药学学报

Strategy	Brand name	Matrix material	Active pharmaceutical ingredient	Delivery system	Adminis- tration site	Company
Mucosal adhesion	Pilopine HS	Carbopol 940	Pilocarpine	Gel	Ocular	Alcon Laboratories, Inc.
Advantage-S	Polycarbophil and carbopol	Nonoxinol	Gel	Vaginal	Columbia Laboratories, Inc.
CRINONE	Polycarbophil and carbopol	Progesterone	Gel	Vaginal	Columbia Laboratories, Inc.
Mucus penetration	INVELTYS	Pluronic F127 (modified with PEG in a non-covalent fashion)	Loteprednol etabonate 1%	Suspension	Ocular	Kala Pharmaceuticals, Inc.
EYSUVIS	Pluronic F127 (modified with PEG in a non-covalent fashion)	Loteprednol etabonate 0.25%	Suspension	Ocular	Kala Pharmaceuticals, Inc.

Strategy	Brand name	Matrix material	Active pharmaceutical ingredient	Delivery system	Adminis- tration site	Company
Mucosal adhesion	Pilopine HS	Carbopol 940	Pilocarpine	Gel	Ocular	Alcon Laboratories, Inc.
Advantage-S	Polycarbophil and carbopol	Nonoxinol	Gel	Vaginal	Columbia Laboratories, Inc.
CRINONE	Polycarbophil and carbopol	Progesterone	Gel	Vaginal	Columbia Laboratories, Inc.
Mucus penetration	INVELTYS	Pluronic F127 (modified with PEG in a non-covalent fashion)	Loteprednol etabonate 1%	Suspension	Ocular	Kala Pharmaceuticals, Inc.
EYSUVIS	Pluronic F127 (modified with PEG in a non-covalent fashion)	Loteprednol etabonate 0.25%	Suspension	Ocular	Kala Pharmaceuticals, Inc.

Adhesion strategy	Delivery system	Administration site	Mechanism, advantage and disadvantage	Reference
Cationization	Nanogel	Bladder mucosa	Electrostatic effect enhances adhesion and improves the cell internalization, but the effect is unstable due to the presence of electrolytes	[12]
Gel	Vaginal mucosa	[13]
Nanocrystal	Vaginal mucosa	[14]
Lipid nanoemulsion	Nasal mucosa	[15]
Thiolation	Nanoparticles	Intestine	The disulfide bond is covalently bonded, which is a simple modification method, while the sulfhydryl group is easy to oxidize and lead to unsuccessful modification	[16, 17]
Gel	Nasal mucosa	[18]
Microspheres	Nasal mucosa	[19]
Maleimide modification	Liposomes	Bladder mucosa	The thioether bond is covalently bonded, the stronger adhesion results in obvious adhesion effect, but the functional groups are easy to oxidize and lead to failure	[20]
Tables	Oral mucosa	[21]
Prodrugs	Oral mucosa	[22]
Lectinization	Microspheres	Gastric mucosa	Binds specifically to glycosyls improves adhesion. While lectin is easily deactivated, causing immunogenicity or toxic effects in the body	[23]
Nanoparticles	Nasal mucosa	[24]
Micelles	Bladder mucosa	[25]
Thermosensitive gel	Ocular	[26]
Liposomes	Ocular	[27]
Catechol conjugation	Capsule	Intestine	Irreversible covalent binding effectively enhances the affinity of mucin. It is a kind of safe material from a wide range of sources, but its adhesion ability is sensitive to pH	[28]
Gel	Intestine	[29]

Adhesion strategy	Delivery system	Administration site	Mechanism, advantage and disadvantage	Reference
Cationization	Nanogel	Bladder mucosa	Electrostatic effect enhances adhesion and improves the cell internalization, but the effect is unstable due to the presence of electrolytes	[12]
Gel	Vaginal mucosa	[13]
Nanocrystal	Vaginal mucosa	[14]
Lipid nanoemulsion	Nasal mucosa	[15]
Thiolation	Nanoparticles	Intestine	The disulfide bond is covalently bonded, which is a simple modification method, while the sulfhydryl group is easy to oxidize and lead to unsuccessful modification	[16, 17]
Gel	Nasal mucosa	[18]
Microspheres	Nasal mucosa	[19]
Maleimide modification	Liposomes	Bladder mucosa	The thioether bond is covalently bonded, the stronger adhesion results in obvious adhesion effect, but the functional groups are easy to oxidize and lead to failure	[20]
Tables	Oral mucosa	[21]
Prodrugs	Oral mucosa	[22]
Lectinization	Microspheres	Gastric mucosa	Binds specifically to glycosyls improves adhesion. While lectin is easily deactivated, causing immunogenicity or toxic effects in the body	[23]
Nanoparticles	Nasal mucosa	[24]
Micelles	Bladder mucosa	[25]
Thermosensitive gel	Ocular	[26]
Liposomes	Ocular	[27]
Catechol conjugation	Capsule	Intestine	Irreversible covalent binding effectively enhances the affinity of mucin. It is a kind of safe material from a wide range of sources, but its adhesion ability is sensitive to pH	[28]
Gel	Intestine	[29]

Mucus penetration material	Delivery system	Administration site	Mechanism, advantage and disadvantage	Reference
PEG	Nanovesicles	Vaginal	The dense hydrophilic coating makes the particles invisible in the mucus and diffuse quickly, but PEG is easily oxidized and unstable, and the coating leads to poor cell internalization	[38]
Gene nanocarrier	Vaginal	[39]
Nanocages	Lung	[40]
Microspheres	Lung	[41]
Liposomes	Gastrointestinal tract	[42]
Nanoparticles	Vaginal	[43]
PVA	Nanoparticles	Vaginal mucus	PVA enhanced penetration efficiency by destroying hydrophobic interactions and protected the coated particles. PVA with a specific degree of hydrolysis were required, and there were few relatively reports	[44]
Nanoparticles	Cervical mucus	[45]
POZ	Nanoparticles	Gastric mucosa	POZ with high in vivo stability provided hydrophilic neutral coating. But POZ has not been approved by FDA	[46, 47]
Zwitterionic polymer	Nanoparticles	Intestine	Zwitterionic polymers provided hydrophilic neutral surface and the form of protein corona resisted adsorption of proteins, which not only improved mucus penetration but also enhanced cell uptake. However, current lack of studies report the use of zwitterionic polymers in drug delivery	[48, 49]

Mucus penetration material	Delivery system	Administration site	Mechanism, advantage and disadvantage	Reference
PEG	Nanovesicles	Vaginal	The dense hydrophilic coating makes the particles invisible in the mucus and diffuse quickly, but PEG is easily oxidized and unstable, and the coating leads to poor cell internalization	[38]
Gene nanocarrier	Vaginal	[39]
Nanocages	Lung	[40]
Microspheres	Lung	[41]
Liposomes	Gastrointestinal tract	[42]
Nanoparticles	Vaginal	[43]
PVA	Nanoparticles	Vaginal mucus	PVA enhanced penetration efficiency by destroying hydrophobic interactions and protected the coated particles. PVA with a specific degree of hydrolysis were required, and there were few relatively reports	[44]
Nanoparticles	Cervical mucus	[45]
POZ	Nanoparticles	Gastric mucosa	POZ with high in vivo stability provided hydrophilic neutral coating. But POZ has not been approved by FDA	[46, 47]
Zwitterionic polymer	Nanoparticles	Intestine	Zwitterionic polymers provided hydrophilic neutral surface and the form of protein corona resisted adsorption of proteins, which not only improved mucus penetration but also enhanced cell uptake. However, current lack of studies report the use of zwitterionic polymers in drug delivery	[48, 49]

Number	Sequence	Net charge at pH 7.4
1	LTAQPSTGGGS	-0.1
2	VNRSSLYGGGS	0.9
3	APTAVSKGGGS	0.9
4	TPHPLRLGGGS	1.1
5	APKQSLEGGGS	-0.1
6	VSTPSTPGGGS	-0.1
7	GGLSSRPGGGS	0.9
8	YPSPWGYGGGS	-0.1
9	TVRTSADGGGS	-0.1
10	TLNRVPNGGGS	0.9
11	GVPTALPGGGS	-0.1
12	QLVYPAPGGGS	-0.1
13	SSQLSRPGGGS	0.9
14	LGTSMQLGGGS	-0.1
15	SLGPSPGGGGS	-0.1
16	ISLPSPTGGGS	-0.1
17	MISSNSSGGGS	-0.1
18	YNSPTHHGGGS	0.4
19	SGTHHKAGGGS	1.4
20	TNTMTRAGGGS	0.9
21	KPFPPMKGGGS	1.9
22	ETTHLTGGGGS	-0.8
23	SPHDVAYDGGGS	-1.8
24	LPLWEVYGGGS	-1.1
25	QLKPLEFGGGS	-0.1
26	GETRAPLGGGS	-0.1

Number	Sequence	Net charge at pH 7.4
1	LTAQPSTGGGS	-0.1
2	VNRSSLYGGGS	0.9
3	APTAVSKGGGS	0.9
4	TPHPLRLGGGS	1.1
5	APKQSLEGGGS	-0.1
6	VSTPSTPGGGS	-0.1
7	GGLSSRPGGGS	0.9
8	YPSPWGYGGGS	-0.1
9	TVRTSADGGGS	-0.1
10	TLNRVPNGGGS	0.9
11	GVPTALPGGGS	-0.1
12	QLVYPAPGGGS	-0.1
13	SSQLSRPGGGS	0.9
14	LGTSMQLGGGS	-0.1
15	SLGPSPGGGGS	-0.1
16	ISLPSPTGGGS	-0.1
17	MISSNSSGGGS	-0.1
18	YNSPTHHGGGS	0.4
19	SGTHHKAGGGS	1.4
20	TNTMTRAGGGS	0.9
21	KPFPPMKGGGS	1.9
22	ETTHLTGGGGS	-0.8
23	SPHDVAYDGGGS	-1.8
24	LPLWEVYGGGS	-1.1
25	QLKPLEFGGGS	-0.1
26	GETRAPLGGGS	-0.1

黏膜给药中的黏液屏障及相关递送策略研究进展

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吕风梅 , 随力 , 刘哲鹏 ^*

药学学报 | 综述 2022,57(3): 670-680

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药学学报 | 综述 2022, 57(3): 670-680

黏膜给药中的黏液屏障及相关递送策略研究进展

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吕风梅, 随力, 刘哲鹏^*

作者信息

上海理工大学医疗器械与食品学院, 上海 200093

通讯作者:

*刘哲鹏, Tel: 13917505026; E-mail: zhepengliu@126.com

Research progress of delivery strategies related mucus barrier in mucosal drug delivery

Feng-mei LÜ, Li SUI, Zhe-peng LIU^*

Affiliations

School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China

出版时间: 2022-03-12 doi: 10.16438/j.0513-4870.2021-0935

文章导航

摘要

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黏液屏障是黏膜给药系统需要应对的一大生理障碍, 应对这一生理屏障, 研究者开展了大量关于黏膜黏附和黏液穿透的工作, 并取得一定成果。本文主要介绍了关于阳离子化、巯基化、马来酰亚胺功能化、凝集素化及儿茶酚缀合等新型黏膜黏附策略; 聚乙二醇、聚乙烯醇、聚(2-烷基-2-恶唑啉) 和两性离子聚合物等黏液惰性材料, 以及酶功能化、还原剂预处理等增强黏液穿透能力的研究, 并分析各策略存在的问题, 以期为临床转化提供参考。

关键词

黏膜给药 / 黏液屏障 / 黏膜黏附 / 黏液惰性 / 黏液穿透

Abstract

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The mucous barrier is a major physiological obstacle that the mucosal drug delivery system needs to deal with. In response to this physiological barrier, many achievements have been made in research of mucosal adhesion and mucus penetration. This review puts emphasis on the progress of the research on new mucosal adhesion strategies such as cationization, sulfhydrylization, maleimide functionalization, lectinization and catechol conjugation; polyethylene glycol (PEG), polyvinyl alcohol (PVA), poly (2-alkyl-2-oxazoline) (POZ), zwitterionic polymers and other mucus-inert materials, strategies to enhance mucus penetration ability such as enzyme functionalization, reducing agent pretreatment and so on. The problems of each strategy are also analyzed and discussed, which can provide some references for clinical transformation.

Key words

mucosal drug delivery / mucus barrier / mucosal adhesion / muco-inert / mucus penetration

引用本文

吕风梅, 随力, 刘哲鹏. 黏膜给药中的黏液屏障及相关递送策略研究进展. 药学学报, 2022 , 57 (3) : 670 -680 . DOI: 10.16438/j.0513-4870.2021-0935

Feng-mei LÜ, Li SUI, Zhe-peng LIU. Research progress of delivery strategies related mucus barrier in mucosal drug delivery[J]. Acta Pharmaceutica Sinica, 2022 , 57 (3) : 670 -680 . DOI: 10.16438/j.0513-4870.2021-0935

正文

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黏膜给药系统(mucosal drug delivery system, MDDS) 是一种新型给药系统, 主要是指将药物与适宜的载体材料施用于腔体黏膜部位, 起到局部作用或吸收进入体循环引发全身治疗作用的给药方式。黏膜给药有以下优势: ①相比于口服给药, 药物通过黏膜吸收进入体循环, 不经肝脏, 可以有效规避肝脏首过作用^[1]; ②黏膜内酶种类及数量有限, 对药物的酶促降解反应活性相对较低^[2]; ③局部给药, 提高作用部位的药物浓度, 提高生物利用度^[3]; ④局部施药, 方便患者自主操作, 提高患者依从性。

黏膜作为生物体免疫系统的第一道防线, 主要分布在口腔、鼻腔、眼部、胃肠道、阴道和呼吸道等部位, 由其上皮组织和结缔组织构成的膜状结构, 其上皮组织部分被称为上皮, 内部有丰富的血管和神经, 表面被黏液覆盖。黏液是黏蛋白、碳水化合物、类脂、水和细菌等的复杂混合物^[4], 由杯状细胞分泌的黏蛋白通过二硫键、钙交联和氢键等相互作用形成复杂的网状结构, 且黏蛋白富含疏水性半胱氨酸区域和带负电荷的低聚糖, 使黏液具有黏滞、凝聚和胶状等特性, 从而赋予黏液捕获外来物质的能力、保护黏膜的作用^{[4, 5]}。黏液层是一个动态系统, 具有天然的自我更新能力, 如眼部约5~7 min^[6]、胃肠道约4~6 h^[7]会完成一次黏液更新, 黏膜给药的有效物质如果不能及时地穿透黏液就会因黏液的更新而被清除^[4], 降低其生物利用度, 这就是黏膜给药系统中需要应对的黏液屏障(图 1)。

近年来, 增强药物跨黏液渗透的递送策略成为黏膜递药系统的一个研究方向。有研究者利用黏液屏障, 采用黏膜黏附策略, 确保药物能在黏液层保留一定时间进而扩散到上皮并由细胞摄取。而细胞内药物递送需要穿透黏液, 有学者则通过克服药物载体与黏蛋白纤维束之间的黏附作用, 使其迅速穿过黏液层到达下层上皮进而提高药物向细胞内运输效率。目前已上市的黏膜制剂(表 1) 仍以传统黏附材料和经典的黏液惰性材料为主, 如2020年, 由Kala公司研发的依托泊洛替诺酯眼用混悬液(EYSUVIS loteprednol etabonate ophthalmic suspension 0.25%) 被批准用于干眼病的短期治疗。Kala公司以其特有的黏液穿透颗粒药物递送技术AMPPLIFY开发了EYSUVIS, 以增强氯替泼诺向眼部黏膜组织的渗透。

本文将目前应对黏液屏障的相关递送策略的研究现状进行较全面的综述, 并分析其利弊, 为实现临床转化提供一定的参考价值。

1 黏膜黏附策略

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黏膜黏附策略是指以具有黏附性的聚合物为载体装载药物, 通过载体的生物黏附作用, 长时间黏附于黏液, 并通过接触黏膜上皮进入作用部位或循环系统, 发挥局部或全身的治疗作用^[8]。黏附材料的分子链与黏液中的黏性链段互相穿透, 通过机械嵌合、范德华力、静电吸引力、共价键、疏水作用和氢键等综合作用, 提供聚合物材料与黏膜接触机会, 从而发生生物黏附, 并维持一定时间, 使药物渗透进入组织, 达到作用部位。

1.1 传统黏附材料

天然的黏附材料主要有淀粉、透明质酸和明胶等。半合成黏附材料主要有脱乙酰壳多糖和纤维素衍生物, 脱乙酰壳多糖通过大量分子间氢键与黏蛋白层产生相互作用, 且与带负电的黏蛋白发生电荷效应, 对黏膜产生强黏附性^[9]; 应用较多的纤维素衍生物材料有羟乙基纤维素、羟丙甲纤维素及羧甲基纤维素钠, 这类材料以氢键和范德华力与黏蛋白之间发生黏附作用^[10]。目前应用最多的合成黏附材料主要有聚丙烯酸、聚卡波菲和卡波姆等。对于含有羧基和羟基的聚合物卡波菲, 氢键被认为是主导的黏附作用力^[10]; 卡波姆与黏蛋白发生物理缠绕并与黏蛋白寡糖链形成氢键, 从而形成强度较高的凝胶网状结构, 在黏膜表面保持较长的黏附时间^[11]。

但是, 传统的黏附材料普遍存在致命的缺点: 基于松散的相互作用, 不仅黏附作用强度低, 而且易受组织液中金属离子、pH值和组织运动等因素的影响, 滞留能力较弱且效果不稳定。

1.2 新型黏附性策略

近年来, 为提高生物黏附性能, 研究者开展了大量新型黏附性策略的工作, 其研究宗旨是将载体功能化从而加强载体材料与黏液间的相互作用, 如通过载体阳离子化策略增强静电吸引、通过将载体巯基或马来酰亚胺修饰以共价结合提高黏附作用或通过与糖基特异性结合的凝集素介导黏膜递送等, 表 2^[12-29]归纳总结了新型黏附策略在黏膜递药系统中的相关研究。

1.2.1 阳离子化策略

阳离子化是一种新兴的提高材料黏附性的功能化策略。黏液本身荷负电, 荷正电的载体可通过增强静电吸引作用延长黏液表面的滞留时间。研究表明, 与带负电或电中性的给药系统相比, 带正电荷的阳离子化给药系统具有更好的黏膜滞留性能。

Guo等^[12]将10-羟基喜树碱(10-hydroxycamptothecin, HCPT) 包封于基于聚(L-赖氨酸)-聚(L-苯丙氨酸-L-胱氨酸) 的阳离子化纳米凝胶(NG/HCPT, 表面电位~+16.3 mV) 中通过膀胱灌注法施用于荷原位膀胱癌的小鼠, 体内滞留实验结果表明, 单次施药6 h后, NG/HCPT的黏附性能是游离HCPT的5.3倍, 阳离子纳米凝胶递药系统有效延长了膀胱黏膜的保留时间。

泊洛沙姆407 (Pluronic F127, F127) 是最常用的温度敏感型凝胶基质材料之一, 但因缺乏黏附性, 在腔道液体作用下溶蚀后迅速流失, 在黏膜表面滞留时间短, 限制了药物疗效的充分发挥。Ci等^[13]将氨基修饰在F127分子长链的两端, 得到氨基化泊洛沙姆407 (F127-NH₂), 使其在生理条件下荷正电, 与荷负电的黏膜及黏膜表面的黏液发生电性作用, 旨在提高其黏液黏附性, 并以F127-NH₂凝胶包封醋酸棉酚用于阴道递药, 与F127即型凝胶相比, F127-NH₂即型凝胶在健康小鼠阴道给药8 h后, 阴道滞留量提高了3.2倍, 有效延长即型凝胶黏膜给药后的局部滞留。

随后Ci等^[14]又开展了一项关于阳离子化策略的工作, 将N-(叔丁氧羰基)-1, 2-二氨基乙烷通过迈克加成共价修饰到聚多巴胺膜包被的伊马替尼纳米晶表面, 经脱保护后, 将伊马替尼纳米晶成功阳离子化, 其表面电位高达+27 mV。结果表明, 阳离子化伊马替尼纳米晶对黏蛋白的黏附能力显著强于非阳离子化伊马替尼纳米晶, 且随着纳米晶表面电荷的增加其黏附能力也逐步提升。

阳离子化策略不仅可以增加黏附性延长滞留, 还因其表面荷正电可增强与带负电的上皮细胞间的相互作用, 从而提高细胞内化效率, 提高生物利用度。然而, 阳离子化黏附材料与黏蛋白间的电荷作用是可逆的, 且静电作用强度对电解质敏感性强, 其黏附作用并不是牢固可控的, 临床转化前景有限。

1.2.2 巯基或马来酰亚胺修饰

黏蛋白束富含半胱氨酸, 巯基可以与半胱氨酸基团的巯基侧链通过加成反应生成二硫键而增加紧密联系, 同样马来酰亚胺也可以与黏蛋白的巯基发生迈克加成形成硫醚键偶联。经巯基或马来酰亚胺修饰的载体可以通过更加牢固的共价键来加强与黏蛋白间的相互作用, 提高其黏附能力。

Mao等^[16]将N-(2-羟丙基) 甲基丙烯酰胺[N-(2-hydroxypropyl)methacrylamide, HPMA] 和硫醇化-N-甲基丙烯酰基-甘氨酰甘氨酸(thiolated-N-methacryloyl-glycylglycine, MA-GG-SH) 加成得到巯基化聚合物(thiolated polymer, PSH), 并将可分离的PSH亲水涂层包覆在介孔二氧化硅纳米粒表面, 使之具有很强的黏附强度, 大大增加了肠道停留时间。Marschütz等^[30]报道了巯基化的聚丙烯酸对黏蛋白的吸附量是未修饰聚丙烯酸的10倍, 巯基化聚丙烯酸微球能更有效地黏附于肠道表面, 滞留时间延长了3倍。Mahajan等^[18]通过巯基化泊洛沙姆407来增强模型药物木葡聚糖在绵羊鼻黏膜上的黏膜滞留能力。结果表明, 巯基化泊洛沙姆407显著改善了泊洛沙姆407凝胶的黏膜黏附性。

Kaldybekov等^[20]开发了常规脂质体、聚乙二醇化脂质体和带有马来酰亚胺官能化PEG (maleimide-functionalised PEG, PEG-Mal) 的脂质体(PEG-Mal脂质体) 用于膀胱内给药, PEG-Mal脂质体在膀胱组织中表现出较高的体外滞留性。Shtenberg等^[21]合成了用马来酰亚胺封端的PEG修饰的海藻酸盐(alginate-polyethylene glycol-maleimide, Alg-PEGM), 黏膜黏附研究显示, 与未改性聚合物相比, Alg-PEGM黏膜保留时间提高了2.8倍, 表现出优异的黏膜黏附特性。Liu等^[22]通过酯键将疏水药物5-氟尿嘧啶(5-fluorouracil, 5-FU) 和含有马来酰亚胺的1-烷基羰氧基甲基共价连接得到两亲性5-氟尿嘧啶前药(maleimide group-containing 5-FU prodrug, EMC-5-FU), 黏膜黏附研究表明, 与5-FU相比, 含马来酰亚胺基团的5-FU前药EMC-5-FU的肠道生物黏附力显著提高, 增强的黏膜黏附特性导致药物的良好黏膜保留并改善了5-FU口服吸收, EMC-5-FU成为一种创新的口腔黏膜黏附前药。

然而巯基化修饰和马来酰亚胺功能化在稳定性上存在明显缺陷, 巯基和马来酰亚胺基团都容易氧化失效, 在储存过程中必须特殊保护。

1.2.3 凝集素修饰

凝集素是一种能够结合糖基的蛋白质, 通常从植物中提取并以其来源植物命名, 如小麦胚芽凝集素、马铃薯凝集素、大豆凝集素和花生凝集素等。黏膜上皮细胞高表达多种糖基, 凝集素因具有对某一特异性糖基专一性结合能力可与黏膜特异性结合, 增强其黏附能力, 被誉为第二代生物黏附材料的代表。

近年来, 凝集素被广泛应用于黏膜给药系统^[23-26], Li等^[25]合成了两亲性嵌段共聚物: 聚(ε-己内酯)-嵌段-聚[2-(α-D-吡喃甘露糖) 丙烯酰胺乙基] (poly (ε-caprolactone)-block-poly [2-(α-D-mannopyranosyloxy) ethyl acrylamide], PCL-b-PManEA), 该嵌段共聚物自组装成胶束并装载抗癌药物多柔比星(doxorubicine, DOX)。为了赋予胶束的黏附特性, 将刀豆球蛋白A (concanavalin A, ConA) 凝集素进一步与胶束缀合(PCL-b-PManEA@ ConA)。黏蛋白的浊度测定结果表明, PCL-b-PManEA@ ConA胶束具有黏附性。Luo等^[26]以可降解材料明胶(gelatin, G) 和热响应型聚合物聚(N-异丙基丙烯酰胺) [poly (N-isopropylacrylamide), PN] 为基质, 构建了温敏凝胶[poly (N-isopropylacrylamide)-grafted gelatin, GN], 并通过碳二亚胺介导的偶联反应将螺旋藻凝集素(Helix pomatia agglutinin, HPA) 共价修饰到GN表面(GN-HPA), 局部施用于干眼症兔模型的眼部, 单次给药14天后, GN-HPA在眼内保留率高达13%, 是GN组的10倍, 显著增强其黏膜黏附性。

经凝集素修饰后的给药系统与各种黏膜具有较好的结合能力, 药物的吸收也有所增加, 但目前凝集素修饰策略存在一些问题如蛋白易变性失活, 且可能引发免疫原性^[31]和机体毒害作用^[32]等。

1.2.4 儿茶酚缀合

共价结合的方式被认为是一种增强黏附的高效方法, 而巯基化聚合物和黏蛋白的半胱氨酸残基之间的二硫键是可逆的, 故硫醇基团在黏膜表面的保留通常是短暂的, 此外马来酰亚胺通过硫醚键与黏蛋白的偶联及凝集素与上皮细胞表面糖基的结合都是可逆的。因此, 巯基化、马来酰亚胺修饰和凝集素化策略可能都不是增加现有聚合物黏附性的最佳方案。有研究^[33]发现, L-3, 4-二羟基苯丙氨酸(3, 4-dihydroxy-L-phenylalanine-lysine, DOPA) 是一种对贻贝强大的水下附着力至关重要的氨基酸, 受贻贝黏附机制的启发, 儿茶酚在自然界中作为DOPA的侧链被发现, 儿茶酚可与胺或羧酸基团进行生物偶联, 此外, 还具有通过氧化邻苯二酚形成邻醌与硫醇和胺形成不可逆共价键的能力^[34], 而在黏蛋白中存在伯胺基团和硫醇基团, 儿茶酚基团可以通过席夫碱或迈克尔加成与伯胺基团和硫醇基团反应, 形成不可逆的共价键, 从而可以有效增强与黏蛋白的亲和力。

Kim等^[28]将儿茶酚与壳聚糖缀合(chitosan-catechol, Chi-C), Chi-C与黏蛋白形成儿茶酚介导的共价交联以增强壳聚糖的黏膜黏附特性, 通过表面等离子体共振光谱检测到黏蛋白表面的Chi-C的残留量, 与未修饰的壳聚糖相比, 增加了4倍以上, 且口服给药后Chi-C的体内保留时间长达10 h。Heichel等^[29]将丝素蛋白成功地与酪胺结合, 酪胺是一种含酚分子, 蘑菇酪氨酸酶可将其氧化成儿茶酚官能团。丝素蛋白的水溶液可以在电场内形成黏性水凝胶, 但该体系的黏性不稳定会随着电场逆转, 而儿茶酚官能团化赋予丝素蛋白稳定的黏附能力。结果表明, 儿茶酚官能团化增加了凝胶和猪肠之间的黏合强度, 产生比市售纤维蛋白胶更强的黏合力。

儿茶酚衍生物廉价易得, 且有研究表明小鼠口服壳聚糖-儿茶酚偶联物后不会产生任何毒性。因此, 壳聚糖-儿茶酚偶联物可以被推荐用于开发不同药物递送系统的安全聚合物材料^[35]。然而有研究^[36]表明, 在酸性环境下, 壳聚糖-儿茶酚偶联物的黏膜黏附性差, 儿茶酚在碱性环境中比在酸性环境中更容易氧化成醌导致其黏附性对pH敏感。且目前以儿茶酚缀合聚合物增强黏膜黏附性的研究工作开展的不多, 或许正因为其强有力的黏附性能在一定程度上会导致其负载药物的提前泄露, 而降低其生物利用度。

1.3 多种黏附策略联用

近年来, 也有一些研究工作将具有提高黏附功能的官能团与现有黏附性聚合物材料化学共轭, 实现协同增强黏膜黏附特性。

Sudhakar等^[17]以季戊四醇四(3-巯基丙酸酯) [pentaerythritol tetrakis (3-mercaptopropionate), PETMP] 共轭壳聚糖(chitosan, CS) 得到巯基化CS, 构建了硫醇化壳聚糖纳米粒(thiolated chitosan nanoparticles, TCNPs) 用于口服胰岛素递送, 壳聚糖本身就有黏膜黏附性, 但以氢键和静电力为主的黏附作用强度低, 将壳聚糖硫醇化后, 可通过巯基与黏蛋白中的半胱氨酸残基共价形成二硫键, 赋予壳聚糖更好的黏附性能, 研究结果证实了荷正电TCNPs对覆盖肠上皮的负电黏液层具有吸引力, 且TCNPs的硫醇基团可以通过与黏液糖蛋白形成二硫键来延长停留时间, 显著改善黏膜黏附性。

Adebisi等^[23]以乙基纤维素和壳聚糖为骨架制备了装载克拉霉素的黏附性微球, 以刀豆球蛋白A与微球缀合, 构建了一个外源凝集素-药物载体复合物的共轭微球, 旨在增强微球的黏附能力。结果表明, 共轭微球对猪胃黏蛋白的亲和力显著高于未共轭微球, 其黏附能力增强了85%。

以上新型黏附策略的研究工作均从黏液的生理结构和性质出发, 通过赋予载体不同的功能, 进而加强药物载体与黏液之间的相互作用如静电吸引和共价结合等, 增加其黏附性能, 延长相互作用时间。

2 克服黏液屏障的递药策略

收起

黏液屏障会阻碍药物等活性成分接触黏膜导致有效物质流失, 在一定程度上降低生物利用度。有学者^[37]为避免药物载体黏附在黏蛋白纤维束上, 使其迅速穿过黏液层到达下层上皮进而提高药物向细胞内运输效率而采用黏液惰性材料或通过破坏黏蛋白等方式克服黏液屏障, 为有效物质穿透黏液到达黏膜部位争取时间, 以提高其生物利用度。表 3^[38-49]总结了各黏液惰性材料在黏膜递送系统中的研究应用。

2.1 经典的黏液惰性材料: 聚乙二醇

聚乙二醇(polyethylene glycol, PEG) 中的醚氧原子和糖基化黏蛋白上的糖基之间的氢键作用^[50]及PEG链和黏液的凝胶网络结构之间的互穿聚合物网络(interpenetrating polymer network, IPN) 效应^[51-53]赋予PEG一定的黏膜黏附性。随后在2007年, Justin Hanes研究团队^[54]发现, PEG的黏附性取决于PEG链的运动, 如果PEG链受到足够的约束, 降低IPN效应, 其黏膜黏附能力也会被削弱, 以PEG修饰的黏液穿透粒子(mucus-penetrating particle, MPP) 因PEG高度亲水性可“隐身”于黏液中, 且电中性的表面因静电排斥而削弱了与黏蛋白纤维束之间的相互作用, 从而实现在黏液中快速扩散, 此后PEG成为经典的黏液穿透材料, 大量的研究结果证明了其优越的黏液穿透特性^[42-47]。Huang等^[40]以PEG修饰铁蛋白纳米笼(polyethylene glycol modified ferritin heavy-chain nanocages, PEG-FTn) 克服肺部黏液屏障, 未经PEG修饰的FTn在气道上分布不均发生团聚, 经PEG修饰后, PEG-FTn在黏液中扩散速度快, 均匀分布于气道, 且负载多柔比星可有效延长肺癌小鼠的中位生存期。Li等^[41]将PEG修饰在微球表面构建可吸入的黏液穿透性微球用于肺部递送药物, 与不加PEG修饰的微球相比, PEG微球显示出优越的黏液穿透性, 且增强了肺组织的药物吸收。

