GC‐AuNPs showed much lower renal clearance efficiency (10 %ID) than GS‐AuNPs (28 %ID), indicating that the renal clearance was slowed down with decreasing zeta potential in the negative charge range.…”

“…To understand the tumor vasculature and acidity effects on the tumor targeting of NPs, we compared the accumulation of renal clearable glutathione/cysteamine‐coated AuNPs (GC‐AuNPs) with acidity targeting to the GS‐AuNPs without acidity targeting in two prostate cancer models PC‐3 (pH e =6.9, high MVD, small vascular endothelial area) and LNCaP tumors (pH e =6.5, low MVD, large vascular endothelial area) . The luminescent renal clearable GC‐AuNPs were designed to target the tumor acidic microenvironment by showing acidic pH‐induced adsorption onto the live‐cell membrane while having little interaction with cells at neural pH (Figure ) . Through biodistribution studies at 1, 24, and 72 h after intravenous injection, we found that for the same type of AuNPs, differences in the tumor microvasculature had little impact on the tumor permeability of NPs in early targeting stages (at 1 h p.i.…”

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

“…To understand the surface-charge effect on renal clearance and PK of AuNPs,w ec ompared two same-sized, negatively charged zwitterionic AuNPs,GS-AuNPs (core size of 2.1 nm, zeta potential of À48.0 mV at pH 7.4) [40,57] and glutathione/cysteamine-coated AuNPs (GC-AuNPs,core size of 2.3 nm, zeta potential of À22.1 mV at pH 7.4). At 1hpostintravenous injection, liver uptake of the two types of NPs was less than 7%ID g À1 but GC-AuNPs showed much lower renal clearance efficiency (10 %ID) than GS-AuNPs (28 %ID), indicating that the renal clearance was slowed down with decreasing zeta potential in the negative charge range.PKs tudies suggested that GC-AuNPs and GS-AuNPs had comparable V d values (2.81 vs.2 .98 mL;T able S6).…”