title: Designing dapsone polymer conjugates for controlled drug delivery.
abstract: Polymer-drug conjugates have significantly influenced polymer therapeutics over the last decade via controlled pharmacokinetics. Dapsone (4,4'-diamino diphenylsulphone) is not only widely used in the treatment of leprosy but forms an essential component in the treatment of autoimmune inflammatory diseases and malaria. However, its low bioavailability and non-specific distribution in the body leads to absorption throughout organs including skin, liver, and kidneys that can cause serious side effects. Thus, in this study we report the synthesis of polymer-drug conjugates of dapsone covalently bonded to macromolecular chains towards the development of new bioactive polymeric formulations with anti-inflammatory properties. Dapsone was functionalised with an acrylic moiety in which the acrylamide residue was directly bonded to one of the aromatic rings of dapsone. This functionalisation yielded an unsymmetrical dapsone methacrylamide (DapMA) structure, which on free radical polymerisation and co-polymerisation with HEMA yielded polymers of hydrocarbon macromolecules with pendant dapsone units. Thermal and size-exclusion chromatographic analysis revealed an increase in thermal stabilisation of the homopolymer (p(DapMA)) in comparison to the copolymer (p(Dap-co-HEMA)) with relatively high average molecular weight. The polymer conjugates exhibited high stability with low dapsone release from the polymeric backbone due to hydrolysis. However, a significant anti-inflammatory activity in a nitric oxide inhibition assay confirmed that this property was the consequence of only the macromolecular composition and not related to the release of low molecular weight compounds. Thus, the conjugation of dapsone to macromolecular systems provides a synthetic route to incorporate this drug into polymeric systems, facilitating their development into new anti-inflammatory therapies.
  
  
  CONCLUSIONS
  The dapsone-conjugated methacrylic monomer and polymer derivatives with anti-inflammatory properties described are previously unreported. The scientific impact of this work lies in its potential to expand the clinical applications of dapsone toward the development of advanced anti-inflammatory therapies based on polymer-therapeutic approaches. These approaches facilitate the treatment of existing rare auto-immune and other inflammatory related diseases.
authors: Institute of Polymer Science & Technology, CSIC and CIBER-BBN, Juan de la Cierva, 3, 28006 Madrid, Spain; Division of Tissue Engineering and Biophotonics, King's College London Dental Institute, Guy's Hospital, London, United Kingdom; Department of Materials, Imperial College London, United Kingdom. Electronic address: luis.rojo_del_olmo@kcl.ac.uk.
authors: Luis
authors: L
authors: Rojo
authors: Institute of Polymer Science & Technology, CSIC and CIBER-BBN, Juan de la Cierva, 3, 28006 Madrid, Spain.
authors: Mar
authors: M
authors: Fernandez-Gutierrez
authors: Division of Tissue Engineering and Biophotonics, King's College London Dental Institute, Guy's Hospital, London, United Kingdom.
authors: Sanjukta
authors: S
authors: Deb
authors: Department of Materials, Imperial College London, United Kingdom; Institute for Biomedical Engineering, Imperial College London, United Kingdom; Department of Bioengineering, Imperial College London, United Kingdom.
authors: Molly M
authors: MM
authors: Stevens
authors: Institute of Polymer Science & Technology, CSIC and CIBER-BBN, Juan de la Cierva, 3, 28006 Madrid, Spain.
authors: Julio
authors: J
authors: San Roman
mesh_terms: D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000737:chemistry; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003622:Dapsone / Q000008:administration & dosage* / Q000737:chemistry*; D003692:Delayed-Action Preparations / Q000138:chemical synthesis*; D004058:Diffusion; D015195:Drug Design; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects*; D058726:Nanoconjugates / Q000737:chemistry* / Q000648:ultrastructure; D011102:Polyhydroxyethyl Methacrylate / Q000031:analogs & derivatives* / Q000737:chemistry; D011108:Polymers / Q000737:chemistry
chemical_list: D000893:Anti-Inflammatory Agents; D003692:Delayed-Action Preparations; D058726:Nanoconjugates; D011108:Polymers; D011102:Polyhydroxyethyl Methacrylate; C047731:hydroxyethyl methacrylate-ethyl methacrylate; D003622:Dapsone
keywords: Anti-inflammatory polymers; Dapsone; HEMA; Nitric oxide inhibition assay; Polymer–drug conjugate