Quantifying nanoparticle delivery: challenges, tools, and advances

Nanoparticles show great promise for drug and gene delivery applications. Nanoparticle-based carrier systems can enhance the solubility of hydrophobic drugs, extend blood circulation time, control temporal release of drugs, and deliver cargo to specific cell types. Nanoparticle delivery quantification is important because nanoparticles need to access their intended target site at sufficient dosage to elicit their therapeutic function [1]. There are three main modes of quantifying nanoparticle delivery: (1) functional readouts, (2) nanocarrier tracking, and (3) cargo tracking (as shown in Figure 1a). It is inappropriate to compare different nanoparticle delivery system designs when different measurement modalities are used. For example, in cancer nanomedicine, many meta-analyses have been conducted to evaluate tumor delivery of different nanoparticle designs. Notably, Wilhelm et al. systematically analyzed hundreds of nanoparticle tumor delivery datasets and found that only 0.7% (median) of systemically administered nanoparticles reached the tumor [2]. Other groups have refined or updated the inclusion criteria 3, 4, considered additional measured parameters [5], or performed more comprehensive pharmacokinetic modeling 3, 4, 6 to quantify delivery efficiency more accurately. However, a significant conceptual gap still exists since the quantification methodologies are vastly different throughout literature. It is known that nanocarrier distribution can be different from its cargo distribution, and delivery of the therapeutic cargo may not yield sufficient observable functional effects 7, 8, 9, as shown schematically in Figure 1a. We reanalyzed Wilhelm et al. dataset and recategorized the entries as carrier or cargo tracking, and further subcategorized by analytical quantification techniques. Functional readout measurements were excluded from the initial dataset already. Our reanalysis (Figure 1b) shows that ∼66% of entries used cargo tracking versus ∼34% used carrier tracking methods. Imaging-based techniques were preferred in cargo tracking entries (∼69%), whereas spectrometric techniques were majorly used in carrier tracking (∼78%). As such, it is evident that the delivery efficiency values and pharmacokinetic parameters derived from these nanoparticle tumor delivery meta-analyses may be misleading due to the mixed quantification methodologies used, akin to comparing apples to oranges.

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