Recently, Professor Yao Ke's team from the eye center of the second hospital of Zhejiang University and the eye hospital of Zhejiang University published a research paper entitled "ferrostatin-1-loaded liposome for treatment of corneal alkaliburn via targeting ferroptosis" in the authoritative journal Bioengineering & translational medicine (impact factor 10.711).
This study found for the first time that there is a new cell death mode of iron death in the process of corneal alkali burn, It is the first in the world to use liposomes to deliver ferrostatin-1, a specific inhibitor of iron death (fer-1) can effectively improve the corneal injury caused by alkali burn and alleviate the inflammatory reaction and neovascularization caused by alkali burn. Compared with free fer-1, the liposome loaded with fer-1 has more significant therapeutic effect and good safety. It is expected to become a potential new treatment method for clinically targeting iron death and improving alkali burn cornea.
As one of the common diseases in ophthalmic emergency, corneal alkali burn often causes corneal opacity and neovascularization, and even leads to the loss of vision. The existing therapies have some shortcomings, such as invasive, limited curative effect and drug side effects. Therefore, exploring a safer, effective and convenient new treatment for corneal alkali burn has become a hot spot in ophthalmic research in recent years.
Limited by complex physiological and anatomical structures, ocular drug delivery has always been a major technical challenge. Liposomes are micro vesicles composed of phospholipids and cholesterol. Hydrophobic drugs and hydrophilic drugs can be encapsulated in their phospholipid bilayer and water core respectively. Liposomes have good corneal penetration and biocompatibility, and can realize the continuous delivery of drugs. Therefore, liposomes can be used as potential nano carriers for ocular drug delivery to repair damaged cornea. The purpose of this study is to explore the new mechanism in the occurrence and development of corneal alkali burn, and further use liposomes to deliver therapeutic drugs according to its target, so as to achieve the purpose of accurate, safe, effective and convenient treatment.
According to previous research, Alkali burns can cause reactive oxygen free radicals (ROS) increase, which causes serious damage to the cornea by activating inflammatory reaction and promoting corneal neovascularization. In addition, neovascularization is also easy to lead to lipid exudation and deposition in the cornea. Iron death is a lipid peroxidation product and iron ion dependent programmed cell death. Both ROS and free iron ion increase can lead to lipid peroxidation products Accumulation, which attacks cell membranes and mitochondria and causes iron death. Many studies suggest that iron death specific inhibitor fer-1 can improve the occurrence and development of a variety of iron death related diseases, indicating its potential for clinical transformation treatment of related diseases. However, the role of iron death in corneal alkali burn and the efficacy of fer-1 are unclear.
This study found that compared with healthy controls, the ocular surface of alkali burned mice showed obvious corneal opacity and neovascular growth, and the histological results showed obvious corneal edema, inflammatory cells and neovascular infiltration. Fer-1 administration can significantly improve these injuries, suggesting that there is iron death in corneal injury caused by alkali burn.
Effect of fer-1 administration on corneal injury induced by alkali burn in mice
Subsequent experiments showed that alkali burn resulted in the activation of iron death promoting pathway and the inhibition of blocking pathway. At the same time, a large number of ROS attacked mitochondria. Both of them jointly promoted the occurrence of iron death in corneal tissue. Fer-1 treatment improved the abnormal expression of the above indexes, suggesting that iron death can be used as a target for the treatment of corneal alkali burn.
There was iron death during corneal alkali burn injury in mice
Eye drops have the advantages of simplicity and safety, but limited by tear flushing, blink reflex and eye surface barrier, the bioavailability of traditional eye drops is often very low. In addition, due to the poor water solubility and short effective time in vivo, the application of fer-1 in clinical treatment has certain limitations. Although some excipient materials can be used as solubilizers to deliver drugs, the irritation to the eyes and the complexity of components limit their clinical application. In contrast, liposomes can be used for mass production because of their simple and mature preparation process. Its biocompatibility has also been widely recognized. Since adriamycin liposomes were introduced in 1995, a large number of liposome drugs have been approved by FDA for clinical use. Therefore, liposome loading technology is more likely to affect clinical practice and promote medical product innovation. Based on this, our research team further prepared liposome eye drops loaded with fer-1 by film dispersion method. A number of material characterization showed that compared with free drugs, liposome loaded drugs showed excellent drug release behavior, and effectively improved cell uptake and ocular surface residence time, indicating that liposome delivery system is helpful to improve drug bioavailability.
