title: pH-sensitive polymeric micelles for targeted delivery to inflamed joints.
abstract: Effective treatment for rheumatoid arthritis is hindered by the lack of drugs that selectively target inflamed joints. Liposomes, nanoparticles and conventional micelles loaded with limited amounts of drugs may be unstable in the circulation and result in uncontrolled drug release kinetics. Here we developed a new drug delivery system of pH-sensitive polymeric micelles based on an acid-labile hydrazone bond. Amphiphilic conjugates of a PEG-based derivative and the hydrophobic drug prednisolone (PD) self-assembled into PD micelles with a drug loading of 19.29%. When the micelles reached the acidic environment of synovial fluid, the hydrazone bonds hydrolyzed, releasing free PD. Intravenous injection of PD micelles into mice with collagen-induced arthritis led to PD accumulation in affected joint tissues. PD concentrations in plasma and joints of arthritic mice were significantly higher after injection with PD micelles than after injection with free PD. The enhancement effect in joints was 4.63-fold based on the area under the concentration-time curve and 2.50-fold based on the maximum concentration (Cmax). In vivo pharmacodynamics experiments showed PD micelles to have better anti-inflammatory and disease-modifying effects than free PD. Our results indicate the promise of PD micelles for targeted drug delivery in inflammatory disease.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, PR China.
authors.forename: Chunhong
authors.initials: C
authors.lastname: Li
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, PR China.
authors.forename: Hanmei
authors.initials: H
authors.lastname: Li
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, PR China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, PR China.
authors.forename: Meiling
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, PR China.
authors.forename: Man
authors.initials: M
authors.lastname: Li
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, PR China.
authors.forename: Tao
authors.initials: T
authors.lastname: Gong
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, PR China.
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, PR China. Electronic address: xunsun22@gmail.com.
authors.forename: Xun
authors.initials: X
authors.lastname: Sun
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000473:pathology; D003692:Delayed-Action Preparations / Q000737:chemistry*; D016503:Drug Delivery Systems; D065546:Drug Liberation; D006863:Hydrogen-Ion Concentration; D007596:Joints / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008823:Micelles; D011092:Polyethylene Glycols / Q000737:chemistry; D011239:Prednisolone / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D013501:Surface-Active Agents / Q000737:chemistry
chemical_list: D000893:Anti-Inflammatory Agents; D003692:Delayed-Action Preparations; D008823:Micelles; D013501:Surface-Active Agents; D011092:Polyethylene Glycols; D011239:Prednisolone
keywords: Acidosis; PD micelles; Rheumatoid arthritis; Targeting