Article(id=1246531412975837897, tenantId=1146029695717560320, journalId=1246415772164075586, issueId=1246531406415941821, articleNumber=null, orderNo=null, doi=10.13699/j.cnki.1001-6821.2025.16.024, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1727712000000, receivedDateStr=2024-10-01, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1775125848287, onlineDateStr=2026-04-02, pubDate=1756310400000, pubDateStr=2025-08-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1775125848287, onlineIssueDateStr=2026-04-02, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1775125848287, creator=13701087609, updateTime=1775125848287, updator=13701087609, issue=Issue{id=1246531406415941821, tenantId=1146029695717560320, journalId=1246415772164075586, year='2025', volume='41', issue='16', pageStart='2251', pageEnd='2400', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=1, specialIssue=null, createTime=1775125846723, creator=13701087609, updateTime=1775125956861, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1246531868481446285, tenantId=1146029695717560320, journalId=1246415772164075586, issueId=1246531406415941821, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1246531868481446286, tenantId=1146029695717560320, journalId=1246415772164075586, issueId=1246531406415941821, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=2386, endPage=2392, ext={EN=ArticleExt(id=1246531413244273370, articleId=1246531412975837897, tenantId=1146029695717560320, journalId=1246415772164075586, language=EN, title=Research status in innovative drug delivery at the posterior segmental site of the eye, columnId=1246531408630534361, journalTitle=Chinese Journal of Clinical Pharmacology, columnName=Review, runingTitle=null, highlight=null, articleAbstract=

The treatment of posterior segment diseases has always been a challenge in the field of ophthalmology. How to overcome obstacles in drug delivery and improve the bioavailability of drugs in the posterior segment of the eye is one of the most challenging aspects in the field of drug research. The innovation of drug delivery routes and dosage forms, as well as breakthroughs in drug development, have brought new hope for the delivery of drugs in the posterior segment of the eye. This article reviews three aspects of innovative drug delivery routes for subretinal drug delivery, suprachoroidal drug delivery, and vitreous cavity implantation, innovative drug delivery form design for nano-formulations and exosomal formulations, and innovative drug development for intraocular injections, topical drops, and oral drugs, with the aim of providing new strategies for the treatment of diseases of the posterior segment of the eye.

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眼后节段疾病的治疗一直是眼科领域的难点。如何克服药物输送过程中的障碍,提高眼后节段药物生物利用度,是药物研究领域最具挑战性的方面之一。给药途径、给药剂型的创新以及药物研发的突破为眼后节段药物递送带来了新的希望。本文综述了视网膜下给药、脉络膜上给药、玻璃体腔植入的创新给药途径,纳米剂型和外泌体剂型的创新给药剂型设计,以及眼内注射剂、局部滴剂、口服药物的创新药研发3个方面,旨在为眼后节段疾病的治疗提供新的策略。

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赵磊,副主任医师,研究生导师 MP:15040212468 E-mail:
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张静涵(2001-),女,硕士研究生,主要从事中西医结合防治眼病方面的研究

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张静涵(2001-),女,硕士研究生,主要从事中西医结合防治眼病方面的研究

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张静涵(2001-),女,硕士研究生,主要从事中西医结合防治眼病方面的研究

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眼后节段部位创新给药的研究进展
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张静涵 1 , 左韬 2 , 赵磊 2
中国临床药理学杂志 | 综述 2025,41(16): 2386-2392
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中国临床药理学杂志 | 综述 2025, 41(16): 2386-2392
眼后节段部位创新给药的研究进展
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张静涵1, 左韬2, 赵磊2
作者信息
  • 1.辽宁中医药大学 第二临床学院,辽宁 沈阳 110032
  • 2.辽宁中医药大学 附属第二医院 眼科,辽宁 沈阳 110034
  • 张静涵(2001-),女,硕士研究生,主要从事中西医结合防治眼病方面的研究

通讯作者:

