In this work, low molecular weight hyaluronan was chemically modified by oleoyl moieties utilising mixed anhydrides methodology. The activation of oleic acid with benzoyl chloride in organic solvents miscible with water was followed by NMR spectroscopy. The product selectivity correlates with the solvent's Hildebrand solubility parameter. Furthermore, the effect of the solvent for the mixed anhydride formation was elucidated by density functional theory (DFT) and showed that the reactions are faster in acetonitrile or alcohols than in hexane. Furthermore, the solvent demonstrated to control the substituent distribution pattern along HA chain during esterification. An even distribution of substituents was observed in reactions performed in water mixed with ethers. The substituent distribution pattern clearly influenced the aggregation behaviour of amphiphilic HA, controlling the stability of the delivery system, while increasing the encapsulation capacity.

Charles University Faculty of Science Department of Physical and Macromolecular Chemistry Hlavova 2030 8 128 40 Prague 2 Czech Republic

Contipro a s Dolni Dobrouč 401 561 02 Dolní Dobrouč Czech Republic

Contipro a s Dolni Dobrouč 401 561 02 Dolní Dobrouč Czech Republic; Charles University Faculty of Science Department of Physical and Macromolecular Chemistry Hlavova 2030 8 128 40 Prague 2 Czech Republic

Department of Computational Chemistry J Heyrovský Institute of Physical Chemistry Czech Academy of Sciences Prague Dolejškova 2155 3 182 23 Prague 8 Czech Republic

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Retinoic Acid Grafted to Hyaluronic Acid Activates Retinoid Gene Expression and Removes Cholesterol from Cellular Membranes