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Letters in Drug Design & Discovery

Author(s): Suneela Dhaneshwar* and Shakuntala Chopade

DOI: 10.2174/1570180819666220430004123

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Conjugation of Mycophenolic Acid with Dextran: A Potential Strategy for Colon-Targeted Delivery for Mitigation of Inflamed Colon in Ulcerative Colitis

Page: [1264 - 1273] Pages: 10

  • * (Excluding Mailing and Handling)

Abstract

Background: Adverse effects induced by upper GIT release of mycophenolic acid (MPA) and its prodrug mycophenolate mofetil (MMF) have created a great deal of concern in the treatment of inflammatory bowel disease (IBD).

Objective: The goal of this work was to create a polymer-based prodrug (MDS) by attaching MPA to dextran to enable colon-targeted drug delivery and, as a result, minimize the adverse effects of MPA and MMF.

Methods: MPA was conjugated with dextran via a bio-cleavable ester bond utilizing the EDCI coupling process. MDS was characterized by spectral analysis. The degree of substitution was estimated by complete hydrolysis of the conjugate in phosphate buffer (pH= 9.0). The prodrug was screened for gastrosparing potential using TNBS-induced colitis model in Wistar rats.

Results: Physicochemical parameters, such as degree of substitution (9.32 mg MPA/100mg of MDS), DSC study (Melting point: 194.3°C), and molecular weight (70307 Da) were determined. The significant mitigating effect of MDS on quantifying parameters of TNBS-induced colitis, i.e., disease activity score rate (0.72±0.35), colon to body weight ratio (0.024±0.003), MPO activity (36.9±0.67mU/100mg of tissue), ulcerogenic potential (2.85±0.08), and histopathological data showed that prodrug restored distorted colonic architecture to normal.

Conclusion: Hydrophilicity was improved, allowing for more effective transport of MPA to the colon. In TNBS-induced colitis, the prodrug was found 1.5 times more efficient than MPA at lowering quantifiable markers of colonic inflammation. Histopathology data showed that MDS might be developed as a potential approach for directing MPA to the colon for the treatment of IBD.

Keywords: Mycophenolic acid, mycophenolate mofetil, dextran, inflammatory bowel disease, colon targeted drug delivery, macromolecular prodrug.

Graphical Abstract

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