赵磊,副主任医师,研究生导师 MP:15040212468 E-mail:
Research status in innovative drug delivery at the posterior segmental site of the eye
Jing-han ZHANG1, Tao ZUO2, Lei ZHAO2
Affiliations
  • 1.College of the Second Clinical, Liaoning University of Traditional Chinese Medicine, Shenyang 110032, Liaoning Province, China
  • 2.Department of Ophthalmology, Second Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, Shenyang 110034, Liaoning Province, China
出版时间: 2025-08-28 doi: 10.13699/j.cnki.1001-6821.2025.16.024
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眼后节段疾病的治疗一直是眼科领域的难点。如何克服药物输送过程中的障碍,提高眼后节段药物生物利用度,是药物研究领域最具挑战性的方面之一。给药途径、给药剂型的创新以及药物研发的突破为眼后节段药物递送带来了新的希望。本文综述了视网膜下给药、脉络膜上给药、玻璃体腔植入的创新给药途径,纳米剂型和外泌体剂型的创新给药剂型设计,以及眼内注射剂、局部滴剂、口服药物的创新药研发3个方面,旨在为眼后节段疾病的治疗提供新的策略。

眼后节段  /  给药方式  /  视网膜下给药  /  脉络膜上给药  /  纳米途径  /  外泌体

The treatment of posterior segment diseases has always been a challenge in the field of ophthalmology. How to overcome obstacles in drug delivery and improve the bioavailability of drugs in the posterior segment of the eye is one of the most challenging aspects in the field of drug research. The innovation of drug delivery routes and dosage forms, as well as breakthroughs in drug development, have brought new hope for the delivery of drugs in the posterior segment of the eye. This article reviews three aspects of innovative drug delivery routes for subretinal drug delivery, suprachoroidal drug delivery, and vitreous cavity implantation, innovative drug delivery form design for nano-formulations and exosomal formulations, and innovative drug development for intraocular injections, topical drops, and oral drugs, with the aim of providing new strategies for the treatment of diseases of the posterior segment of the eye.

