Abstract
Tacrolimus has been widely applied to prevent organ rejection after transplantation. However, the conventional pharmaceutical formulation of tacrolimus limits its applications in ocular therapy due to its hydrophobicity and low corneal penetrability. We optimized tacrolimus-loaded methoxy poly (ethylene glycol-block-poly (d, l)-lactic-co-glycolic acid) nanoparticles (TAC-NPs) by simple and effective nanotechnology as a drug delivery system for corneal graft rejection to overcome these drawbacks. The prepared TAC-NPs were 82.9 ± 1.3 nm in size, and the drug loading and encapsulation efficiency were 8.01 ± 0.23% and 80.10 ± 2.33%. Furthermore, New Zealand rabbits were used to analyze the single-dose pharmacokinetics of the TAC-NPs using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). In rats with allogenic penetrating keratoplasty, the administration of TAC-NPs dispersion drops improved the TAC concentrations in the aqueous humor and cornea, consistent with a significantly higher effective inhibition of IL-2, IL-17, and VEGF expression compared with conventional 0.1% tacrolimus drops. Meanwhile, we also compared two different topical administration methods (including eye drop and subconjunctival injection) of TAC-NPs to maximize the sustained release characteristic of NPs. In summary, the small-sized TAC-NPs enhanced transcorneal permeation and absorption of TAC and more effectively inhibited corneal allograft rejection, which indicated that biodegradable polymeric nanomaterials-based drug delivery system had great potential for improving the clinical therapy efficacy of hydrophobic drugs.
Highlights
Irreversible rejection constitutes a high proportion (34%) of the reasons for graft failure, especially for penetrating keratoplasty, which is performed for visual improvement (Williams et al, 2008)
This study aimed to develop a nano-sized and biocompatible drug delivery system for tacrolimus, based on an amphiphilic copolymer consisting of methoxy PEG and PLGA
(ethylene glycol)-block-poly (D, L)-lactic-co-glycolic acid was provided by the laboratory of Professor Fangming Zhu at the School of Chemistry, Sun Yat-sen University, and tacrolimus was obtained from Selleck Chemicals (Shanghai, China)
Summary
Irreversible rejection constitutes a high proportion (34%) of the reasons for graft failure, especially for penetrating keratoplasty, which is performed for visual improvement (Williams et al, 2008). Challenges still exist in the application of tacrolimus because of its limited aqueous solubility and low corneal penetrability (Tamura et al, 2002). Polymeric carriers have the capacity to maintain therapeutic doses and release drugs in a controlled manner with low toxicity and biodegradability. One of the most attractive polymeric NP for biomedicine applications is poly (lactic-co-glycolic acid) (PLGA) (Honda et al, 2013), which does not exhibit electrophysiological or histological toxicity (Moritera et al, 1991; Giordano et al, 1995). In previous studies, Shin et al (2010) prepared TAC-PLGA NPs with a poly (ethylene glycol) (PEG) surface modification and administered the prepared NPs to rats intravenously.
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