Six-month effective treatment of corneal graft rejection

Abstract

Topical corticosteroid eye drop is the mainstay for preventing and treating corneal graft rejection. While the frequent topical corticosteroid use is associated with risk of intraocular pressure (IOP) elevation and poor patient compliance that leads to graft failure and the requirement for a repeated, high-risk corneal transplantation. Here, we developed dexamethasone sodium phosphate (DSP)–loaded dicarboxyl-terminated poly(lactic acid) nanoparticle (PLA DSP-NP) formulations with relatively high drug loading (8 to 10 weight %) and 6 months of sustained intraocular DSP delivery in rats with a single dosing. PLA DSP-NP successfully reversed early signs of corneal rejection, leading to rat corneal graft survival for at least 6 months. Efficacious PLA DSP-NP doses did not affect IOP and showed no signs of ocular toxicity in rats for up to 6 months. Subconjunctival injection of DSP-NP is a promising approach for safely preventing and treating corneal graft rejection with the potential for improved patient adherence.

Combination Nanomedicine Strategy for Preventing High-Risk Corneal Transplantation Rejection

“…Previously, we developed dexamethasone sodium phosphate (DSP)-loaded PLA-2COOH nanoparticle (PLA DSP-NP) that provided 6 month DSP release in rat eyes following a single subconjunctival (SCT) injection. 19 Here, we demonstrated that a single dosing of PLA DSP-NP, alone, prevented rat HR graft rejection for 6 months. We further engineered an axitinib-loaded nanowafer (Axi NW) for topical delivery of the TKI Axi.…”

“…Previously, we developed a DSP- months. 19 To formulate PLA DSP-NP, the DSP−Zn complex was first prepared by mixing the two aqueous solutions, and the forming efficiency was more than 95% (Figure S1A). XRD analysis indicated that DSP displayed a classical crystalline structure with specific reflection in the range of 5−45°, whereas it switched to amorphous status after forming the DSP−Zn complex, indicating the coordination effects between DSP and zinc ions (Figure 2A).…”

“…21 The PLA-2COOH 8.2 kDa DSP-NP could achieve more than 3 months in vitro drug release as well as maintaining the more than 7 wt % DSP loading. 19 Furthermore, the PLA-2COOH 8.2 kDa NP provided sustained drug delivery in rat eyes for 6 months after a single SCT injection. 19 Herein, we used PLA-2COOH 8.2 kDa DSP-NP (PLA DSP-NP) for the later efficacy studies.…”

Long‐Acting Ocular Injectables: Are We Looking In The Right Direction?

“…A single subconjunctival injection of PLA DSP nanoparticles effectively reversed early signs of corneal graft rejection and maintained the graft survival for at least 6 months in rats. [ 117 ] To further prolong the release of hydrophobic small molecules, PCL can be leveraged to form LAIs as it is more hydrophobic than PLGA and hence degrades at a slower rate. [ 118 ] Indeed, rapamycin and omidenapag isopropyl (DE‐117) were released from PCL for 16 and 24 weeks, respectively.…”

“…[115,116] Meng et al formulated long-acting PLA-based microparticles for the sustained release of dexamethasone disodium phosphate (DSP) to prevent corneal graft failure. [117] They increased the encapsulation efficiency of DSP via the formation of an ionic bridge between the terminal carboxyl groups of their customized PLA and the phosphate groups from DSP using zinc. A single subconjunctival injection of PLA DSP nanoparticles effectively reversed early signs of corneal graft rejection and maintained the graft survival for at least 6 months in rats.…”