posterior segment  /  mode of administration  /  subretinal administration  /  suprachoroidal administration  /  nano-pathway  /  exosomes
张静涵, 左韬, 赵磊. 眼后节段部位创新给药的研究进展. 中国临床药理学杂志, 2025 , 41 (16) : 2386 -2392 . DOI: 10.13699/j.cnki.1001-6821.2025.16.024
Jing-han ZHANG, Tao ZUO, Lei ZHAO. Research status in innovative drug delivery at the posterior segmental site of the eye[J]. Chinese Journal of Clinical Pharmacology, 2025 , 41 (16) : 2386 -2392 . DOI: 10.13699/j.cnki.1001-6821.2025.16.024
眼球是一个极其精细且复杂的器官,它主要分为前部和后部。前部占据了眼睛大约三分之一的体积,由房水、结膜、角膜、虹膜、睫状体和晶状体构成。其余三分之二位于后部,包括脉络膜、神经视网膜、视神经、视网膜色素上皮、巩膜和玻璃体[1]。由于其存在复杂的解剖结构和生理学障碍,眼科药物递送一直是药物研究领域最具挑战性的方面。眼部屏障包括泪膜屏障、鼻泪引流系统、角结膜屏障和血液-眼屏障,血液-眼屏障由血液-房水屏障(blood aqueous barrier,BAB)和血液-视网膜屏障(blood retinal barrier,BRB)组成。血液-视网膜屏障主要负责限制药物在眼球后部的吸收,而其他屏障阻止药物在眼球前部的吸收。独特的静态和动态眼屏障不仅排除了外源性物质的进入,以保护眼睛免受外部环境潜在有害分子的侵害,还阻碍了治疗剂的主动吸收,降低眼部药物生物利用度[2]。为了克服眼部药物输送过程中的这些障碍,提升眼后节段药物生物利用度,新型给药途径和药物输送系统应运而生,同时许多创新药物也在研发。尽管目前大多数研究尚在基础阶段,且面临着技术成熟与推广挑战,但眼后节段部位的创新给药方法有望成为眼内药物治疗的主要趋势。本文对此进行综述,为眼后节段疾病的治疗提供新的策略。
眼内注射(intraocular injections),亦称眼球内注射,主要涵盖前房内注射、玻璃体腔内注射,以及近年来新兴的视网膜下给药、脉络膜上给药和玻璃体腔植入技术。这类注射通常用于治疗玻璃体视网膜疾病,特别是那些导致视力丧失的疾病,例如年龄相关性黄斑变性(age-related macular degeneration,AMD)[3]、糖尿病视网膜病变(diabetic retinopathy,DR)[4]等。眼内注射的优势在于绕过角膜和巩膜的屏障(与局部眼药水相比),直接输送药物至视网膜和玻璃体,同时绕过BRB(与全身用药不同),确保药物在目标区域的高生物利用度,迅速发挥治疗效果。因此,这种给药方式备受青睐。然而,眼内注射作为一种侵入性操作,可能引发严重并发症,如眼内炎、视网膜脱离和玻璃体出血等[5-6]。因此,在进行眼内注射时,需特别注意将组织损伤降至最低,并充分考虑眼球内组织对药物的耐受性,即药物对组织的潜在毒性。
在目前的临床治疗中,玻璃体注射(intravitreal injection,IVI)已成为治疗眼后节段病变的首选方法。但由于内部限制膜和Müller细胞的屏障作用[7-8],玻璃体内药物难以在视网膜外层和视网膜色素上皮层达到理想浓度。相比之下,视网膜下注射能够满足靶向视网膜下间隙细胞的需求,使药物能够直接进入视网膜下空间,与光感受器层和视网膜色素上皮层接触,从而提高药物在细胞内的浓度[9]。25例患者联合使用视网膜下注射重组组织纤溶酶原激活剂和气体填塞剂,所有25只眼(100%)均成功实现黄斑下出血移位,术后12个月最佳矫正视力(best-corrected visual acuity,BCVA)从术前的1.81±0.33显著改善至1.37±0.52 LogMAR(P=0.001),黄斑中心厚度从基线时的(922.00±273.69) μm显著下降至(403.53±314.64) μm(P<0.001)[10]。近年来,视网膜下药物递送在基因治疗和细胞治疗领域得到了广泛应用。9名RPE65基因突变相关视网膜变性患者分别接受视网膜下注射低剂量(12.20~20.00 vg)或高剂量(32.70~48.00 vg)腺相关病毒2/4血清型RPE65-RPE65载体,所有患者治疗结束后视力改善、功能磁共振成像可见视觉通路皮层激活,表现出良好的眼科及全身耐受性[11]。在一项纳入的12项研究的Mate分析结果显示,共有140只患有AMD的眼睛接受了细胞疗法的干预。与治疗前相比,BCVA评分显著降低(g=-0.47,95%CI=-0.91至-0.03,P=0.04),表明光感受器和视觉功能得到了一定程度的恢复[12]。迄今为止,视网膜下递送作为一种更精确有效的眼部药物递送途径已被广泛应用,但其长期的安全性和有效性仍需进一步的研究来评估。
