Abstract
For many chronic fibrotic conditions, there is a need for local, sustained antifibrotic drug delivery. A recent trend in the pharmaceutical industry is the repurposing of approved drugs. This paper investigates drugs that are classically used for anthelmintic activity (pyrvinium pamoate (PYR)), inhibition of adrenal steroidgenesis (metyrapone (MTP)), bactericidal effect (rifampicin (RIF), and treating iron/aluminum toxicity (deferoxamine mesylate (DFOA)), but are also under investigation for their potential positive effect in wound healing. In this role, they have not previously been tested in a localized delivery system suitable for obtaining the release for the weeks-to-months timecourse needed for wound resolution. Herein, two cyclodextrin-based polymer systems, disks and microparticles, are demonstrated to provide the long-term release of all four tested non-conventional wound-healing drugs for up to 30 days. Higher drug affinity binding, as determined from PyRx binding simulations and surface plasmon resonance in vitro, corresponded with extended release amounts, while drug molecular weight and solubility correlated with the improved drug loading efficiency of cyclodextrin polymers. These results, combined, demonstrate that leveraging affinity interactions, in combination with drug choice, can extend the sustained release of drugs with an alternative, complimentary action to resolve wound-healing and reduce fibrotic processes.
Highlights
In many cases, from rheumatic diseases to liver fibrosis, unresolved wound healing can contribute to fibrosis [1,2]
The diisocyanate-crosslinked CD polymer depots are known to be refillable in vivo [15,48], even through biofilms and in the presence of serum molecules [10,26], yet the effects of fibrotic processes such as collagen deposition and immune system activity on drug refilling into cyclodextrin polymer depots have yet to be determined
Polymer microparticles and disks were synthesized from either inclusion-complex-forming β-CD or linear/branched dextran
Summary
From rheumatic diseases to liver fibrosis, unresolved wound healing can contribute to fibrosis [1,2]. Fibrosis may affect a range of internal organs with little indication until later stages. This can necessitate surgery, lead to hospital readmission and introduce other costly complications. Better understanding of the pathways involved in wound resolution is increasing the opportunities for alternative uses of United States Food and Drug Administration approved pharmaceuticals to improve wound healing and reduce or even prevent fibrotic progression. Patient compliance and dosing regimens to maintain effects may be impractical for the wound resolution timeline, which can span months [5,6]. We examine polymer depots and drug combinations which can extend therapeutic effect to timelines matching wound resolution to improve anti-fibrotic outcomes
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