Functional Peptide-Loaded Gelatin Nanoparticles as Eyedrops for Cornea Neovascularization Treatment

Ya-Chun Chu; Hsu-Wei Fang; Yu-Yi Wu; Yu-Jun Tang; Erh-Hsuan Hsieh; YiZhou She; Che-Yi Chang; I-Chan Lin; Yin-Ju Chen; Guei-Sheung Liu; Ching-Li Tseng

doi:10.2147/IJN.S398769

Functional Peptide-Loaded Gelatin Nanoparticles as Eyedrops for Cornea Neovascularization Treatment

Int J Nanomedicine. 2023 Mar 23:18:1413-1431. doi: 10.2147/IJN.S398769. eCollection 2023.

Authors

Ya-Chun Chu^#^{1

2}, Hsu-Wei Fang^#^{2

3}, Yu-Yi Wu¹, Yu-Jun Tang¹, Erh-Hsuan Hsieh¹, YiZhou She⁴, Che-Yi Chang¹, I-Chan Lin^{5

6}, Yin-Ju Chen^{1

7

8

9}, Guei-Sheung Liu^{1

10

11

12}, Ching-Li Tseng^{1

8

9

13}

Affiliations

¹ Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei City, Taiwan.
² Department of Chemical Engineering and Biotechnology, National Taipei University of Technology, Taipei City, Taiwan.
³ Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli County, Taiwan.
⁴ School of Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei City, Taiwan.
⁵ Department of Ophthalmology, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan.
⁶ Department of Ophthalmology, School of Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan.
⁷ Department of Radiation Oncology, Taipei Medical University Hospital, Taipei City, Taiwan.
⁸ International Ph.D. Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei City, Taiwan.
⁹ Center for Precision Medicine and Translational Cancer Research, Taipei Medical University Hospital, Taipei City, Taiwan.
¹⁰ Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, VIC, Australia.
¹¹ Ophthalmology, Department of Surgery, University of Melbourne, East Melbourne, VIC, Australia.
¹² Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.
¹³ Research Center of Biomedical Device, College of Biomedical Engineering, Taipei Medical University, Taipei City, Taiwan.

^# Contributed equally.

Abstract

Background: Corneal neovascularization (NV) is a process of abnormal vessel growth into the transparent cornea from the limbus and can disturb the light passing through the cornea, resulting in vision loss or even blindness. The use of nanomedicine as an effective therapeutic formulation in ophthalmology has led to higher drug bioavailability and a slow drug release rate. In this research, we designed and explored the feasibility of a new nanomedicine, gp91 ds-tat (gp91) peptide-encapsulated gelatin nanoparticles (GNP-gp91), for inhibiting corneal angiogenesis.

Methods: GNP-gp91 were prepared by a two-step desolvation method. The characterization and cytocompatibility of GNP-gp91 were analyzed. The inhibition effect of GNP-gp91 on HUVEC cell migration and tube formation was observed by an inverted microscope. The drug retention test in mouse cornea was observed by in vivo imaging system, fluorescence microscope, and DAPI/TAMRA staining. Finally, the therapeutic efficacy and evaluation of neovascularization-related factors were conducted through the in vivo corneal NV mice model via topical delivery.

Results: The prepared GNP-gp91 had a nano-scale diameter (550.6 nm) with positive charge (21.7 mV) slow-release behavior (25%, 240hr). In vitro test revealed that GNP-gp91 enhanced the inhibition of cell migration and tube formation capacity via higher internalization of HUVEC. Topical administration (eyedrops) of the GNP-gp91 significantly prolongs the retention time (46%, 20 min) in the mouse cornea. In chemically burned corneal neovascularization models, corneal vessel area with a significant reduction in GNP-gp91 group (7.89%) was revealed when compared with PBS (33.99%) and gp91 (19.67%) treated groups via every two days dosing. Moreover, GNP-gp91 significantly reduced the concentration of Nox2, VEGF and MMP9 in NV's cornea.

Conclusion: The nanomedicine, GNP-gp91, was successfully synthesized for ophthalmological application. These data suggest that GNP-gp91 contained eyedrops that not only have a longer retention time on the cornea but also can treat mice corneal NV effectively delivered in a low dosing frequency, GNP-gp91 eyedrops provides an alternative strategy for clinical ocular disease treatment in the culture.

Keywords: control release; corneal neovascularization; eye drops; gelatin; gp91 peptide; nanoparticles; ocular retention.

MeSH terms

Animals
Cornea
Corneal Neovascularization* / drug therapy
Gelatin / pharmacology
Mice
Nanoparticles* / chemistry
Ophthalmic Solutions / pharmacology
Peptides / pharmacology

Substances

Gelatin
Ophthalmic Solutions
Peptides

Grants and funding

This work was supported by grants from the Ministry of Science and Technology, Taiwan (grant number: MOST 106-2628-E-038 -001 -MY3 and MOST 110-2314-B-038 -044 -MY2). This work was also partially supported by a grant from the Integrated Research Grant in Health and Medical Sciences from the National Health Research Institute, Taiwan (NHRI-EX111-10933SI).