脉络膜上腔(supra-choroidal space,SCS)是巩膜和脉络膜之间的一个解剖学龛位,为精确给药提供微创通道。脉络膜上注射是一种新兴的靶向药物输送方法,旨在提高眼后节段药物浓度,增强生物利用度并延长作用时间。此外,它通过区隔作用限制药物与非靶组织的接触,降低诸如白内障形成和眼压升高等并发症的风险[13]。脉络膜上注射曲安奈德(triamcinolone acetonide,TA)混悬液在非感染性葡萄膜炎(non-infectious uveitis,NIU)中有显著疗效。38例患者接受两次4 mg(0.1 mL,40 mg·mL-1)角膜缘干细胞靶向TA脉络膜上腔注射(间隔12周),在研究期间,注射后血浆TA浓度均<1 ng·mL-1,研究眼的平均眼压从基线期的13.3 mmHg升高至24周时的15.2 mmHg,且未观察到严重的眼部不良事件[14]。KHANANI等[15]的研究表明,通过脉络膜上腔RGX-314基因递送有可能在治疗新生血管性AMD(neovascular age-related macular degeneration,nAMD)时提供持续的临床改善,且有可能只需进行一次性治疗。在脉络膜上注射TA联合IVI贝伐珠单抗治疗中心性糖尿病黄斑水肿的临床研究中,单药治疗组和联合治疗组的BCVA平均改善值分别为(-0.20±0.20) logMAR(P=0.004)和(0.37±0.24) logMAR(P<0.001),组间比较显示显著差异(P=0.014),两组均未观察到眼压升高或白内障等不良事件[16]。由此可见,脉络膜上注射联合其他给药途径疗法可成为有效的治疗选择。
玻璃体作为眼科疾病,特别是眼底病药物治疗的关键通道,其注射技术是通过皮下注射针将药物直接输送到玻璃体腔内,有效绕过角膜和巩膜屏障以及BRB,从而在玻璃体和视网膜中达到较高的药物浓度。这已成为治疗眼后节组织疾病的主流方法[17-18]。为了延长IVI药物的作用时间并减少注射次数,玻璃体腔内植入技术应运而生。该技术通过巩膜切开术的手术部位将药物植入玻璃体内,直接作用于眼后节段部位,同时减少对睫状环的破坏。地塞米松(dexamethasone,Dex)玻璃体内植入物是一种获得批准的缓释、可生物降解的长效眼科植入物,能够将皮质类固醇Dex输送到眼睛后段。1项纳入6项临床试验的Mate分析结果显示,Dex玻璃体腔植入与IVI抗血管内皮生长因子(anti-vascular endothelial growth factor,Anti-VEGF)相比,前者在短期(1~3个月)内能更快速改善视网膜分支静脉阻塞继发黄斑水肿患者的视功能和解剖结构,BCVA数值更小,均值差异(mean difference,MD)为-0.11(P<0.0001),改善幅度更大,MD为-0.35(P<0.00001),但6个月时两组疗效相当。鉴于其早期优势,Dex玻璃体内植入可考虑作为该疾病的首选治疗方案[19]。BOIA等[20]的研究表明,含有腺苷A3受体激动剂的眼内植入物能够减少缺血性视网膜神经节细胞的损伤,并促进细胞的存活。随着研究的不断深入,玻璃体植入剂的材料也经历了显著的发展,从非生物可降解材料到生物可降解材料,但两者各有优缺点,因此植入物的选择仍然是术前需要仔细权衡的问题[21]
眼科常用的药物剂型包括滴眼液、眼药膏和眼胶,但眼睛的球状形状和复杂的生理屏障大大减少了局部应用制剂的吸收。因此,创新增加渗透性或能有效克服眼屏障的药物剂型已成为最近的研究热点。
纳米材料,其尺寸介于1至1 000纳米之间,已成为多种医学和临床应用的基石。自1980年代起[22],基于纳米技术的药物递送方法已被应用于治疗眼部疾病。随着技术的不断进步,具备纳米级空间分辨率的眼部药物递送系统在将眼组织转变为疾病治疗的诱人靶点方面扮演了至关重要的角色,为眼部疾病治疗带来了新的干预手段。相较于传统药物制剂,纳米载体在提升药物的渗透性和生物利用度、减少酶促药物降解方面表现出色,同时还能在作用部位实现受控、持续和延长的药物释放,显著降低给药频率,从而获得更佳的药理效果。纳米胶束、纳米悬浮液、纳米颗粒、纳米酶、立方体、脂质体、纳米晶片等多种纳米载体已被研究用于治疗前眼部和后眼部疾病,本文接下来将对一些最新的纳米载体研究进行介绍[23-27]
