Self-assembly of diclofenac prodrug intonanomicelles for enhancing the anti-inflammatory activity

Assali, Mohyeddin
Shawahna, Ramzi
Alhawareen, Raeda
Najajreh, Haifa
Rabaya, Oraib
Faroun, Maryam
Zyoud, Ahed
Hilald, Hikmat
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Royal Society of Chemistry
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for the treatment of various types ofinflammatory conditions. Diclofenac is a very common NSAID that is utilized to relieve pain and reduce feverand, most importantly, inflammation. However, it suffers from low water solubility and a low dissolutionprofile. Therefore, we aim to develop a new drug delivery system based on the synthesis of amphiphilicstructures that are capable of self assembling into nano-micelles which will be a water-soluble deliverysystem for the diclofenac. The amphiphilic structure consists of a hydrophilic moiety of triethylene glycol(TEG), polyethylene glycol PEG 400, or PEG 600 linked with the hydrophobic drug diclofenac throughan ester linkage. The diclofenac derivatives were successfully synthesized as confirmed by nuclearmagnetic resonance. Moreover, the formation of the micellar structure of the synthesized amphiphilicderivatives was confirmed by atomic force microscopy obtaining a spherical shape of the micelles withaverage diameters of 200 nm for Dic-PEG400-Dic, and 110 nm for Dic-PEG600-Dic. The critical micelleconcentration has been determined as 2.7 10 3mg mL 1for Dic-PEG400-Dic, and 1 10 4mg mL 1for Dic-PEG600-Dic. Thein vitrodiclofenac release profile by esterase enzyme was conducted andshowed almost complete conversion to free diclofenac within 35 h in the case of Dic-PEG400-Dicmicelles and more than 85% of Dic-PEG600-Dic micelles. Then the anti-inflammatory activity wasdetermined by testing the TNF-aproduction in LPS-stimulated Balb/c mice. Diclofenac micellessignificantly suppressed TNF-aproduction after a 5 mg kg 1dose was given. The developed micellesshowed TNF-ainhibition up to 87.4% and 84% after 48 hours of treatment in the case of Dic-PEG400-Dic and Dic-PEG600-Dic micelles respectively in comparison to 42.3% in the case of diclofenac alone.Dic-PEG400-Dic micelles showed the most potent anti-inflammatory activity with improved TNF-asuppression through time progress. Therefore, the developed nano-micelles provide a facile syntheticapproach to enhance diclofenac water solubility, improve the anti-inflammatory effect and achievea sustained release profile to get better patient compliance.