Local release of tacrolimus from hydrogel-based drug delivery system is controlled by inflammatory enzymes in vivo and can be monitored non-invasively using in vivo imaging

Abstract

BackgroundLocal drug delivery systems that adjust the release of immunosuppressive drug in response to the nature and intensity of inflammation represent a promising approach to reduce systemic immunosuppression and its side effects in allotransplantation. Here we aimed to demonstrate that release of tacrolimus from triglycerol monostearate hydrogel is inflammation-dependent in vivo. We further report that by loading the hydrogel with a near-infrared dye, it is possible to monitor drug release non-invasively in an in vivo model of vascularized composite allotransplantation.Materials and methodsInflammation was induced by local challenge with lipopolysaccharides in naïve rats 7 days after injection of tacrolimus-loaded hydrogel in the hind limb. Tacrolimus levels in blood and tissues were measured at selected time points. A near-infrared dye was encapsulated in the hydrogel together with tacrolimus in order to monitor hydrogel deposits and drug release in vitro and in vivo in a model of vascularized composite allotransplantation.ResultsInjection of lipopolysaccharides led to increased blood and skin tacrolimus levels (p = 0.0076, day 7 vs. day 12 in blood, and p = 0.0007 in treated limbs, 48 h after injection compared to controls). Moreover, lipopolysaccharides-injected animals had higher tacrolimus levels in treated limbs compared to contralateral limbs (p = 0.0003 for skin and p = 0.0053 for muscle). Imaging of hydrogel deposits and tacrolimus release was achieved by encapsulating near-infrared dye in the hydrogel for 160 days. The correlation of tacrolimus and near-infrared dye release from hydrogel was R2 = 0.6297 and R2 = 0.5619 in blood and grafts of transplanted animals respectively and R2 = 0.6066 in vitro.ConclusionsHere we demonstrate the inflammation-responsiveness of a tacrolimus-loaded hydrogel in vivo. Moreover, we show that encapsulating a near-infrared dye in the hydrogel provides a reliable correlation of tacrolimus and dye release from the hydrogel, and an accessible non-invasive method for monitoring drug release from hydrogel deposits.

Delivery of Rapamycin Using In Situ Forming Implants Promotes Immunoregulation and Vascularized Composite Allograft Survival

“…Moreover, systemic concentrations reached subtherapeutic levels one week after injection and were measurable until POD58 whereas tissue levels were measurable until POD100, demonstrating a lower systemic drug exposure and higher tissue concentrations than FK506 disks 9 . We recently reported the formation of a capsule around injected tacrolimus-loaded hydrogel 26 and the same is reported for other ISFI and biomaterials 27 . It is likely that also Rapa-ISFI are encapsulated after injection.…”

“…It is likely that also Rapa-ISFI are encapsulated after injection. However, we could not retrieve any of the implant in long term surviving rats, suggesting that, similarly to tacrolimus hydrogels 26 , the formation of a fibrous wall did not prevent the interaction of the ISFI with the surrounding tissues. However, the degree of the foreign body reaction triggered by the ISFI injection should be further investigated to support the translation of this approach to patients.…”

Silk based scaffolds with immunomodulatory capacity: anti-inflammatory effects of nicotinic acid

“…26,27 Also, common immunosuppressive drugs like calcineurin inhibitors, glucocorticoids and anti-TNF-α antibodies have been used to promote the functionality and tissue regeneration around the biomaterials. [28][29][30] For instance, inhibiting inflammation by loading collagen-hydrogels with resveratrol improved bone and cartilage regeneration and repair, 31 suppression of IFN-γ and TNF-α was able to enhance bone regeneration 32 and incorporating resolvin D1 in chitosan 3D sponges showed a general decrease in pro-inflammatory cytokines. 33 Regarding silkbased biomaterials, Kweon and colleagues have reported that 4-hexylresorcinol is able to inhibit FBGC formation in response to silk fibroin.…”

Novel immunological and clinical insights in vascularized composite allotransplantation

“…Cellbased therapies might also improve the immunologic outcomes in VCA [50][51][52]. The use of locally administered immunosuppression bears a huge potential to minimize the side-effects of systemic immunosuppression as well [53][54][55][56][57][58]. Recently, a new desensitization protocol including fludarabine, myeloablative irradiation, and bone marrow transplant showed promise in small animal model of VCA, as sensitized transplant candidates are highly prevalent and are major barriers for a successful VCA transplant [59].…”