胶束是在表面活性剂或聚合物浓度超过临界胶束浓度时,在溶液中自发形成的胶体结构。纳米胶束是一种纳米级胶体载体系统,能够在水或其他极性溶剂中自组装。它们以疏水基团为核心,亲水基团为外壳,这种独特的结构使得纳米胶束成为封装疏水性化合物并将其输送到体内特定位置的理想选择[28]。研究人员通过纳米胶束将药物输送到眼后节段,取得了显著的疗效。例如,XU等[27]基于肽转运体-1的主动靶向性,设计了一种用于局部眼部给药的壳聚糖寡糖-缬氨酸-硬脂酸(chitosan oligosaccharide-valylvaline-stearic acid ,CSO-VV-SA)纳米胶束,与游离Dex相比,CSO-VV-SA(5:2)/Dex和CSO-VV-SA(5:4)/Dex混合纳米胶束在6 h内的累积释放率分别为55.45%和65.45%,表现出明显的缓释模式。CSO-VV-SA通过结膜途径进入后段,能在兔子眼泪中检测到Dex超过3 h,且在角结膜上皮细胞中均未产生显著细胞毒性。MEHRA等[29]利用Soluplus®(一种聚乙烯己内酰胺-聚乙烯醇-聚乙二醇的结合共聚物)开发了一种免疫抑制剂药物依维莫司的局部纳米胶束制剂。实验证明,该胶束制剂通过山羊角膜的渗透率为(67.14±2.40)%,显著高于依维莫司药物混悬液的(34.06±2.40)%(P<0.001),被视为治疗葡萄膜炎(uveitis,UV)的一种前景广阔的局部给药载体。
药物纳米混悬液是经表面活性剂稳定的不溶性药物颗粒的纳米级异质水性分散体,它能够保持活性药物成分的结晶状态,从而解决药物递送问题,同时提升溶解度和溶出速率、增加药物负载、增强稳定性等[30]。JOSYULA等[31]采用离子对方法制备了不溶性莫西沙星-双羟萘酸酯复合物(moxifloxacin-pamoate,MOX-PAM),并将其配制成纳米混悬剂。在健康大鼠眼内,MOX-PAM纳米混悬剂在房水中药物最大浓度达到莫西沙星滴眼液(Vigamox®)的1.6倍,房水药物总暴露量较 Vigamox® 提高1.7倍(P<0.05)。在眼金黄色葡萄球菌感染大鼠模型中,一滴 MOX-PAM 纳米混悬剂更加有效,展现出高速、高效的递送能力和治疗效果。纳米悬浮液与溶解微针的混合系统,作为传统皮下注射针头的替代品,可用于疏水药物的经巩膜微创递送。研究发现该系统能够刺穿猪巩膜,插入深度超过针头高度的80%,TA经巩膜沉积量(56.46±7.76) μg·mm-2较普通微针(12.56±2.59) μg·mm-2提高4.5倍,为治疗视网膜疾病提供了一种新颖且有前景的技术[24]。尽管纳米悬浮液带来了诸多令人振奋的研究成果,但其稳定性问题依然存在挑战。静电和空间稳定剂的稳定性、可达到的最大粒径以及物理稳定性等关键因素仍需进一步深入研究[30]
纳米酶是一种创新的纳米材料,它具备与酶相似的催化活性,能够将酶底物转化为产物。相较于传统酶,纳米酶拥有诸多优势,例如合成过程简单、成本低廉、稳定性高以及具备多功能的催化活性。随着纳米酶研究的不断深入,其在眼部疾病治疗方面的潜力逐渐显现[32-34]。纳米酶的稳定性和高光散射特性使其成为加强眼病监测和诊断的理想选择[34]。GUI等[25]的研究报告介绍了一种用于治疗后发疾病的铁基纳米酶。通过将槲皮素与低毒性的铁离子结合,形成超小铁-槲皮素(iron-quercetin nanozyme,Fe-Quer)纳米酶,可展现了卓越的水分散性和高效的活性氧清除能力。体外和体内实验均证实了Fe-Quer纳米酶在炎症、氧化应激损伤、微血管渗漏以及血管生成方面的积极作用,特别是在早期DR中的血管保护作用。日后Fe-Quer纳米酶有望作为微血管保护剂,在临床上用于治疗DR及其他活性氧相关疾病。然而,湿度和氧气等外部条件可能会改变纳米酶在储存期间的表面特性,因此,开发具有高度稳定活性和催化稳定性的纳米酶在实际应用中仍是一项挑战[35]
立方体是一种由纳米级液晶、逆双连续脂质层和对称性晶体构成的三维结构,其粒径小于500纳米,能在极性溶剂中自组装,形成热力学稳定的结构[36-37]。得益于其广阔的表面积,立方体具有极高的负载能力,能够改善角膜的渗透性并增强抗炎活性,从而在眼部给药时展现出更长的停留时间和更高的生物利用度。为了更有效地将药物输送到眼后节段,GABALLA等[26]制备了二丙酸倍氯米松(beclomethasone dipropionate,BDP)立方体,与BDP混悬液相比,该立方体的牛角膜渗透性提高了4倍,渗透通量提升5.8倍。将优化后的立方体加入到立方体凝胶中,其更优的流变特性和更高的眼部耐受性使其在治疗内毒素诱导的兔UV模型中表现出显著的抗炎特性。
