Full Text | PDF

Theranostics 2021; 11(11):5107-5126. doi:10.7150/thno.54755 This issue Cite

Research Paper

Exosome-mediated delivery of an anti-angiogenic peptide inhibits pathological retinal angiogenesis

Xue Dong^1,2,3*, Yi Lei^1,3*, Zeyang Yu^2,3, Tian Wang^1,3, Yi Liu^2,3, Gang Han⁴, Xiaodan Zhang^1,3, Yiming Li^1,3, Yinting Song^1,3, Heping Xu⁵, Mei Du^2,3, Haifang Yin⁶, Xiaohong Wang^2,3✉, Hua Yan^1,3✉

1. Department of Ophthalmology, Tianjin Medical University General Hospital, 300070, Tianjin, China.
2. Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, 300070, Tianjin, China.
3. Laboratory of Molecular Ophthalmology, Tianjin Medical University.
4. School of Medical Laboratory, Tianjin Medical University, Guangdong Road, Tianjin 300203, China.
5. The Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK.
6. Tianjin Key Laboratory of Cellular Homeostasis and Human Diseases & Department of Cell Biology, Tianjin Medical University, Qixiangtai Road, Heping District, Tianjin, 300070, China.
* These authors contributed equally.

✉ Corresponding authors: Dr. Hua Yan (zyyyanhuaedu.cn), Dr. Xiaohong Wang (xiaohongwangedu.cn)

Abstract

Background: Pathological angiogenesis is the hallmark of many vision-threatening diseases. Anti-VEGF is a primary treatment with substantial beneficial effects. However, such agents require frequent intravitreal injections. Our previous work established a method for effectively modifying exosomes (EXOs) for loading therapeutic peptides. Here, we used this system to load the anti-angiogenic peptide KV11, aiming to establish an EXO-based therapy strategy to suppress neovascularization in the retina.

Methods: Using an anchoring peptide, CP05, we linked KV11 to endothelial cell (EC) derived EXOs, yielding EXO_KV11. We tested the delivery efficiency of EXO_KV11 via two commonly used ocular injection methods: retro-orbital injection and intravitreal injection. Deploying an oxygen-induced retinopathy (OIR) model and a VEGF injection model, we tested the effects of EXO_KV11 on neovascular formation, EC proliferation, and vascular permeability. In vitro experiments were used to test the mechanism and to analyze the effects of EXO_KV11 on EC proliferation, migration, and sprouting.

Results: By using the EXO loading system, KV11 was more efficiently delivered to the blood vessels of the mouse retina via retro-orbital injection. In both OIR model and VEGF injection model, EXO_KV11 was more effective than KV11 alone in inhibiting neovascularization and vessel leakage. The therapeutic effect of retro-orbital injection of EXO_KV11 was comparable to the intravitreal injection of VEGF-trap. Mechanistically, KV11 alone inhibited VEGF-downstream signaling, while EXO_KV11 showed a stronger effect.

Conclusions: We used EXOs as a carrier for intraocular delivery of KV11. We showed that KV11 itself has an anti-angiogenic effect through retro-orbital injection, but that this effect was greatly enhanced when delivered with EXOs. Thus, this system has the potential to treat proliferative retinopathy via retro-orbital injection which is a less invasive manner compared with intravitreal injection.

Keywords: Exosomes (EXOs), drug delivery, proliferative retinopathy, pathological angiogenesis, VEGF signaling.

Citation styles

©2024 Ivyspring International Publisher. Terms of use