SAHA-coupled biocompatible cellulose-based nanoparticles as HDAC-inhibitory drug delivery systems with slow and sustained release behavior.

Nanoparticles (NPs) are being increasingly investigated as drug delivery systems to overcome common challenges in drug therapy, such as rapid drug metabolism and short serum half-life. In this study, a facile method was applied to combine the incorporation of a physiologically cleavable linkage with the introduction of a strained alkyne enabling efficient attachment of SAHA, a histone deacetylase inhibitor, to various structures. SAHA was chemically attached to a cellulose backbone hydrophobized by valproate groups, allowing the formulation of NPs by the emulsion-evaporation technique, resulting in well-defined spherical particles (170 nm) with narrow size distribution (PDI 0.06). Cellular uptake was observed within 15 min but strongest after 6-12 h, revealing that the NPs predominantly reside in the cytoplasm, indicating a cytoplasmic drug release mechanism. SAHA-coupled NPs were biocompatible and non-toxic in vitro and the ex ovo hen's egg model. Quantification of SAHA release in vitro highlighted the initial structural stability of the carrier system despite the forces applied by the high-energy formulation process, and confirmed a slow and sustained release of SAHA for at least 48 h. Furthermore, protein corona analysis revealed qualitative and quantitative differences in protein corona composition depending on structural changes within the cellulose backbone.