A Reversibly Thermoresponsive, Theranostic Nanoemulgel for Tacrolimus Delivery to Activated Macrophages: Formulation and In Vitro Validation

Abstract

Despite long-term immunosuppression, organ transplant recipients face the risk of immune rejection and graft loss. Tacrolimus (TAC, FK506, Prograf®) is an FDA-approved keystone immunosuppressant for preventing transplant rejection. However, it undergoes extensive first-pass metabolism and has a narrow therapeutic window, which leads to erratic bioavailability and toxicity. Local delivery of TAC directly into the graft, instead of systemic delivery, can improve safety, efficacy, and tolerability. Macrophages have emerged as promising therapeutic targets as their increased levels correlate with an increased risk of organ rejection and a poor prognosis post-transplantation. Here, we present a locally injectable drug delivery platform for macrophages, where TAC is incorporated into a colloidally stable nanoemulsion and then formulated as a reversibly thermoresponsive, pluronic-based nanoemulgel (NEG). This novel formulation is designed to undergo a sol-to-gel transition at physiological temperature to sustain TAC release in situ at the site of local application. We also show that TAC-NEG mitigates the release of proinflammatory cytokines and nitric oxide from lipopolysaccharide (LPS)-activated macrophages. To the best of our knowledge, this is the first TAC-loaded nanoemulgel with demonstrated anti-inflammatory effects on macrophages in vitro.

Novel Therapeutic Hybrid Systems Using Hydrogels and Nanotechnology: A Focus on Nanoemulgels for the Treatment of Skin Diseases

“…Aside from controlled drug delivery, nanoemulgels exhibit several advantages over alternative topical formulations, which include compatibility with the skin, high viscosity, adhesiveness, good spreadability, and longlasting therapeutic effects [139,140]. In what concerns common excipients that are used as part of a nanoemulgel's composition, oil selection is usually dependent on the intended hydrophobicity, viscosity, permeability, and stability in the formulated nanoemulsion, but oils from natural sources, such as oleic acid, are commonly used, or chemically modified oils with medium chain mono-, di-, or tri-glycerides, such as Capryol ® 90, Miglyol ® 812, or Labrafac™ [141][142][143]. Additionally, there are several categories of surfactants, and among the most used are cationic surfactants (such as amines and quaternary ammonium compounds, or lecithin), anionic surfactants (such as sodium bis-2-ethylhexylsulfosuccinate, or sodium dodecyl sulfate), zwitterionic surfactants (such as phospholipids), and nonionic surfactants (such as Tweens, Lauroglycol ® 90, Cremophor ® EL, or Cremophor ® RH 40) [137,144,145].…”