Scheme 1.

Two distinct renal clearance pathways in the kidneys as well as renal cell carcinoma (RCC) targeting of fluorescent agents. a) Glomerular filtration happens at the glomeruli (G) and is a passive, non-specific process to eliminate molecules and nanoparticles from glomerular capillaries to Bowman’s space as long as their sizes are below the kidney filtration threshold (≈6 nm or 40 kDa). The filtrated molecules are then transported into bladder by travelling through the renal tubules of the nephrons such as proximal tubules (PT). b) The renal tubular secretion is an active, specific process for removal of small molecules from peritubular capillary (PTC) to renal tubular lumen through 1) binding of the molecule to the transporters on the basolateral side of tubular cells, influx into the cells and 2) efflux from the luminal side of tubular cells. Arrows indicate the direction of transport of exogenous substances. c) RCC originates from the renal tubular epithelial cells because of genetic mutation. d) For fluorescent-guided partial nephrectomy for RCC, fluorescent agents that selectively target kidney cancers over normal kidney tissues (hyperfluorescent) are preferred to improve the precision of tumor removal and preservation of kidney functions. However, most of current agents, especially for passive targeting agent, are retained in and light up normal kidney tissue, resulting in hypofluorescent imaging of primary RCC.