Injectable Gel-PEG hydrogels as promising delivery system for intravitreal PACAP release: Novel therapeutics for unilateral common carotid artery occlusion induced retinal ischemia

MoXin Chen; XiaoYi Liang; XiRui Chen; Yuan Yang; Qin Shu; YaHan Ju; WanQin Nie; XueFeng Yang; YongLin Guo; XiaoJing Li; Ping Gu; Lin Li

Biomedicine & Pharmacotherapy (Oct 2024)

Injectable Gel-PEG hydrogels as promising delivery system for intravitreal PACAP release: Novel therapeutics for unilateral common carotid artery occlusion induced retinal ischemia

MoXin Chen,
XiaoYi Liang,
XiRui Chen,
Yuan Yang,
Qin Shu,
YaHan Ju,
WanQin Nie,
XueFeng Yang,
YongLin Guo,
XiaoJing Li,
Ping Gu,
Lin Li

Affiliations

MoXin Chen: Department of Ophthalmology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
XiaoYi Liang: Department of Ophthalmology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
XiRui Chen: Department of Ophthalmology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
Yuan Yang: Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Qin Shu: Department of Ophthalmology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
YaHan Ju: Department of Ophthalmology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
WanQin Nie: Department of Ophthalmology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
XueFeng Yang: Department of Ophthalmology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
YongLin Guo: Department of Ophthalmology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
XiaoJing Li: Department of Ophthalmology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China
Ping Gu: Department of Ophthalmology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China; Corresponding authors at: Department of Ophthalmology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Lin Li: Department of Ophthalmology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, China; Corresponding authors at: Department of Ophthalmology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Journal volume & issue: Vol. 179
p. 117427

Abstract

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Retinal ischemia is an ophthalmic emergency often caused by cardiovascular diseases, leading to irreversible vision loss and even blindness. Innovative retinal ischemia treatments are needed due to limited options. The pathological mechanisms involve retinal cell apoptosis and microglial activation. The pituitary adenylate cyclase-activating polypeptide (PACAP) is a well distributed neuropeptide found in both central nervous system and peripheral organs. Though it shows great anti-apoptosis and anti-microglia activation properties, it is rapidly cleared by intravitreal injection. Herein, we established a novel poly(ethylene glycol) (PEG) hydrogel system by cross-linking 4arm-PEG-NHS and 4arm-PEG-NH2 to load PACAP (PACAP@Gel-PEG), which exhibited great fluidity, injectability, structural recovery ability, moderate swelling ratio and drug release ability that were appropriate for drug delivery. Then the safety and effectiveness of the PACAP@Gel-PEG were evaluated in vitro in three retinal cell lines (ARPE-19, 661 W and rRMC) and in vivo using the unilateral common carotid artery occlusion (UCCAO) mice model. The CCK-8 test and live/dead staining demonstrated that PACAP@Gel-PEG exhibited excellent biocompatibility in three retinal cell lines. Furthermore, after PACAP@Gel-PEG treatment, a great anti-apoptotic effect was observed in cells treated by CoCl2. Application of PACAP@Gel-PEG greatly improved the therapeutic efficacy of PACAP in restoring retinal function, maintaining retinal integrity, and suppressing apoptosis and microglia activation in retinal tissues. Moreover, in mice, the biosafety of PACAP@Gel-PEG was confirmed by H&E staining of systemic organs. Taken together, our results demonstrated PACAP@Gel-PEG as a promising therapeutic option for retinal ischemia, providing new strategies for vision restoration.

Published in Biomedicine & Pharmacotherapy

ISSN: 0753-3322 (Print); 1950-6007 (Online)
Publisher: Elsevier
Country of publisher: France
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.journals.elsevier.com/biomedicine-and-pharmacotherapy

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