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

• Published in: PloS one Vol. 13; no. 8; p. e0203409
• Main Authors: Dzhonova, Dzhuliya, Olariu, Radu, Leckenby, Jonathan, Dhayani, Ashish, Vemula, Praveen Kumar, Prost, Jean-Christophe, Banz, Yara, Taddeo, Adriano, Rieben, Robert
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 30.08.2018; Public Library of Science (PLoS)
• Subjects: Animals; Biology and Life Sciences; Drug Delivery Systems; Humans; Hydrogels; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - blood; Immunosuppressive Agents - pharmacokinetics; Inflammation - drug therapy; Male; Medicine and Health Sciences; Physical Sciences; Rats; Rats, Inbred BN; Rats, Inbred Lew; Tacrolimus; Tacrolimus - administration & dosage; Tacrolimus - blood; Tacrolimus - pharmacokinetics; Tissue transplantation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0203409

Local 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. Inflammation 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. Injection 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. Here 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.