Designing novel bioconjugates of hydroxyethyl cellulose and salicylates for potential pharmaceutical and pharmacological applications

• Published in: International journal of biological macromolecules 2017-10, Vol.103, p.441-450
• Main Authors: Abbas, Khawar, Amin, Muhammad, Hussain, Muhammad Ajaz, Sher, Muhammad, Bukhari, Syed Nasir Abbas, Jantan, Ibrahim, Edgar, Kevin J.
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - metabolism; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Cell Line; Cellulose - analogs & derivatives; Cellulose - chemistry; Cytokines - secretion; Cytotoxicity; Drug Design; Drug Stability; Half-Life; Hydrophobic and Hydrophilic Interactions; Hydroxyethyl cellulose; Immunomodulatory assay; Kinetics; Male; Pharmacokinetics; Prodrugs - metabolism; Rabbits; Salicylates; Salicylates - chemistry; Salicylates - metabolism; Salicylates - pharmacokinetics; Salicylates - pharmacology; Temperature; Tissue Distribution
• ISSN: 0141-8130; 1879-0003
• DOI: 10.1016/j.ijbiomac.2017.05.061

•Fabrication of hydroxyethyl cellulose (HEC) based prodrugs of salicylates.•Pharmacokinetics of HEC-based salicylic acid (SA) and aspirin (ASP) prodrugs.•Self-assembly of HEC-SA and HEC-ASP conjugates.•Anti-inflammatory, cytotoxicity and immunomodulatory assays of prodrugs.•Thermal stability of HEC-SA and HEC-ASP conjugates. This deals with fabrication of macromolecular prodrugs (MPDs) of salicylic acid (SA) and aspirin (ASP) based on a hydrophilic cellulose ether, hydroxyethyl cellulose (HEC). Degrees of substitution (DS) of SA and ASP per HEC repeating unit (HEC-RU) were achieved ranging from 0.60 to 2.18 and 0.53 to1.50, respectively. The amphiphilic HEC-SA conjugate 2 assembled into nanowire-like structures, while HEC-ASP conjugate 6 formed nanoparticles (diameter 300–00nm) at a water/DMSO interface. After oral administration in rabbit models, conjugates 2 and 6 showed plasma half-life of 6.96 and 7.01h with maximum plasma concentration (Cmax) of 15.27 and 23.01μg L−1, respectively, and each reached peak plasma concentration (tmax) at 4.0h. Immunomodulatory assays (interleukin 6 and tumor necrosis factor-α values) revealed that anti-inflammatory properties of SA and ASP were unaltered in conjugates. Swelling inhibition of 61 and 71% was observed for conjugates 2 and 6, respectively, in a carrageenan induced paw edema test. Cytotoxic profiling (MTT assay) showed that conjugates were safe for administration in the concentration range of 2–10mM up to 24h. Thermal analyses revealed that Tdm values of SA and ASP conjugates were increased by 99 and 154̊C, respectively, indicating extraordinary thermal stability imparted to drugs after MPD formation.