title: Design, preparation and characterization of pH-responsive prodrug micelles with hydrolyzable anhydride linkages for controlled drug delivery.
abstract: We report a new prodrug micelle-based approach in which a model hydrophobic non-steroidal anti-inflammatory drug (NSAID), ibuprofen (Ibu), is tethered to amphiphilic methoxy polyethylene glycol-polypropylene fumarate (mPEG-PPF) diblock copolymer via hydrolytic anhydride linkages for potential controlled release applications of NSAIDs. Synthesized mPEG-PPF-Ibu polymer drug conjugates (PDCs) demonstrated high drug conjugation efficiency (∼90%) and self-assembled to form micellar nanostructures in aqueous medium with critical micelle concentrations ranging between 16 and 30μg/mL. The entrapment efficiency of Ibu in prepared PDC micelles was as high as 18% (w/w). Crosslinking of prodrug micelles with N,N'-dimethylaminoethyl methacrylate conferred pH-responsive characteristics. pH-responsive PDC micelles averaged 100nm in size at pH 7.4 and exhibited concomitant changes in size upon incubation in physiologically relevant mildly acidic conditions. Ibu release was observed to increase with increasing acidic conditions and could be controlled by varying the amount of crosslinker used. Furthermore, the prepared mPEG-PPF-based micelles demonstrated excellent cytocompatibility and cellular internalization in vitro. More importantly, PDC micelles exerted anti-inflammatory effects by significantly decreasing monosodium urate crystal-induced prostaglandin E2 levels in rabbit synoviocyte cultures in vitro. Cumulatively, our results indicate that this new prodrug micelle approach is promising for NSAID-based therapies in the treatment of arthritis and cancer.
authors.affiliation: Polymer Science Division, BMT Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram 695012, Kerala, India.
authors.forename: Girija
authors.initials: G
authors.lastname: Seetharaman
authors.affiliation: Polymer Science Division, BMT Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram 695012, Kerala, India.
authors.forename: Adarsh R
authors.initials: AR
authors.lastname: Kallar
authors.affiliation: Polymer Science Division, BMT Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram 695012, Kerala, India.
authors.forename: Vineeth M
authors.initials: VM
authors.lastname: Vijayan
authors.affiliation: Polymer Science Division, BMT Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram 695012, Kerala, India.
authors.forename: Jayabalan
authors.initials: J
authors.lastname: Muthu
authors.affiliation: Polymer Science Division, BMT Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram 695012, Kerala, India. Electronic address: sselvam@sctimst.ac.in.
authors.forename: Shivaram
authors.initials: S
authors.lastname: Selvam
mesh_terms: D000812:Anhydrides / Q000737:chemistry; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers; D065546:Drug Liberation; D005650:Fumarates / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D057927:Hydrophobic and Hydrophilic Interactions; D007052:Ibuprofen / Q000008:administration & dosage* / Q000737:chemistry* / Q000494:pharmacology; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011126:Polypropylenes / Q000138:chemical synthesis / Q000494:pharmacology; D011355:Prodrugs / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D012995:Solubility; D013499:Surface Properties
chemical_list: D000812:Anhydrides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004337:Drug Carriers; D005650:Fumarates; D008823:Micelles; D011126:Polypropylenes; D011355:Prodrugs; C000621141:methoxy polyethylene glycol-polypropylene fumarate; C508734:poly(ethylene glycol fumarate); D011092:Polyethylene Glycols; D007052:Ibuprofen
keywords: Anhydride linkages; Controlled release; Crosslinkable; Polypropylene fumarate; Prodrug micelles; pH responsive