Single subcutaneous injection of the minocycline nanocomposite-loaded thermosensitive hydrogel for the effective attenuation of experimental autoimmune uveitis

Abstract

Autoimmune uveitis induces a serious pathological and inflammatory response in the retina/choroid and results in vision impairment and blindness. Here, we report a minocycline (Mino) nanocomposite-loaded hydrogel offering a high drug payload and sustained drug release for the effective control of ocular inflammation via a single subcutaneous injection. In the presence of divalent cations (i.e., Ca2+), Mino was found to co-assemble with a phosphorylated peptide (i.e., NapGFFpY) via electrostatic interaction and consequently generating Mino nanocomposite. The drug entrapment efficiency (EE) of the Mino nanocomposite varied from 29.93 ± 0.76% to 67.90 ± 6.57%, depending on different component concentrations. After incorporation into 30 wt% poly (D,L-lactide)-b-poly (ethylene glycol)-b-poly (D,L-lactide) (PDLLA-PEG-PDLLA) thermosensitive hydrogel, the resulting Mino nanocomposite-loaded hydrogel provided a sustained drug release over 21 days. In the experimental autoimmune uveitis (EAU) rat model, a single subcutaneous injection of the Mino nanocomposite-loaded hydrogel effectively alleviated ocular inflammation in a dose-dependent manner. As indicated by optical coherence tomography (OCT) and electroretinogram (ERG) measurements, the Mino nanocomposite-loaded hydrogel treatment not only remarkably reduced destruction of the retina by EAU, but also greatly rescued retinal functions. Moreover, the proposed Mino nanocomposite-loaded hydrogel exerted its therapeutic effect on EAU primarily through a significant reduction of the influx of leukocytes and Th17 cells as well as suppression of microglia activation and apoptosis in the retina. Overall, the proposed Mino nanocomposite-loaded hydrogel might be a promising strategy for the clinical management of EAU.