The mode of dexamethasone decoration influences avidin-nucleic-acid- nano-assembly organ biodistribution and in vivo drug persistence

Avidin-Nucleic-Acid-NanoASsemblies (ANANAS) possess natural tropism for the liver and, when loaded with dexamethasone, reduce clinical progression in an autoimmune hepatitis murine model. Here, we investigated the linker chemistry (hydrazide-hydrazone, Hz-Hz, or carbamate hydrazide-hydrazone, Cb-Hz bond) and length (long, 5 kDa PEG, or short, 5-6 carbons) in biotin-dexamethasone conjugates used for nanoparticle decoration through in vitro and in vivo studies. All four newly synthesized conjugates released the drug at acidic pH only. In vitro, the Hz-Hz and the PEG derivatives were less stable than the Cb-Hz and the short chain ones, respectively. Once injected in healthy mice, dexamethasone location in the PEGylated ANANAS outer layer favors liver penetration and resident macrophages uptake, while drug Hz-Hz, but not Cb-Hz, short spacing prolongs drug availability. In conclusion, the tight modulation of ANANAS decoration can significantly influence the host interaction, paving the way for the development of steroid nanoformulations suitable for different pharmacokinetic profiles. (c) 2021 Elsevier Inc. All rights reserved.

Automated summary

This study investigated the effects of linker chemistry and length on the nanoparticle decoration of biotin-dexamethasone conjugates. The results showed that all four synthesized conjugates released the drug at acidic pH only. The Hz-Hz and PEG derivatives were found to be less stable in vitro. In vivo experiments showed that dexamethasone located in the PEGylated ANANAS outer layer facilitated liver penetration and macrophage uptake, while the Hz-Hz linker prolonged drug availability.