Several
drug–fatty acid (FA) prodrugs have been reported
to exhibit desirable physicochemical and pharmacological profile;
however, comparative beneficial effects rendered by different FAs
have not been explored. In the present study, four different FAs (linoleic
acid, oleic acid, palmitic acid, and α-lipoic acid) were selected
based on their chain length and degree of unsaturation and conjugated
to Lisofylline (LSF), an antidiabetic molecule to obtain different
drug–FA prodrugs and characterized for molecular weight, hydrophobicity,
purity, self-assembly, and efficacy in vitro and in vivo in type 1 diabetes model. Prodrugs demonstrated
a 2- to 6-fold increase in the plasma half-life of LSF. Diabetic animals
treated with prodrugs, once daily for 5 weeks, maintained a steady
fasting blood glucose level with a significant increase in insulin
level, considerable restoration of biochemical parameters, and preserved
β-cells integrity. Among the different LSF-FA prodrugs, LSF-OA
and LSF-PA demonstrated the most favorable physicochemical, systemic
pharmacokinetic, and pharmacodynamic profiles.