Development of Polymeric Micelles for Site Specific Delivery of Nonsteroidal Anti-Inflammatory Drugs: Effect on the Cardiovascular Risk in an Experimental Model of Arthritis

  • Author / Creator
    Al Lawati, Hanan M
  • Non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenase (COX) enzymes, are among the most widely used medications worldwide with proven efficacy in controlling inflammation and pain associated various disease conditions. The chronic systemic use of most NSAIDs, however, is known to be associated with an increased risk of cardiovascular (CV) events, including myocardial infarction and stroke. Cardiovascular complications associated with the use of NSAIDs are believed to be partly linked to the extent of their exposure to the cardiac tissue among other factors. Research in the field of nanomedicine has shown a remarkable progress in the design of targeted drug delivery systems which can improve drug disposition towards the diseased sites. A systematic search of the scientific literature revealed that reports on the use of such advanced systems for the delivery of NSAIDs that show evidence of improved cardiac safety are lacking. Therefore, in this research work we considered designing nano-formulations for the delivery of diclofenac as a model NSAID for its known serious CV toxicity. The aim was to improve diclofenac pharmacokinetics and biodistribution whereby reducing its accumulation and toxicity in the cardiac tissue. We hypothesize that reduced diclofenac cardiac exposure will lower its CV side effects. Towards this goal, different polymeric micellar formulations based on a shell of poly(ethylene oxide) (PEO) and various hydrophobic polyesters as the hydrophobic core were tried for the encapsulation of diclofenac or its ethyl ester prodrug. The micellar formulations were characterized for size, size distribution, morphology, and in vitro as well as ex vivo drug release. The results pointed to the superiority of polymeric micelles with a core of poly(caprolactone) (PCL) or poly(α-benzyl carboxylate -caprolactone) (PBCL) encapsulating diclofenac ethyl ester as the optimal formulations. In the next step, the biodistribution of the optimal polymeric micellar formulations of diclofenac was investigated in vivo in healthy rats following intravenous (iv) and/or intraperitoneal (ip) administration and compared to that of the free diclofenac. The intravenous administration of the polymeric micellar formulation resulted in prolonged diclofenac systemic circulation and reduced its accumulation in the heart and kidneys compared to the free drug. The polymeric micellar formulations of diclofenac administered through ip route proved to be equally bioavailable as the iv administration. In the following step, multiple dose administration of polymeric micellar formulation of diclofenac in an experimental model of arthritis in rats was employed to assess the anti-inflammatory activity and the safety of the micellar formulation over free drug. To assess the cardiac safety of polymeric micellar formulation versus free drug, the levels of cardioprotective versus cardiotoxic metabolites of arachidonic acid (ArA) was measured in plasma, heart and kidneys following drug administration to these rats with adjuvant arthritis. The results showed that the micellar formulation provided similarly effective therapy for the management of inflammation when compared to the free drug. On the other hand, administration of diclofenac as polymeric micellar formulation reduced the ratio of cardiotoxic over cardioprotective metabolites of ArA in the heart and plasma when compared to the free drug administration. These results provide the first evidence for a potential role in the tissue disposition of diclofenac on its cardiac-safety. It also points to the potential of developed formulations for effective and safe delivery of NSAIDs.

  • Subjects / Keywords
  • Graduation date
    Fall 2019
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
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