Written by: Piotr S. Kowalski
Original Articles: Williams et al. Nano Letters 2015 and Williams et al. Hypertension 2018
The Gist of it:
Delivering drugs only to cells that require treatment is a holy grail of modern medicine that holds the potential to limit toxicity and increase the efficacy of many therapies. Nanoparticles, roughly a thousand times smaller than the diameter of a human hair, are often used to carry drugs to cells in distinct parts of the body, but some destinations such as kidneys seem more challenging to reach. Kidneys are specialized organs that filter waste products from the blood and control the production of hormones that influence blood pressure and calcium levels. Due to their important functions, diseases affecting kidneys pose major health problems. Scientists have been trying to design new approaches using nanoparticles to safely deliver drugs into kidneys.
For drug delivery, researchers typically use nanoparticles with diameters of 50-200 nm or micro particles with diameters above 1000 nm. A study led by Dr. Daniel Heller focused on investigating mesoscale nanoparticles, which are made of poly(lactic-co-glycolic acid) conjugated to polyethylene glycol (PEG-PLGA) and are 300-400 nm in diameter. They found that these nanoparticles localized in the kidneys 7-times more than in other organs such the liver, lungs, or spleen; these nanoparticles preferentially targeted a specific set of kidney cells called kidney proximal tubule epithelial cells.
To explain these findings, Heller’s team studied how various characteristics of these nanoparticles, including their surface charge (like an electric charge) and surface hydrophilicity (how the particle interacts with water), affect kidney selectivity. They concluded that nanoparticle localization to the kidney is mainly dependent on the relatively large size and hydrophilicity of the particles, but not their surface charge. In a follow-up study in 2018, the researchers demonstrated that selecting the optimal dose of the nanoparticles drastically increased uptake in the kidney. Moreover, localization to the kidney was not dependent on the cargo within the particles, and this method of drug delivery did not cause negative effects on kidney and liver function. The exact mechanism of the selectivity of these nanoparticles for kidney proximal tubule epithelial cells remains unknown, but it may be related to the inability of the kidney’s filtration system to filter out such large particles.
This study shows that finding a sweet spot for nanoparticle properties, including their size, chemical composition, and surface makeup, can help design drug delivery systems that selectively target cells in the kidneys or other organs that are currently hard to reach and improve our ability to treat disease.
How do we tell nanoparticles where to go? Turns out, their size, chemical composition, and surface properties can help us direct them to specific sites — like the kidney.
The Nitty Gritty:
To test the effect of surface charge, mesoscale nanoparticles (MNPs) with a negative charge were formed using PEG-PLGA (A-MNP), while positively charged particles (C-MNPs) were prepared by modifying A-MNPs with didodecyldimethylammonium bromide. Biodistribution studies in mice intravenously injected with A-MNPs and C-MNPs encapsulating fluorescent dye showed no dependence on the charge for kidney localization. To study the effect of the surface hydrophilicity, non-PEGylated anionic PLGA particles were synthesized that predominantly localized in the liver and to a lesser extent in the intestine, suggesting their clearance though the hepatobiliary tract. Tissue localization of fluorescently labeled MNPs was investigated in mice at day 3 after nanoparticle administration using immunofluorescence. Fluorescence was brighter in proximal tubules compared to distal tubules as revealed by co-staining with E-cadherin, a marker of distal tubules. This tissue distribution pattern was confirmed by staining kidneys for the presence of PEG. This showed that both the polymer and the encapsulated dye cargo were present in the proximal tubules. In the follow-up work (Williams et al. 2018), the ability of MNPs to encapsulate both small molecules and larger biomolecules (double-stranded DNA) without affecting their kidney selectivity was shown. Toxicity of MNPs was evaluated over the course of 28 days by measuring blood metabolites (blood urea, nitrogen, and creatinine), which are cleared by healthy kidneys. No changes in the levels of these metabolites were observed in MNP-treated mice compared to control mice, demonstrating the potential of this approach for the development of renal-targeted drugs for the treatment of kidney diseases.
Original Research Articles: