中国药学杂志

Ingredients	Drug	Therapy modality	Routes of administration	in vitro/vivo observation	Ref.
PLGA	Dexamethasone acetate	Anti-angiogenesis	Intravitreal injection	Controlled release;Drug release for 40 d;Inhibition of CNV;Low toxicity	[24]
PLGA	Sunitinib malate	Tyrosine kinase receptor inhibitor	Topical	Increased penetration;Cell compatibility;Superior anti-angiogenic potential, and prolonged inhibition of VEGF activity	[57]
RGD functionalized PLGA	Flt23k intraceptor plasmid	Anti-angiogenesis	Intravenous injection	Decrease in CNV;Improved visual acuity;No ocular or systemic toxicity	[58]
PLGA+polyethy- lenimine	Bevacizumab mAb+ Dexamethasone	Anti-VEGF	Intravitreal injection	Sustained drug release Anti-angiogenic effect on HUVECs; Reduce the amount of blood vessels; Decrease the leakage area of CNV	[59]
PEG coated albumin	Bevacizumab	Anti-VEGF	Topical	Enhanced efficacy; Inhibiting neovascularization	[60]
Albuminated PLGA	Bevacizumab mAb	Anti-VEGF	Intravitreal injection	Sustained release over 8 weeks; Prolong the time of eye retention	[27]
Albumin	Bevacizumab mAb	Anti-VEGF	-	Biphasic release pattern; Low cytotoxicity; Increase the retention time of eye drops in eyes	[61]
Chitosan	Bevacizumab	Anti-VEGF	Intraocular implant	Sustained release with efficacious delivery; Low cytotoxicity	[37]
Chitosan coated PLGA	Bevacizumab	Anti-VEGF	Intraocular	Sustained release over 72 h; No irritation and improved tolerability	[36]
PEG-PLGA:Fe₃O₄	Ranibizumab	Anti-VEGF	-	Enhanced anti-angiogenic activity with effective drug transfer; Less cytotoxicity	[50]
Trimethyl chitosan with HA	siRNA	Anti-VEGFR-2	Intravitreal injection	No significant cytotoxicity Reduced area of laser induced CNV with effective delivery to posterior tissues; Reduced VEGFR-2 mRNA expression	[41]
HA	pDNA	Nucleic acid	Intravitreal injection	Minimal toxicity;Improved gene transfection; Improved ARPE cellular uptake via gene delivery	[17]
PLGA MP+Chitosan NP	Ranibizumab	-	-	Enhanced anti-angiogenic activity; Slow drug release; Low cytotoxicity; Improved the encapsulation efficiency of ranibizumab	[55]

Ingredients	Drug	Therapy modality	Routes of administration	in vitro/vivo observation	Ref.
PLGA	Dexamethasone acetate	Anti-angiogenesis	Intravitreal injection	Controlled release;Drug release for 40 d;Inhibition of CNV;Low toxicity	[24]
PLGA	Sunitinib malate	Tyrosine kinase receptor inhibitor	Topical	Increased penetration;Cell compatibility;Superior anti-angiogenic potential, and prolonged inhibition of VEGF activity	[57]
RGD functionalized PLGA	Flt23k intraceptor plasmid	Anti-angiogenesis	Intravenous injection	Decrease in CNV;Improved visual acuity;No ocular or systemic toxicity	[58]
PLGA+polyethy- lenimine	Bevacizumab mAb+ Dexamethasone	Anti-VEGF	Intravitreal injection	Sustained drug release Anti-angiogenic effect on HUVECs; Reduce the amount of blood vessels; Decrease the leakage area of CNV	[59]
PEG coated albumin	Bevacizumab	Anti-VEGF	Topical	Enhanced efficacy; Inhibiting neovascularization	[60]
Albuminated PLGA	Bevacizumab mAb	Anti-VEGF	Intravitreal injection	Sustained release over 8 weeks; Prolong the time of eye retention	[27]
Albumin	Bevacizumab mAb	Anti-VEGF	-	Biphasic release pattern; Low cytotoxicity; Increase the retention time of eye drops in eyes	[61]
Chitosan	Bevacizumab	Anti-VEGF	Intraocular implant	Sustained release with efficacious delivery; Low cytotoxicity	[37]
Chitosan coated PLGA	Bevacizumab	Anti-VEGF	Intraocular	Sustained release over 72 h; No irritation and improved tolerability	[36]
PEG-PLGA:Fe₃O₄	Ranibizumab	Anti-VEGF	-	Enhanced anti-angiogenic activity with effective drug transfer; Less cytotoxicity	[50]
Trimethyl chitosan with HA	siRNA	Anti-VEGFR-2	Intravitreal injection	No significant cytotoxicity Reduced area of laser induced CNV with effective delivery to posterior tissues; Reduced VEGFR-2 mRNA expression	[41]
HA	pDNA	Nucleic acid	Intravitreal injection	Minimal toxicity;Improved gene transfection; Improved ARPE cellular uptake via gene delivery	[17]
PLGA MP+Chitosan NP	Ranibizumab	-	-	Enhanced anti-angiogenic activity; Slow drug release; Low cytotoxicity; Improved the encapsulation efficiency of ranibizumab	[55]

聚合物纳米粒在抗年龄相关性黄斑变性中的研究进展

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丛会婧 , 胡静 , 王婧 , 刘佳欣 ^* , 唐景玲 ^*

中国药学杂志 | 综述 2024,59(20): 1925-1930

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中国药学杂志 | 综述 2024, 59(20): 1925-1930

聚合物纳米粒在抗年龄相关性黄斑变性中的研究进展

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丛会婧, 胡静, 王婧, 刘佳欣^*, 唐景玲^*

作者信息

哈尔滨医科大学药学院, 哈尔滨 150086

丛会婧,女,硕士研究生研究方向:靶向药物递送系统

通讯作者:

^* 刘佳欣,女,博士,讲师研究方向:药物新剂型与制剂新技术 Tel:(0451)86660103;

唐景玲,女,博士,教授,硕士生导师研究方向:药物新剂型与制剂新技术 Tel:(0451)86660103

Progress of Polymer Nanoparticles for Combating Age-Related Macular Degeneration

Huijing CONG, Jing HU, Jing WANG, Jiaxin LIU^*, Jingling TANG^*

Affiliations

School of Pharmacy, Harbin Medical University, Harbin 150086, China

出版时间: 2024-10-22 doi: 10.11669/cpj.2024.20.006

文章导航

摘要

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年龄相关性黄斑变性(age-related macular degeneration,AMD)是一种退行性视网膜疾病,AMD主要又分为两种形式:干性(萎缩性)和湿性(渗出性)。玻璃体内注射抗血管内皮生长因子药物是最常用的治疗湿性AMD的方法,然而该方法仅能缓解并不能根治,且部分患者并不适应该给药方式。纳米技术的应用为改善AMD的药物输送提供了新的策略,其中聚合物纳米粒可提供持续的药物释放,经修饰可靶向病变部位并增加药物靶部位沉积,穿透眼部屏障延长药物滞留时间。本文综述了基于聚合物纳米粒治疗AMD的药物递送系统的研究进展,为AMD的治疗提供可行性参考。

关键词

年龄相关性黄斑变性 / 视网膜疾病 / 纳米技术 / 聚合物纳米粒 / 药物递送

Abstract

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Age-related macular degeneration (AMD) is a degenerative retinal disease. AMD is divided into two major forms: dry (atrophic) AMD and wet (exudative) AMD. The most common treatment for wet AMD is intravitreal injection of anti-vascular endothelial growth factor drugs. However, the treatment can only relieve but not care, and there are some patients who aren’t adapted to this treatment of administration. The application of nanotechnology offers new strategies for improving drug delivery in AMD, where polymeric nanoparticles can provide sustained drug release, can be modified to target the lesion and increase drug target site deposition, can penetrate the ocular barrier and extend drug retention times. This paper reviews the current research advances in polymeric nanoparticles-based drug delivery systems for the treatment of AMD, providing a viable reference to the treatment of AMD.

Key words

age-related macular degeneration / retinal disease / nanotechnology / polymer nanoparticle / drug delivery

引用本文

丛会婧, 胡静, 王婧, 刘佳欣, 唐景玲. 聚合物纳米粒在抗年龄相关性黄斑变性中的研究进展. 中国药学杂志, 2024 , 59 (20) : 1925 -1930 . DOI: 10.11669/cpj.2024.20.006

Huijing CONG, Jing HU, Jing WANG, Jiaxin LIU, Jingling TANG. Progress of Polymer Nanoparticles for Combating Age-Related Macular Degeneration[J]. Chinese Pharmaceutical Journal, 2024 , 59 (20) : 1925 -1930 . DOI: 10.11669/cpj.2024.20.006

正文

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年龄相关性黄斑变性(age-related macular degeneration,AMD)是一种退行性视网膜疾病,分为干性和湿性两种。其中,湿性AMD是导致视力丧失的主要原因,而脉络膜血管新生(choroidal neovascularization,CNV)是引起湿性AMD的主要病理机制^[1-6]。由于眼部存在的血-视网膜屏障等,常用的眼部滴眼液并不适合抗湿性AMD。临床一线抗湿性AMD的方法是玻璃体内注射抗血管内皮生长因子(VEGF)药物,常用的抗VEGF药物包括雷珠单抗、贝伐单抗、阿柏西普等,需每4周左右注射1次,但该方法并不能根治AMD,仅起到缓解病情的作用,且给药方式风险高、人眼能承受的次数有限,患者依从性较差^[7-14]。聚合物纳米粒(polymer nanoparticles, PNPs)作为纳米药物递送方式之一,在AMD的治疗中展现出独特的优势:PNPs具有无毒、非免疫原性和生物相容性等特点;可对PNPs进行表面修饰,从而使其获得不同的降解和释药速率,并可实现靶向、空间和时间的药物释放,这对于经常需要玻璃体内注射的药物,尤其是小分子药物是非常有意义的。此外有研究表明,对PNPs进行表面修饰后可使PNPs通过静脉注射实现定向靶向,使药物在病变部位累积发挥药效^[15-16]。本文综述了PNPs在AMD中的应用,为AMD的治疗和制剂研发提供新的思路与方法。

1 单一PNPs释药系统

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PNPs是由包裹的药物和聚合物辅料组成的,这些聚合物是天然的或合成的,如白蛋白、透明质酸(HA)、壳聚糖(CS)、聚乳酸-羟基乙酸(PLGA)、聚乙二醇(PEG)等,具有无毒性、非免疫原性和生物相容性的特点。通过调节PNPs的表面化学(电荷和亲水性)和修饰物,可以实现不同的降解速率和释放行为。根据PNPs释放活性物质的速率和分子固有的半衰期,可以调节给药频率,降低给药次数,解决玻璃体内频繁注射的问题^[17-18]。PNPs为抗AMD提供了巨大的优势,包括提高生物利用度,增强药物药代动力学,通过生物识别提高药效^[19],控制释放,在血管渗透区域累积等,这些优点克服了眼部给药面临的主要障碍^[15],纳米药物眼部局部给药途径见图1。

1.1 PLGA纳米粒

PLGA是由乳酸和羟基乙酸构成的聚合物,具有可生物降解性、生物相容性、无毒性、无抗原性等特点,已被美国食品药品监督管理局(FDA)批准广泛应用于生物医学和药物输送领域。

局部输送药物靶向视网膜治疗AMD仍然是药物开发的挑战之一,但有研究表明局部应用PLGA-NPs已成功到达视网膜。Sousa等^[21]制备了包载贝伐单抗的PLGA-NPs(Bev-PLGA-NPs),在不影响其生物活性的情况下控制贝伐单抗的释放并延长其保存时间。贝伐单抗可在生物学基础上缓慢释放,从而发挥单抗预期的作用。Zhang等^[22]制备的Bev-PLGA-NPs对内皮细胞和小鼠视网膜无明显毒性,药物持续释放达21 d。在体内研究显示,PLGA-NPs使贝伐单抗的表观半衰期增加,几乎是玻璃体内游离药物的2倍[(8.65±0.08) vs (4.96±0.15)]。与标准贝伐单抗溶液玻璃体内注射相比,药物平均停留时间(MRT)也显示出双倍的效果。负载非诺贝特的PLGA-NPs的载药量和包封率较高;Brown Norway大鼠经玻璃体内注射后,可在眼组织中缓慢释放维持60 d;在激光诱导的CNV大鼠和Vldlr-/-小鼠中均可减少视网膜血管渗漏和CNV形成,且无任何毒性^[23]。Xu等^[24]制备的醋酸地塞米松PLGA-NPs(DA-PLGA-NPs)经玻璃体内注射后对激光诱导的CNV大鼠模型具有剂量依赖性抑制作用。此外,DA-PLGA-NPs对视网膜细胞无明显毒副作用且在体外可持续释放40 d左右。Narvekar等^[25]制备的阿西替尼PLGA-NPs具有显著的抗血管生成能力。综上所述,使用PLGA-NPs作为抗AMD药物的递送载体,包封率更高,可明显发挥抗AMD作用^[21,26-27]。

1.2 白蛋白纳米粒

白蛋白具有内源性、水溶性、低免疫原性、天然丰度和生物相容性,而且体内存在其结合位点,所以在所有可用的蛋白质中,白蛋白是制备和优化蛋白质NPs的可靠选择。白蛋白常用的有牛血清白蛋白(bovine serum albumin,BSA)和人血白蛋白(human serum albumin,HSA),作为一种潜在的药物载体,在药物递送中发挥着重要的作用。白蛋白NPs通过与亲脂性药物结合而增加其疏水性,促使HSA自组装形成聚合胶束并增加载药量^[28-29]。白蛋白同时具有非凡的配体结合能力,所以可利用白蛋白对NPs进行表面修饰,通过与配体结合进行主动运输和选择^[30-31]。

Varshochian等^[27]制备的负载贝伐单抗的白蛋白化PLGA-NPs经兔玻璃体腔注射后,玻璃体内药物浓度可维持在500 ng·mL^-1以上且持续约8周,白蛋白化PLGA-NPs实现了控释,极大地延长药物释放时间,玻璃体MRT和t_1/2分别提高了3.3倍和1.6倍,因此该白蛋白化PLGA-NPs有望减少贝伐单抗的注射次数,进而减少相关并发症的发生。在另一项研究中,Koo等^[32]制备的HSA-NPs经玻璃体注射后表现出很强的渗透力,能够穿过整个视网膜到达视网膜色素上皮细胞(RPE);视网膜的TEM结果表明,HSA-NPs与Müller细胞相互作用,通过加强对视网膜结构的渗透来打破内限制膜的物理障碍(图2)。

1.3 壳聚糖(chitosan,CS)纳米粒

CS是一种由几丁质脱乙酰而得到的一种阳离子多糖,具有生物相容性、可生物降解性、无毒和非免疫原性的特点,作为眼内给药的纳米载体被广泛应用^[16,33],但主要用于眼前段。另外,CS可作为表面涂布剂,涂布于PLGA-NPs表面,利用其亲水性和黏附性用于眼后段给药。Tahara等^[34]将香豆素-6为荧光药物模型载入PLGA-NPs中,以CS、乙二醇壳聚糖(GCS)和聚山梨酯80(P80)对PLGA-NPs进行表面修饰,经修饰后的PLGA-NPs可能通过角膜、非角膜或葡萄膜路径到达视网膜,表明CS涂布PLGA-NPs可能是一种很有前景的靶向视网膜递送系统。

已有研究表明,玻璃体内注射负载贝伐单抗的CS-NPs是一种有效的抗VEGF药物的输送方式,且作用时间较长^[35]。Pandit等^[36]利用响应面法优化了CS包被的PLGA-NPs(CS-coated PLGA NPs),以贝伐单抗作为模型药物研究其缓释效果,贝伐单抗在72 h内的缓释率为25%;经优化的纳米处方无刺激性,可耐受眼内给药。Badiee等^[37]将负载贝伐单抗的CS-NPs均匀分散到HA和硫酸锌基质中,制备了眼部缓释植入剂,CS-NPs的载药量可达到(15.7±5.7)%。另有研究表明,利用CS-coated PLGA NPs和CS NPs经巩膜给药后贝伐单抗释放缓慢且无明显毒副作用,可作为玻璃体内注射抗AMD的一种很有前景的替代方案^[36-38]。

1.4 透明质酸(hyaluronic acid,HA)纳米粒

HA是一种阴离子生物多糖聚合物,由β-1,4-d-葡萄糖醛酸和β-1,3-n-乙酰葡糖糖胺的替代双糖单位组成^[39]。HA是玻璃体液的重要组成部分之一^[40]。此外,HA是CD44受体的主要配体,靶向CD44过表达的视网膜细胞,用于眼部药物传递。在处方中使用HA可增强细胞摄取,表现出优先积累并降低毒性和药物降解^[41]。

Mochimaru等^[42]研究了CD44和HA在CNV进展中的作用。利用敲除CD44的C57BL/6小鼠建立激光诱导的CNV小鼠模型。DNA芯片技术、PT-PCR和免疫组化研究显示,HA合成酶HAS-2和CD44基因在CNV小鼠模型中的RPE脉络膜复合体中表达。此外,将HA合成抑制剂(4-甲基伞形酮)或抗CD44中和抗体注射到激光诱导的CNV小鼠模型中,发现CNV病变体积减小。综上所述,HA-CD44阻断机制可能是一种很有前景的抗AMD的替代疗法。在另一项研究中,带负电荷的HA-NPs表现出很强的渗透力,能够打破内限制膜的物理屏障,穿过视网膜到达RPE细胞,这种渗透作用可能是因为HA-NPs具有对视网膜内血管的特异性靶向能力,也可能与Müller细胞内吞和胞吐作用相关的特定途径相关,其中Müller细胞的相互作用是克服内限制膜的物理屏障并渗透到视网膜深层结构的重要机制,这对抗AMD提供了新的策略^[32]。Chaharband等^[41]制备了CS-HA纳米复合材料,内部负载siRNA,用于改善AMD的基因治疗。CS-HA纳米复合物无明显细胞毒性,PT-PCR显示人脐静脉内皮细胞基因表达明显下调;经兔玻璃体内注射后,发现CS-HA纳米复合物能有效克服玻璃体和视网膜屏障明显减小CNV面积。

1.5 聚乳酸(PLA)纳米粒

PLA已被证明可以有效靶向特定的眼组织,这为脂肪族聚酯NPs在眼内疾病中的应用提供了机会。 Bourges等^[43]制备了含有荧光染料的PLA-NPs。玻璃体给药4个月后,仍可在大鼠视网膜色素上皮细胞中检测到荧光素。Kim等^[44]研制的包载水溶性整合素拮抗剂肽(C16Y)的聚乳酸/聚乳酸-聚乙烯氧化物(PLA/PLA-peo) NPs经玻璃体给药后可以穿透视网膜并定位到RPE细胞。C16Y半衰期很短,极易在玻璃体内消除,而PLA/PLA-peo NPs作为一种缓释系统,消除了C16Y的半衰期限制。Wang等^[45]用CPP修饰PEG-PLA制备了NPs-[CPP],并将DEACM(光可裂解基团)附着于CPP上,使NPs-[CPP]在静脉注射后通过光触发靶向将药物输送到病变的脉络膜。在激光诱导的CNV小鼠中,静脉注射NPs-[CPP]耦合眼部照射能增强NPs-[CPP]在病变部位的蓄积,显著减少CNV面积。Bolla等^[46]更是设计了一种PLGA-PEG-生物素NPs,通过增强视网膜细胞对叶黄素的吸收来发挥抗AMD的作用。Singh等^[47]分别制备了Flt23K-NPs、RGD-Flt23K-NPs、Tf-Flt23K-NPs和 RGD-Tf-Flt23K-NPs作为静脉给药靶向CNV的基因递送系统。在激光诱导的Brown Norway大鼠CNV模型中,经静脉给药后发现RGD-Flt23K-NPs、Tf-Flt23K-NPs和 RGD-Tf-Flt23K-NPs均增加了Flt23K在视网膜的递送,增加了视网膜血管内皮细胞和RPE细胞中受体内基因的表达,减少CNV面积,RGD-Flt23K-NPs、Tf-Flt23K-NPs和 RGD-Tf-Flt23K-NPs可通过静脉给药的方式将基因递送至病变部位并抑制激光诱导的CNV的发展。该靶向作用是因为RGD肽可与整合素α_vβ₃受体结合,而AMD患者的CNV中整合素α_vβ₃过表达;Tf通过TfR介导的内吞作用进入视网膜细胞,在AMD患者视网膜中观察到铁积累增加和Tf水平增加,因此由RGD和Tf修饰的NPs可对视网膜实现靶向作用。综上所述,靶向给药系统在静脉注射抗AMD中发挥着重要的作用。

1.6 PEG化纳米粒

PEG是一种具有水溶性、生物相容性、可生物降解、无毒、无免疫原性的聚合物,是生物医学和药物输送应用中最常用的聚合物之一^[48]。PEG化(与聚合物、脂类、蛋白质/多肽、药物、核酸偶联)改善了给药系统的药动学特性^[49]。Yan等^[50]制备了雷珠单抗偶联Fe₃O₄/PEG-PLGA-NPs,在Matrigel实验中,Fe₃O₄/PEG-PLGA NPs在不影响细胞增殖的情况下,对人脐静脉内皮细胞导管的形成具有较强的抗血管生成活性,这种抗血管生成的作用可用于CNV。Hoshikawa等^[51]设计的Mab/PEG偶联金纳米粒对抗AMD非常有利。

2 复合PNPs释药系统

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在特殊情况下,单一给药系统可能存在突释、释放周期短、毒性高等问题。复合释药体系以其设计简单、缓释能力强、生物毒性低等优势被广泛关注^[52]。Hirani等^[53]开发了一种由PEG-PLGA-NPs和PLGA-PEG-PLGA组成的热可逆凝胶复合释药体系,这种给药体系建立了一种新的抗AMD的方法。Rudeen等^[54]将DA-NPs和阿柏西普微球共同分散在聚乙二醇-L-乳酸二丙烯酸酯(PEG-PLLA-DA)-NIPAAm水凝胶中,这种复合给药方式可使药物在体外持续释放达到224 d。Elsaid等^[55]利用壳聚糖-N-乙酰-L-半胱氨酸(CNAC)制备了负载雷珠单抗的NPs(CNAC-NPs),并将CNAC-NPs加入到PLGA微粒(MPs)中,以改善雷珠单抗的负载和玻璃体内持续递送。这种复合给药体系显著改善了雷珠单抗的负载和释放特性,使药物释放缓慢且没有爆发释放,所释放的雷珠单抗均保持结构完整和体外活性,该体系增强了雷珠单抗的抗血管生成活性。研究人员还研发了贝伐单抗负载的PLA-NPs,并将其封装在多孔PLGA-MPs(NPinPMP)中,NPinPMP在4个月内的累计释放量约为81%,经大鼠玻璃体腔注射后,NPinPMP可以达到2个月的缓释效果,NPinPMP避免了抗体与有机溶剂的接触并延长了体外释放时间^[43,56]。更多PNPs在抗AMD中的研究见表1。

3 PNPs用于抗AMD的优势

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PNPs所用的载体材料为天然或合成的聚合物,如CS、BSA、PLGA、PEG、PLA等,这些载体材料已被广泛用于制药行业^[32];PNPs保护了常用的药物尤其是单抗类药物不被降解,在短时间内到达病灶,发挥药效;PNPs内部可包载亲水或亲脂类药物,极大地改善了药物的溶解度并增加药物的稳定性;对PNPs进行表面修饰后,能够实现定向靶向,使药物在血管病变区域累积,甚至有希望通过静脉靶向,现已有研究表明,PNPs经表面修饰后可通过静脉注射的方式靶向CNV区域,抑制VEGF表达,并可作为抗AMD的基因递送系统^[47,62]。此外PNPs能打破眼部屏障的限制,增加药物递送,提高利用度。

4 PNPs用于抗AMD的安全性

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生物安全性是毒理学领域关注的主要问题之一。当开发一种新的给药系统时,必须评估释放的药物和给药系统制剂对靶组织的潜在毒性。Narvekar等^[63]制备了阿西替尼负载的PLGA-NPs,体外安全性实验结果表明细胞活力均在90%以上,证实该PNPs给药系统对人类视网膜色素上皮细胞无毒。Kim等^[44]对其制备的PLA/PLA-PEO NPs进行了组织病理学研究,发现经眼部给药后, 视网膜和感光体形态正常,无凋亡细胞和炎症,表明其具有良好的眼生物相容性。虽然大多数PNPs主要还是通过玻璃体内注射的方式给药,但PNPs可提供缓控释放,有希望通过减少注射频率,进而相对减少由玻璃体内注射可能带来的并发症。此外Yao等^[64]制备了Ang 1-anti CD105-PLGA纳米粒(AAP NPs),经尾静脉注射AAP NPs后发现肝肾功能指标无显著差异;全血细胞计数代表性指标(白细胞、红细胞、血小板计数等)均正常, H&E切片显示主要脏器(肝、心、肺、肾、脾)未见明显病理异常。综上,在目前的研究中PNPs具有良好的生物安全性,但临床中的安全性还需进一步评估。

5 总结与展望

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在过去很长时间的研究中,虽然AMD导致的不可逆性失明得到了一定的预防,但完全治愈仍然还未实现,频繁的玻璃体内注射抗VEGF药物也带来了许多副作用。PNPs实现了药物持续释放,改善用药安全性、有效性和生物利用度;同时PNPs可实现靶向作用,增加病变部位的药物浓度,减少对其他部位的毒副作用;复合药物递送体系使药物能够保持持续稳定释放。但相对于上市产品而言,PNPs仍存在一定的局限性,如PNPs的粒径是重要的影响因素^[65],粒径较小则可能难以提供长效的药物释放,粒径较大可能并不适合于眼部给药,所以PNPs的处方与工艺至关重要;复合PNPs释药系统虽能提供较长时间的药物释放,但进一步的药动学考察还很少,因此需要建立合适的体内模型,以确保复合PNPs药物递送系统能够在生物体内持续释放药物,达到抗AMD的效果。

而且,PNPs在抗AMD领域的研究依旧处于早期阶段,而且仅限于临床前研究。这可能是因为AMD的发病机制复杂多变,多种发病机制都可能成为治疗的新靶点;在PNPs开发过程中,特别是复杂的递送系统,其开发需要更长的时间和更高的费用;PNPs的效果依赖于药代动力学、组织分布、药物释放等,这些特征在动物模型与患者身上差异巨大,而且存在患者的异质性;最重要的是,临床前的毒理研究结果可能与临床患者不一致,这也是大部分纳米制剂临床试验失败的原因。所以目前临床中所采用的治疗方式大多还是玻璃体内注射贝伐单抗、雷尼单抗等抗体药物,开发长效眼内持续给药的处方以及新的无创、非侵入性治疗方法仍然是巨大的挑战,依旧需要研究人员对AMD的患病机制有更多的了解;发展新型的纳米制造新技术和新设备;选择合适的动物模型提高人体的药效和毒理预测的准确性。相信随着科研与医疗水平的不断发展,PNPs在抗AMD中将发挥越来越大的优势。

基金

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黑龙江省博士后基金资助(LBH-Z20177)
哈尔滨医科大学药学院杰出青年基金资助(2019-JQ-03)

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2024年第59卷第20期

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doi: 10.11669/cpj.2024.20.006

接收时间：2023-09-21
首发时间：2025-12-30
出版时间：2024-10-22

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收稿日期：2023-09-21

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黑龙江省博士后基金资助(LBH-Z20177)

哈尔滨医科大学药学院杰出青年基金资助(2019-JQ-03)

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哈尔滨医科大学药学院, 哈尔滨 150086

通讯作者:

^* 刘佳欣,女,博士,讲师研究方向:药物新剂型与制剂新技术 Tel:(0451)86660103;

唐景玲,女,博士,教授,硕士生导师研究方向:药物新剂型与制剂新技术 Tel:(0451)86660103

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 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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Ingredients	Drug	Therapy modality	Routes of administration	in vitro/vivo observation	Ref.
PLGA	Dexamethasone acetate	Anti-angiogenesis	Intravitreal injection	Controlled release;Drug release for 40 d;Inhibition of CNV;Low toxicity	[24]
PLGA	Sunitinib malate	Tyrosine kinase receptor inhibitor	Topical	Increased penetration;Cell compatibility;Superior anti-angiogenic potential, and prolonged inhibition of VEGF activity	[57]
RGD functionalized PLGA	Flt23k intraceptor plasmid	Anti-angiogenesis	Intravenous injection	Decrease in CNV;Improved visual acuity;No ocular or systemic toxicity	[58]
PLGA+polyethy- lenimine	Bevacizumab mAb+ Dexamethasone	Anti-VEGF	Intravitreal injection	Sustained drug release Anti-angiogenic effect on HUVECs; Reduce the amount of blood vessels; Decrease the leakage area of CNV	[59]
PEG coated albumin	Bevacizumab	Anti-VEGF	Topical	Enhanced efficacy; Inhibiting neovascularization	[60]
Albuminated PLGA	Bevacizumab mAb	Anti-VEGF	Intravitreal injection	Sustained release over 8 weeks; Prolong the time of eye retention	[27]
Albumin	Bevacizumab mAb	Anti-VEGF	-	Biphasic release pattern; Low cytotoxicity; Increase the retention time of eye drops in eyes	[61]
Chitosan	Bevacizumab	Anti-VEGF	Intraocular implant	Sustained release with efficacious delivery; Low cytotoxicity	[37]
Chitosan coated PLGA	Bevacizumab	Anti-VEGF	Intraocular	Sustained release over 72 h; No irritation and improved tolerability	[36]
PEG-PLGA:Fe₃O₄	Ranibizumab	Anti-VEGF	-	Enhanced anti-angiogenic activity with effective drug transfer; Less cytotoxicity	[50]
Trimethyl chitosan with HA	siRNA	Anti-VEGFR-2	Intravitreal injection	No significant cytotoxicity Reduced area of laser induced CNV with effective delivery to posterior tissues; Reduced VEGFR-2 mRNA expression	[41]
HA	pDNA	Nucleic acid	Intravitreal injection	Minimal toxicity;Improved gene transfection; Improved ARPE cellular uptake via gene delivery	[17]
PLGA MP+Chitosan NP	Ranibizumab	-	-	Enhanced anti-angiogenic activity; Slow drug release; Low cytotoxicity; Improved the encapsulation efficiency of ranibizumab	[55]

Ingredients

Drug

Therapy modality

Routes of administration

in vitro/vivo observation

Ref.

PLGA

Dexamethasone acetate

Anti-angiogenesis

Intravitreal injection

Controlled release;Drug release for 40 d;Inhibition of CNV;Low toxicity

[24]