Designing dapsone polymer conjugates for controlled drug delivery. (November 2015)

• Record Type: Journal Article
• Authors: Rojo, Luis; Fernandez-Gutierrez, Mar; Deb, Sanjukta; Stevens, Molly M.; San Roman, Julio
• Is Part Of: Acta biomaterialia. Volume 27(2015)
• Page Start: 32
• Page End: 41
• Publication Date: 2015-11
• Subjects: Dapsone -- HEMA -- Polymer–drug conjugate -- Anti-inflammatory polymers -- Nitric oxide inhibition assay; Biomedical materials -- Periodicals; 610.28
• DOI: 10.1016/j.actbio.2015.08.047
• Languages: English
• ISSNs: 1742-7061

Abstract

Graphical abstract: 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. Statement of Significance: 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.