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. 2021 Jul 28:9:77-91.
doi: 10.1016/j.bioactmat.2021.07.027. eCollection 2022 Mar.

Effectiveness of an ocular adhesive polyhedral oligomeric silsesquioxane hybrid thermo-responsive FK506 hydrogel in a murine model of dry eye

Yi Han  1 , Lu Jiang  2 , Huihui Shi  3   4 , Chenfang Xu  5 , Minting Liu  5 , Qingjian Li  1 , Lan Zheng  1 , Hong Chi  6 , Mingyue Wang  6 , Zuguo Liu  1 , Mingliang You  7 , Xian Jun Loh  4 , Yun-Long Wu  5 , Zibiao Li  2   8 , Cheng Li  1
Affiliations

Effectiveness of an ocular adhesive polyhedral oligomeric silsesquioxane hybrid thermo-responsive FK506 hydrogel in a murine model of dry eye

Yi Han et al. Bioact Mater. .

Abstract

Dry eye is a common ocular disease that results in discomfort and impaired vision, impacting an individual's quality of life. A great number of drugs administered in eye drops to treat dry eye are poorly soluble in water and are rapidly eliminated from the ocular surface, which limits their therapeutic effects. Therefore, it is imperative to design a novel drug delivery system that not only improves the water solubility of the drug but also prolongs its retention time on the ocular surface. Herein, we develop a copolymer from mono-functional POSS, PEG, and PPG (MPOSS-PEG-PPG, MPEP) that exhibits temperature-sensitive sol-gel transition behavior. This thermo-responsive hydrogel improves the water solubility of FK506 and simultaneously provides a mucoadhesive, long-acting ocular delivery system. In addition, the FK506-loaded POSS hydrogel possesses good biocompatibility and significantly improves adhesion to the ocular surface. In comparison with other FK506 formulations and the PEG-PPG-FK506 (F127-FK506) hydrogel, this novel MPOSS-PEG-PPG-FK506 (MPEP-FK506) hydrogel is a more effective treatment of dry eye in the murine dry eye model. Therefore, delivery of FK506 in this POSS hydrogel has the potential to prolong drug retention time on the ocular surface, which will improve its therapeutic efficacy in the management of dry eye.

Keywords: Dry eye; FK506; Ocular adhesive; Polyhedral oligomeric silsesquioxane.

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Conflict of interest statement

None of the content of the present paper has been published or submitted to any other journal. All the listed authors reviewed and approved the content prior to submission. None of the authors have any ethical conflicts of interest.

Figures

Image 1
Graphical abstract
Scheme 1
Scheme 1
(a) Synthesis of MPEP by polyaddition and (b) illustration of the self-assembly of MPEP and hydrogel formation in water.
Fig. 1
Fig. 1
(a) 1H NMR spectra of MPOSS (blue line) and 2MPEP (red line) in CDCl3. (b) FT-IR spectra of MPOSS, PEG, PPG, and three MPEP copolymers. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 2
Fig. 2
(a) TGA curves of MPOSS, PEG, PPG and three MPEP copolymers. (b) DSC cooling curves of MPOSS, PEG, and MPEP copolymers. (c) DSC heating curves of MPOSS, PEG, and MPEP copolymers. (d) Enlarged graph of the dotted box in (c), indicates the glass transition temperature (Tg) range of MPEP copolymers.
Fig. 3
Fig. 3
(a) UV–vis spectra of aqueous DPH-1MPEP solution at a series of MPEP concentrations at room temperature. (b) CMC determination of 1MPEP by extrapolation. (c) Transmittance at 500 nm of aqueous MPEP solution (2 wt%) with increasing temperature. (d) Size distribution of micelles in aqueous 1MPEP solution (0.5 wt%) at three temperatures. (e) Particle size in relation to temperature and concentration in aqueous 1MPEP solution. (f) Particle size in relation to MPEP type and concentration in aqueous solution at 70 °C.
Fig. 4
Fig. 4
Phase diagram of (a) 1MPEP and (b) Pluronic F127. Rheological properties of 1MPEP (6 wt%) during a (c) temperature sweep and (d) temperature ramp.
Fig. 5
Fig. 5
(a) Determination of the light transmittance of the 1MPEP, 2MPEP, F127, and Commercial carbomer hydrogels. (b) In vitro degradation of the 1MPEP, 2MPEP, and F127 hydrogels. (c) In vitro drug release behavior of FK506 from the 1MPEP, 2MPEP, and F127 hydrogels. (d) In vitro cytotoxicity of the hydrogels toward HCE cells.
Fig. 6
Fig. 6
Surface plasmon resonance was used to evaluate the in vitro binding affinity of mucin and (a) 1MPEP, (b) 2MPEP, (c) F127 polymers.
Fig. 7
Fig. 7
In vivo evaluation of the hydrogels. (a) Slit lamp and (b) OCT images of the hydrogels on the ocular surface after blinking (the red arrow indicates the hydrogel position on the cornea and the green arrow indicates the hydrogel detached from the cornea). (c) Ocular pharmacokinetics studies (n = 4). Data are expressed as the mean ± S.E.M. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 8
Fig. 8
Images of (a) OGD staining from different groups and (c) OGD intensity statistics (n = 5–7). (b) Tear production was measured using the phenol red thread test (n = 6). (d) Representative images of MMP-3 immunofluorescent staining (the red rectangle shows the area of corneal epithelium MMP-3 immunofluorescence staining). MMP3 staining (e) (n = 5–6) and expression (n = 3–4) (f) quantified. Data are expressed as the mean ± S.E.M. *P < 0.05, **P < 0.01, ***P < 0.001. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 9
Fig. 9
Histological images of the conjunctiva. (a) PAS staining showing goblet cells in the conjunctiva from each group (the red arrow indicates the goblet cells). (b) CD4 staining showing the number and position of CD4+ T cells infiltrating the conjunctiva from each group (the red arrow indicates CD4+ T cells). Quantitative analysis of the (c) goblet cell counts (n = 8–10) and (d) CD4 protein expression level in the conjunctiva (n = 3). Data are expressed as the mean ± S.E.M. *P < 0.05, **P < 0.01, ***P < 0.001. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Fig. 10
Fig. 10
Safety analysis of hydrogel administration to the ocular surface. (a) Fundus images and (b) fluorescence fundus angiography of eyes from different groups. (c) and (d) OCT images showing the structure and morphology of the retina and cornea (red line indicates a scanning section of the murine retina and the red rectangle shows a partial view of the retina). There is no difference in retinal (e) and corneal (f) thicknesses among the groups (n = 4). Data are expressed as the mean ± S.E.M. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
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