A basic understanding of how imaging nanoparticles are removed from the normal organs/tissues but retained in the tumors is important for their future clinical applications in early cancer diagnosis and therapy. In this review, we discuss current understandings of clearance pathways and tumor targeting of small-molecule- and inorganic-nanoparticle-based imaging probes with an emphasis on molecular nanoprobes, a class of inorganic nanoprobes that can escape reticuloendothelial system (RES) uptake and be rapidly eliminated from the normal tissues/organs via kidneys but can still passively target the tumor with high efficiency through the enhanced permeability permeability and retention (EPR) effect. The impact of nanoparticle design (size, shape, and surface chemistry) on their excretion, pharmacokinetics, and passive tumor targeting were quantitatively discussed. Synergetic integration of effective renal clearance and EPR effect offers a promising pathway to design low-toxicity and high-contrast-enhancement imaging nanoparticles that could meet with the clinical translational requirements of regulatory agencies.

Up-converting rare-earth nanophosphors (UCNPs) have great potential to revolutionize biological luminescent labels, but their use has been limited by difficulties in obtaining UCNPs that are biocompatible. To address this problem, we have developed a simple and versatile strategy for converting hydrophobic UCNPs into water-soluble and carboxylic acid-functionalized analogues by directly oxidizing oleic acid ligands with the Lemieux-von Rudloff reagent. This oxidation process has no obvious adverse effects on the morphologies, phases, compositions and luminescent capabilities of UCNPs. Furthermore, as revealed by Fourier transform infrared (FTIR) and NMR results, oleic acid ligands on the surface of UCNPs can be oxidized into azelaic acids (HOOC(CH2)7COOH), which results in the generation of free carboxylic acid groups on the surface. The presence of free carboxylic acid groups not only confers high solubility in water, but also allows further conjugation with biomolecules such as streptavidin. A highly sensitive DNA sensor based on such streptavidin-coupled UCNPs have been prepared, and the demonstrated results suggest that these biocompatible UCNPs have great superiority as luminescent labeling materials for biological applications.

After one-decade’s efforts, a large amount of highly luminescent metal nanoparticles with different sizes and surface chemistries have been developed. While the luminescence is often attributed to particle size effect, other structural parameters such as surface ligands, valence states of metal atoms and crystallinity of nanoparticles also have significant influence on emission properties and mechanisms. In this minireview, we summarized the strategies used to create luminescent gold nanoparticles with size from few to millions of atoms and discussed how these structural factors affect their photoluminescence.

Glutathione-coated luminescent gold nanoparticles (GS-AuNPs) of ~ 2.5 nm behave like small dye molecules (IRdye 800CW) in physiological stability and renal clearance, but exhibit much longer tumor retention time and faster normal tissue clearance than the dye molecules, indicating that well-known enhanced permeability and retention (EPR) effect, a unique strength of conventional nanoparticles (NPs) in tumor targeting, still exists in such small NPs. These merits enable the AuNPs to more rapidly detect tumor than the dye molecules without severe accumulation in reticuloendothelial system (RES) organs, holding great promise in cancer diagnosis and therapy.

The glomerular filtration barrier is known as a “size cut-off” slit to retain nanoparticles or proteins larger than 6~8 nm in the body, and to rapidly excrete the smaller ones through the kidneys. However, in a sub-nm size regime, we found that this barrier behaved as an atomically precise “bandpass” filter to significantly slow down renal clearance of few-atom gold nanoclusters (AuNCs) with the same surface ligands but different sizes (Au18, Au15 and Au10–11). Compared to Au25 (~1.0 nm), just few-atom decreases in the size resulted in 4~9 times reductions in the renal clearance efficiency in the early elimination stage because the smaller AuNCs were more readily trapped by the glomerular glycocalyx than the larger ones. This unique in vivo nano-bio interaction in the sub-nm regime also slows down the extravasation of sub-nm AuNCs from normal blood vessels and enhances their passive targeting to cancerous tissues through enhanced permeability and retention effect. This discovery highlights the size precision in the body’s response to nanoparticles and opens a new pathway to develop nanomedicines for many diseases associated with glycocalyx dysfunction.