尽管纳米医学在眼部给药方面优于传统方法,但目前大多数相关技术仍处于临床前研究阶段。要将这些技术真正应用于临床,还需克服后期临床试验和大规模生产等众多挑战。此外,对纳米药物的制备和保存技术的评估应综合考虑无菌性、简便性、制造技术的可重复性、易储存性和稳定性保持等因素。然而我们坚信,在不久的将来,纳米医药将在眼科疾病的治疗中扮演更加重要的角色。
外泌体是由多种细胞分泌的30~150纳米的小细胞外囊泡,它们由脂质双层、蛋白质和遗传物质构成,广泛存在于各种体液中,包括泪液、房水、玻璃体和血液等[38-40]。这些外泌体携带着多种生物活性分子,一旦释放,便能作为独立的细胞信号传导介质,在信号传递、炎症反应、免疫调节以及修复和再生过程中发挥关键作用[41]。作为天然的载体,外泌体相较于合成的纳米药物载体,展现出更高的穿透能力和安全性,并且在眼部疾病的治疗中,能够有效地递送药物或生物活性分子。研究表明,在大鼠视网膜脱离模型中进行视网膜下注射间充质干细胞衍生的外泌体(mesenchymal stem cell-derived exosomes,MSC-Exos),显著降低肿瘤坏死因子-α(tumor necrosis factor-alpha,TNF-α)和白细胞介素-1β(interleukin-1 beta,IL-1β) 的表达,自噬体膜标志物的比值增强,与对照组相比,MSC-Exos治疗还抑制了感光细胞凋亡并维持了正常的视网膜结构[42]
2021年,TIAN等[43]报告了调控性T细胞来源的外泌体(regulatory T cell-derived exosomes,rEXS)的开发成果,rEXS通过基质金属蛋白酶(matrix metalloproteinase,MMP)可裂解肽链(cleavable linker,cL)偶联抗VEGF抗体(anti-VEGF antibody,aV),即rEXS-cL-aV,在新生血管病灶区高表达的MMP2/9作用下释放游离aV,实现局部高浓度给药,减少全身药物不良反应。研究结果显示,在小鼠脉络膜新生血管模型中,玻璃体腔分别注射rEXS与aV混合物(rEXS + aV)和rEXS-cL-aV,rEXS + aV组aV信号24 h内衰减超50%,96 h几乎消失,而rEXS-cL-aV组4天后信号保留超50%,7天后仍存约25%。通过双光子荧光显微成像可观察到所有治疗组的rEXS均能精准靶向脉络膜新生血管[43]。在2023年,同一研究小组提出了一种新的概念,即负载外泌体的可降解聚合物微胶囊制剂。通过IVI将这种微胶囊注射到小鼠视网膜缺血再灌注损伤模型中,发现包裹小鼠间充质干细胞衍生外泌体的微胶囊沉积在玻璃体下腔。在随后的一个多月的降解过程中,外泌体逐渐释放,视网膜厚度得以恢复至接近健康视网膜的水平。这项研究提示了外泌体微胶囊可能为玻璃体视网膜疾病提供一种新的替代治疗方案[44]。外泌体展现出了靶向多种治疗载荷的能力、良好的安全性和低免疫原性潜力等关键特性,使其成为一种极具吸引力的治疗药物载体。尽管如此,我们仍需进行更广泛的研究与验证,以期在外泌体的临床治疗应用中发挥其最大潜力。
GB-102 GB-102是由GrayBug Vision公司开发的一种可注射马来酸舒尼替尼酪氨酸激酶抑制剂,同时针对VEGF-A和血小板衍生生长因子均有活性。注射后,会在玻璃体下部形成一个储存库,随着时间的推移逐渐降解,成为一种持久的抗血管生成方法。临床试验研究证明了GB-102的安全性和有效性,单次IVI 注射后效果持续时间达到6至8个月,且没有出现剂量限制性毒性、药物相关严重不良事件或炎症[45]
KSI-301 Kodiak Science公司开发的一种新型抗体生物聚合物偶联物KSI-301,由人源化的anti-VEGF单克隆抗体和磷酰胆碱聚合物组成,可增强稳定性并延长在眼内的停留时间,用于治疗nAMD和其他视网膜血管疾病[46]
OPT-302 OPT-302是一种首创的重组融合蛋白捕获分子,它通过阻止配体与血管内皮生长因子受体(vascular endothelial growth factor receptor,VEGFR) -2 和VEGFR-3结合,从而与VEGF-C和VEGF-D结合并中和其活性,被认为在 nAMD 病理生理学中起到VEGF-A的补充作用。366名受试者随机接受6次(每4周1次)玻璃体内注射:0.5 mg OPT-302(122例)、2.0 mg OPT-302(123例)或假注射(121例),所有组均联合0.5 mg雷珠单抗治疗。24周时2.0 mg OPT-302组的平均视力改善显著优于假注射组(+14.2±11.61 vs. +10.8±11.52 letters;P=0.01),而0.5 mg组与假注射组无显著差异(+9.44±11.32 letters;P=0.83)。各组不良事件发生率相似,低剂量组、高剂量组和假注射组分别有16例(13.3%)、7例(5.6%)和10例(8.3%)报告至少1例严重不良事件。OPT-302已被证明在治疗 nAMD 中视力提高效果明显,同时还具有解剖学优势和良好的安全性[47]
