A single injection of DSP-NP prevented corneal allograft rejection for 6 months.

Abstract

Purpose : Immunological rejection is the leading cause of corneal transplantation failure. Topical corticosteroid eyedrops are prescribed for preventing and treating corneal graft immunological rejection, but frequent dosing is required. We aim to develop a long-lasting dexamethasone sodium phosphate (DSP) loaded nanoparticle (DSP-NP) that provides sustained drug levels to the eye and achieve up to 6 months efficacy for preventing corneal allograft rejection following one single subconjunctival (SCT) injection.

Methods : DSP has been loaded into dicarboxyl-poly(D,L-lactic acid) (PLA-2COOH_8.2kDa) polymeric nanoparticles (DSP-NP) via a zinc ion-bridge method (Fig.1A). The DSP-NP was characterized in particle size and surface charge, morphology, drug content and in vitro drug release profile. In vivo ocular PK study was conducted after a SCT injection of DSP-NP (600 µg DSP) into adult SD rats, DSP and dexamethasone (DEX) concentrations in ocular tissues were quantified using LC/MS/MS. Corneal allograft rejection model was setup by transplanting a Fisher rat cornea graft to a Lewis rat cornea bed, and a single SCT injection of DSP-NP (400 µg DSP) was given immediately after the PKP surgery followed by routine clinical observation (cornea opacity, edema and neovascularization).

Results : The DSP-NP were spherical with particle size around 200 nm (Fig. 1B) and nearly neutral surface charge (-3.6±0.2 mV). DSP-NP provided 8 wt% drug loading and sustained in vitro drug release for at least 3 months (we call it as 3m DSP-NP) (Fig. 1C). 3m DSP-NP (600 µg DSP) provide sustained level of DSP and DEX in rat eyes for 6 months after a single SCT injection. One single SCT injection of 3m DSP-NP (400 µg DSP) successfully prevented rat corneal allograft rejection for 6 months as evidenced by clear cornea without edema over 6 months (Fig. 1D). In comparison, untreated graft was rejected at 7 days after the surgery (POD7) as revealed by corneal graft completely lost its transparency with serve edema and neovascularization invading from bed to the graft (Fig. 1E).

Conclusions : The SCT injection of DSP-NP can be a promising method for corneal transplantation immunological rejection with improved patient adherence and excellent outcomes.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

 

Fig. 1: (A) Scheme, (B) TEM, and (C) In vitro drug release of 3m DSP-NP. (D) A SCT injection of 3m DSP-NP (400 µg DSP) prevented corneal graft rejection for 6 months (n=7). (E) Control.