Improving kidney targeting: The influence of nanoparticle physicochemical properties on kidney interactions

Abstract

Kidney-targeted nanoparticles have become of recent interest due to their potential to deliver drugs directly to diseased tissue, decrease off-target adverse effects, and increase overall tolerability to patients with chronic kidney disease that require lifelong drug exposure. Given the physicochemical properties of nanoparticles can drastically affect their ability to extravasate past cellular and biological barriers and access the kidneys, we surveyed the literature from the past decade and analyzed how nanoparticle size, charge, shape, and material density affects passage and interaction with the kidneys. Specifically, we found that nanoparticle size impacted the mechanism of nanoparticle entry into the kidneys such as glomerular filtration or tubular secretion. In addition, we found charge, aspect ratio, and material density influences nanoparticle renal retention and provide insights for designing nanoparticles for passive kidney targeting. Finally, we conclude by highlighting active targeting strategies that bolster kidney retention and discuss the clinical status of nanomedicine for kidney diseases.

Keywords: Acute kidney disease; Chronic kidney disease; Nanoparticle; Renal clearance; Targeted drug delivery.

Figure 1.

Schematic of (A) the nephron, (B) the glomerulus, (C) the GFB, and (D) renal excretion. Adapted and reprinted from ref. [–7].

Figure 2.

(A) Renal clearance of nanoparticles of varying size derived from urine measurements results after 24 hours post-i.v. administration [, , , –50, 54, 55, 57]. Renal accumulation of nanoparticles of varying size quantified by (B) % ID [39, 46, 50, 52, 54] and (C) % ID/g [45, 47, 48, 51, 53, 55, 56].

Figure 3.

Intravital images of magnetite clusters accumulation in the renal tubules. (A) Time- lapse imaging of renal cortex upon magnetite clusters-Cy5. (red, MNP-Cy5; blue, neutrophils (arrows); green, platelets (arrowheads)). (B) Dynamics of mean fluorescence intensity in capillaries (pink) and tubules (yellow); results are shown as means ± SEM; Reprinted and adapted with permission from Journal of Controlled Release [71].

Figure 4.

PAMAM dendrimers conjugated with short (2 kD) PEG, which are roughly spherical in shape, show negligible renal accumulation (left). However, when two long, linear PEG (20 kD) are conjugated, imparting a cylindrical shape, enhanced renal accumulation is observed (right). Reprinted and adapted with permission from American Chemical Society [94].

Figure 5.

In vivo biodistribution of RNA nanoparticles of varying shape. Time-course fluorescence images of triangle, square, and pentagon nanoparticles. H, heart; K, kidneys; Li, liver; Lu, lung; S, spleen; T, tumors. Adapted and reprinted with permission from Springer Nature [97].

Figure 6.

Biodistribution of the BSA633-MP nanoconjugates. (A) In vivo imaging, (B) ex vivo imaging of heart, liver, lung, kidney, and spleen. (C) Quantitative analysis of fluorescence imaging values in various organs. (n=3) Reprinted and adapted with permission from International Journal of Molecular Medicine [59].