Short-chain PEGylation of Organic Small Molecule Dyes Can Regulate Their Clearance in The Kidney
Release date：2020/5/21 10:48:55
Studying the body's different responses to small changes in ultra-small nanomaterials is a very important and fundamental issue. These basic research can not only help us understand our organism at the nano level more clearly, but also have important guiding significance for regulating the functionality and toxicity of nanomaterials. In the past few decades, researchers have worked hard to study the relationship between small changes in hard engineered nanomaterials and biological response and discovered a series of size dependencies in both clearance and disease targeting.
The biocompatibility, amphiphilicity, size controllability, and ability to modify the biological characteristics of modified molecules make PEGylation the most widely used bioconjugation chemistry in medicine. The removal of PEG molecules by the glomeruli also has a size effect, that is, PEG molecules with a molecular weight between 1500-4000 Da can quickly pass through the glomerular filtration membrane, larger PEG molecules with MW in the range of 6000–40 000 Da have a stronger interaction with the glomerular filtration membrane, resulting in their slower renal clearance efficiency. Because of this, PEGylation has become a simple and commonly used chemical method for regulating the blood residence time and clearance kinetics of small molecules. However, because PEG molecules with a molecular weight of less than 10 kDa are rapidly filtered by the glomeruli, it cannot significantly and effectively extend the residence time of small organic molecules in the blood. Based on the current research, it is generally believed that PEGylation with a molecular weight greater than 10,000 Da can effectively regulate (decrease) the kidney clearance rate of small molecules, but low molecular weight (<10000 Da) PEGylation can only makes trivial contributions in tailoring the renal clearance of small molecules. However, there is currently no systematic study on how PEGylation of different sizes and less than 10 kDa affects the renal clearance of small molecules.
In response to the above problems, Professor Zheng Jie of the University of Texas at Dallas and the first author of this review, Dr. Du Bujie, chose a representative near-infrared (NIR) -emitting organic dye (IRDye800CW) for a series of PEGylation of different molecular weights (both less than 10 kDa, PEG22, PEG45, PEG77, PEG110, PEG220) and study their biological response. Traditionally, PEGylation with a larger molecular weight can more effectively regulate kidney clearance of small molecules. However, the team of Zheng Jie discovered a unique molecular weight size effect, namely PEG45 (molecular weight 2100 Da) can maximize kidney clearance of IRDye800CW (figure 1). Further research found that PEG45 is unique because PEG45 not only accelerates the glomerular filtration of IRDye800CW but also reduces its role with basic biological tissues.
It is traditionally believed that PEGylation with a larger molecular weight can more effectively regulate kidney clearance of small molecules. However, the team of Zheng Jie discovered a unique molecular weight size effect, namely PEG45 (molecular weight 2100 Da) can maximize renal clearance of IRDye800CW (figure 1). Further research found that PEG45 is unique because PEG45 not only accelerates the glomerular filtration of IRDye800CW but also reduces its role with basic biological tissues. And the fast kidney transport and reduced nonspecific interactions enable 800CW-PEG45 to noninvasively light up the kidneys with high contrast index. (figure 2)。
Figure 1, Source: American Chemical Society
Figure 2, Source: American Chemical Society
The findings of this work highlight the importance of low molecular weight PEGylation in regulating the flow rate of small organic dyes in organisms, which will expand the application of small molecules in biomedicine. The relevant results of this study were published in Bioconjugate Chemistry and selected as ACS Editors' Choice. This project has received financial support from NIH, Welch Research Foundation.
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Tailoring Kidney Transport of Organic Dyes with Low-Molecular-Weight PEGylation, Bioconjugate Chem, https://doi.org/10.1021/acs.bioconjchem.9b00707