PAN-90806 PanOptica 公司研发的PAN-90806是VEGF-A和血小板衍生生长因子的酪氨酸激酶抑制剂。该药物是一种局部滴剂,据推测可通过经巩膜血管途径到达视网膜的靶组织。作为单药治疗nAMD具有预防或长期维持的可能性[48]
AKST4290 AKST4290是一种针对嗜酸性粒细胞趋化因子-1(Eotaxin-1,CCL11)的口服治疗药物,通过抑制CCL11受体,减少AMD患者脉络膜内皮细胞和全身血液循环中的CCL11表达。一项2a临床试验显示30例nAMD患者每日两次口服AKST4290(400mg),持续6周。6周后BCVA平均提高了+7.0 letters(95%CI,2.2~11.7),且没有患者发生严重或重大不良事件[49]
米诺环素 最初是作为抗生素合成的,大约二十年前,它被发现对小胶质细胞活化具有抑制作用,并展现出一种新的神经保护功能。目前米诺环素作为美国国立卫生研究院首家研发的改良型新药,是一种针对MMP靶点的口服制剂,在多种视网膜退行性疾病的模型中具有抗炎和神经保护作用。然而,其临床疗效和安全性仍需进一步的研究和验证[50-51]
眼睛是一个精密而复杂的器官,它拥有众多保护屏障。在眼科领域,有效地传递治疗眼部疾病的药物,尤其是针对眼后段的治疗,一直是一个巨大的挑战。然而,在过去的几年里,视网膜上和脉络膜下的注射、玻璃体腔内的植入给药,以及通过纳米技术和外泌体载体递送药物等创新方法,为治疗眼后节段疾病开辟了新的途径,并取得了显著的疗效。眼后节段部位的药物递送技术正在不断进步,这为眼科领域带来了新的挑战和机遇。我们坚信,随着实验诊断技术、新途径、新剂型和新药的不断研发,以及更多体内外实验和临床试验的进行,以验证其安全性和有效性,我们对眼部给药系统的理解将更加深入,从而能够开发出更加安全、有效、便捷的眼后节段部位给药技术。
  • 国家自然科学基金资助项目(82104714)
  • 辽宁省自然科学基金资助项目(LJKQZ20222404)
  • 辽宁省博士科研启动基金资助项目(2022-BS-069)
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doi: 10.13699/j.cnki.1001-6821.2025.16.024
  • 接收时间:2024-10-01
  • 首发时间:2026-04-02
  • 出版时间:2025-08-28
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  • 收稿日期:2024-10-01
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国家自然科学基金资助项目(82104714)
辽宁省自然科学基金资助项目(LJKQZ20222404)
辽宁省博士科研启动基金资助项目(2022-BS-069)
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    1.辽宁中医药大学 第二临床学院,辽宁 沈阳 110032
    2.辽宁中医药大学 附属第二医院 眼科,辽宁 沈阳 110034

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赵磊,副主任医师,研究生导师 MP:15040212468 E-mail:
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Number of
genus
种数
Number of
species
占总种数比例
Percentage of
total species (%)

Genus
种数
Number of
species
占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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