Clearance properties of nano-sized particles and molecules as imaging agents: considerations and caveats

Abstract

Nanoparticles possess enormous potential as diagnostic imaging agents and hold promise for the development of multimodality agents with both imaging and therapeutic capabilities. Yet, some of the most promising nanoparticles demonstrate prolonged tissue retention and contain heavy metals. This presents serious concerns for toxicity. The creation of nanoparticles with optimal clearance characteristics will minimize toxicity risks by reducing the duration of exposure to these agents. Given that many nanoparticles possess easily modifiable surface and interior chemistry, if nanoparticle characteristics associated with optimal clearance from the body were well established, it would be feasible to design and create agents with more favorable clearance properties. This article presents a thorough discussion of the physiologic aspects of nanoparticle clearance, focusing on renal mechanisms, and provides an overview of current research investigating clearance of specific types of nanoparticles and nano-sized macromolecules, including dendrimers, quantum dots, liposomes and carbon, gold and silica-based nanoparticles.

Figure 1

2D-T1 weighted MR images of kidneys with acute tubular dysfunction (a) and normal function (b) are shown. Glomerular filtration (white arrows) is shown in the kidney when the tubular function is completely impaired (a) and tubular concentration function (black arrows) and urinary excretion (*) are shown in the normal functioning kidney (b).

Figure 2

Renal handling of nanoparticles of different sizes and charges. Circulating nanoparticles enter the glomerular capillary bed via the afferent arteriole. A) The glomerular capillary wall is composed of three layers: fenestrated endothelium; the highly negatively charged glomerular basement membrane (GBM); and podocyte extensions of glomerular epithelial cells. Glomerular filtrate flows through the fenestrate, across the GBM, and through filtration slits formed by spaces between podocyte extensions. The primary size barrier is the filtration slit, which has a physiologic pore size of 4.5-5 nm. Nanoparticles < 6 nm (red) are small enough to be freely filtered, irrespectively of molecular charge. However, glomerular filtration of particles between 6-8 nm (purple) is dependent on charge interactions between the intermediate sized particles and the negative charges of the GBM. Therefore, positively particles are more readily filtered than equally sized negatively charged particles. Due to size limitations, particles > 8 nm do not undergo glomerular filtration. After glomerular filtration, filtered nanoparticles enter the proximal tubule. B) Within the proximal tubule, nanoparticles may be resorbed from the luminal space. Since the brush border of the proximal tubule epithelial cells is negatively charged, positively charged particles are more readily resorbed than comparable negatively charged particles.

Figure 3

3D-maximum intensity projection display of T1-weighted MR images of the abdomen at 15 min post-injection for G9, G8, G7, and G6 and at 3 min after injection for G5, G4, G3, G2, and DTPA are shown. Kidneys are shown with agents of G5 (8 nm in diameter) or smaller. Blood pool is clearly depicted G5 (8 nm) and G4 (5 nm) at 3 min post-injection because of partial and slow glomerular filtration. Kidneys are not shown with agents G6 (9 nm in diameter) or larger even at 15 min post-injection. Intensities in the liver increase as the agent sizes increase.

Figure 4

Comparison of sizes of various nanoparticles. Chemical composition and size range are defining features for nanoparticles. Both characteristics are important determinants of nanoparticle in vivo behavior and clearance properties.