1. Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing 210023, China;
2. Department of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China;
3. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China;
4. Department of Chemical and Biomolecular Engineering and Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD 21218, USA;
5. Department of Oncology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA;
6. Center for Nanomedicine, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 400 North Broadway, Baltimore, MD 21231, USA.
* These authors contributed equally to this work
We report here on the covalent conversion of the anti-inflammatory agent ketoprofen into self-assembling prodrugs that enable the effective purification of ketoprofen enantiomers, the improved selectivity and potency of ketoprofen, as well as the formation of one-component drug-bearing supramolecular hydrogels. We found that the ketoprofen hydrogelator could exhibit much-enhanced selectivity for cyclooxygenase 2 (COX-2) over COX-1, reduce the concentration of inflammatory cytokines (IL-1 and TNFα), and induce apoptosis in fibroblast-like synoviocytes while maintaining biocompatibility with healthy chondrocytes. In addition, these anti-inflammatory agent-containing hydrogels demonstrated the ability to retain the therapeutic within a joint cavity after intra-articular injection, exhibiting a slow, steady release into the plasma. We believe that upon further optimization these drug-based injectable supramolecular hydrogels could provide the basis for a local treatment strategy for rheumatoid arthritis and similar conditions.
Keywords: supramolecular hydrogel, self-assembly, drug delivery, peptide-drug conjugate, rheumatoid arthritis.