Online open-tubular fractionation scheme coupled with push–pull perfusion sampling for profiling extravasation of gold nanoparticles in a mouse tumor model

• The extravasation behavior of gold nanoparticles in a mouse tumor model was studied.
• Push–pull perfusion was employed as a means of sampling tumor extracellular AuNPs.
• An online open-tubular fractionation scheme was developed for AuNP quantification.
• More pegylated AuNPs extravasated into extracellular space than non-pegylated ones.
• Pegylation promoted the extravasation and accumulation of AuNPs for drug delivery.

The extravasation of administered nano-drug carriers is a critical process for determining their distributions in target and non-target organs, as well as their pharmaceutical efficacies and side effects. To evaluate the extravasation behavior of gold nanoparticles (AuNPs), currently the most popular drug delivery system, in a mouse tumor model, in this study we employed push–pull perfusion (PPP) as a means of continuously sampling tumor extracellular AuNPs. To facilitate quantification of the extravasated AuNPs through inductively coupled plasma mass spectrometry, we also developed a novel online open-tubular fractionation scheme to allow interference-free determination of the sampled extracellular AuNPs from the coexisting biological matrix. After optimizing the flow-through volume and flow rate of this proposed fractionation scheme, we found that (i) the system's temporal resolution was 7.5 h−1, (ii) the stability presented by the coefficient of variation was less than 10% (6-h continuous measurement), and (iii) the detection limits for the administered AuNPs were in the range 0.057–0.068 μg L−1. Following an intravenous dosage of AuNPs (0.3 mg kg−1 body weight), in vivo acquired profiles indicated that the pegylated AuNPs (PEG-AuNPs) had greater tendency toward extravasating into the tumor extracellular space. We also observed that the accumulation of nanoparticles in the whole tumor tissues was higher for PEG-AuNPs than for non-pegylated ones. Overall, pegylation appears to promote the extravasation and accumulation of AuNPs for nano-drug delivery applications.