Fer-1 liposomes can improve the bioavailability of drugs
Further study on the therapeutic effect and mechanism of action showed that in the fer-1 liposome treatment group, in addition to the indicators related to iron death, the corneal injury, inflammatory reaction and neovascularization induced by alkali burn were effectively improved, and the curative effect was significantly better than that of the free fer-1 group. Including inflammatory index IL-1 β And IL-6, angiogenesis related regulatory factors VEGFA, VEGFC, VEGFR3, MMP2, α- The abnormal expression of SMA and CD31 can be saved by free fer-1 and fer-1 liposomes, and the effect of fer-1 liposomes is more obvious. The above results show that the therapeutic effect of fer-1 liposome on corneal alkali burn injury is significantly better than that of free fer-1. In addition, this study evaluated the safety of fer-1 liposomes. The experimental results in vivo and in vitro showed that fer-1 liposomes had no obvious toxic and side effects.
Fer-1 liposome can protect alkali burned cornea by resisting iron death
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Fer-1 liposome can protect alkali burned cornea through anti-inflammatory and anti neovascularization
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Team Introduction
Professor Yao Ke from the eye hospital of Zhejiang University and the second Zhejiang Eye Center, researcher Han Haijie is the corresponding author of this paper, and postdoctoral Wang Kai, Jiang Li and Zhong LeYang from the medical school of Zhejiang University are the co first authors of this paper. The research work has been supported by the National Natural Science Foundation of China, national key R & D projects, key R & D projects of Zhejiang Province and the natural science foundation of Zhejiang Province.
Original link:
https://doi.org/10.1002/btm2.10276
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Author introduction
Corresponding author: Professor Yao Ke
Chief physician, doctoral supervisor
President of the ophthalmic hospital of Zhejiang University, director of the Institute of Ophthalmology of Zhejiang University, and director of the Ophthalmic Center of the Second Affiliated Hospital of the Medical College of Zhejiang University. Academician of the International Academy of Ophthalmology and special expert of Zhejiang Province. Chairman of the ophthalmology branch of the Chinese Medical Association, President designate of the Asia Pacific Society of cataract and refractive surgery, executive director of the International Council of Ophthalmology, head of the Asia Pacific Society of ophthalmology in China, director of the Asia Pacific Academy of Ophthalmology, member of the international intraocular lens implantation club, executive director of the Chinese Medical Association, executive director of the Chinese Medical Association, editor in chief of the Chinese Journal of Ophthalmology, Head of cataract and refractive surgery group of Ophthalmology branch of Chinese Medical Association, chairman of Zhejiang Association for science and technology, and President of Zhejiang Medical Association. As the first winner, he won 3 second prizes of national scientific and technological progress, 3 first prizes of scientific and technological progress in Zhejiang Province, more than 10 provincial and ministerial awards of major scientific and technological contribution, Alfred Vogt award of Swiss Ophthalmology, mark Tso Golden Apple award of international ophthalmology Council, gold award of Asia Pacific Society of cataract and refractive surgery, Antonio Scarpa award of Italian Ophthalmology Society, international lecture award, etc. He has published 473 academic papers, of which 258 are included in SCI, won 7 national invention patents, and successively won more than 30 national, provincial and ministerial major projects such as key projects of NSFC, national support projects of the Eleventh Five Year Plan and the twelfth five year plan, and key and general projects of NSFC.
Corresponding author: Han Haijie
Distinguished researcher, doctoral supervisor
In 2018, he graduated from the Department of polymer science and engineering of Zhejiang University under the guidance of Professor Ji Jian. In the same year, he joined the eye center of the Second Affiliated Hospital of the Medical College of Zhejiang University. The main research field is the design of polymer nano drug carrier and its application in ophthalmology. As the first / corresponding author, he published 15 papers in academic journals such as the Journal of the American Chemical Society, ACS Nano, small, bioactive materials, Bioengineering & translational medicine, and 3 papers were selected as ESI highly cited papers. As the person in charge, he presided over and undertook, including national natural youth fund, Zhejiang Youth Fund Zhejiang joint fund and other national, provincial and ministerial projects.
First author: Dr. Wang Kai
In 2021, he graduated from the eight-year clinical medicine major of Zhejiang University, studied under Professor Yao Ke, and is currently engaged in post doctoral research in clinical medicine in the medical school of Zhejiang University. The main research direction is the application of nano drugs and biomaterials in the diagnosis and treatment of eye diseases, and the mechanism of eye diseases is explored by Mendelian randomization. As the first / co-author, he published 16 papers in Bioengineering & translational medicine, Journal of Clinical Endocrinology & metabolism, blood, BMC medicine and other academic journals, and participated in a number of national fund projects.
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