随着对PEG黏液穿透性的深入研究, 研究者逐渐发现了一些影响其黏液穿透特性的因素。①有研究表明PEG的分子质量太低(极短的PEG链, 如小于500 Da) 因无法实现致密的刷状构象而不能赋予纳米粒黏液穿透特性^[55]; 分子质量在5~10 kDa的PEG存在临界相对分子质量, 达到临界相对分子质量时致密的PEG涂层从黏液惰性转变为黏膜黏附; 高分子质量的PEG, 空间位阻更大, 可阻止PEG链之外的反应基团与颗粒表面结合, 从而降低黏蛋白亲和力^[55]; 分子质量高达40 kDa时, 通过增加接枝密度也可实现在黏液中的快速扩散^[56]。②任何分子质量的PEG在纳米粒表面的接枝密度只有达到致密的毛刷状时才不会被黏蛋白纤维束固定, 表现出优越的黏液穿透特性^[43]; 当在纳米粒表面接枝PEG₂₀₀₀时, 只有接枝密度较高的纳米粒方能实现在黏液中的快速扩散^[57]。③纳米粒的粒径对其扩散速率的影响与不同黏膜部位的黏蛋白纤维束网状结构的空隙大小有关, 黏液的网状结构空隙在10~200 nm, 而粒径远远大于这个空隙尺寸的粒子被认为太大而无法通过黏液屏障快速扩散^[58], 而粒径太小会影响其药物包封效率。PEG修饰后的纳米粒的粒径在200~500 nm时容易在宫颈黏液中的扩散, 而100 nm的颗粒更易被黏液固定^[54]。④以相同分子质量的PEG同等接枝密度分别接枝于球形和棒状纳米粒表面时, 由于剪切流和黏液的网状结构促进了棒状纳米粒的旋转运动, 所以棒状纳米粒在黏液中扩散速率比球形纳米粒更快^[59]。

然而, PEG化学稳定性差, 易吸潮、氧化而降解^[60], PEG修饰的纳米粒因其表面高亲水性导致细胞内化差^[61-63], 在一定程度上降低了其疗效。目前PEG已广泛应用于食品、药品及化妆用品等领域, 人体血液中已存在抗PEG抗体, 而黏膜部位是否存在抗PEG抗体、局部PEG使用量是否会引发免疫反应、若黏膜部位存在抗PEG抗体则对基于PEG的黏液穿透纳米粒的性能有怎样潜在影响等问题尚需深入研究。除了PEG外, 其他的黏液惰性聚合物材料, 如聚乙烯醇、聚(2-烷基-2-恶唑啉) 和两性离子聚合物等也被广泛用于克服黏液屏障。

2.2 其他黏液惰性聚合物材料

2.2.1 聚乙烯醇

聚乙烯醇(polyvinyl alcohol, PVA) 是一种常用的赋形剂, 因存在大量羟基能与黏蛋白间形成氢键和疏水作用而显示出黏膜黏附特性^[64]。因此, 很多研究工作^{[65, 66]}将PVA包被策略用于提高递药系统的黏膜黏附特性。然而, Popov等^[44]通过调节PVA的水解程度改变其与黏液的相互作用, 研究证明75%~94%水解PVA中因大量的未水解的醋酸乙烯酯单元的存在, 使PVA涂层可与核心颗粒形成有效的疏水缔合, 形成一个电晕, 电晕的亲水性足以破坏与黏蛋白间的疏水作用, 且不会引起与黏蛋白的氢键作用, 充分保护涂层颗粒免受黏膜黏附相互作用, 增加涂层颗粒在黏液中的流动性, 且75%~94%水解PVA涂层颗粒的黏液穿透特性与PVA的相对分子质量无关。

目前针对PVA涂层颗粒的黏液穿透性研究还没有其他的新进展, 其临床价值也有待深入探索。

2.2.2 聚(2-烷基-2-恶唑啉)

聚(2-烷基-2-恶唑啉) [poly (2-alkyl-2-oxazoline), POZ] 是无毒且具有亲水性、高稳定性和生物相容性的材料^[67], 具有类似于PEG的优异“隐身”能力, 可抵抗蛋白吸附, 但其体内稳定性比PEG强^[68], 可成为PEG潜在的替代品。

Mansfield等^[46]通过改变POZ侧链的长度实现其亲水性的变化, 研究者将甲基、乙基和正丙基分别接枝到POZ侧链, 分别合成了聚(2-甲基-2-恶唑啉) [poly (2-methyl-2-oxazoline), PMOZ]、聚(2-乙基-2-恶唑啉) [poly (2-ethyl-2-oxazoline), PEOZ] 和聚(2-正丙基-2-恶唑啉) [poly (2-n-propyl-2-oxazoline), PNPOZ], 测得其亲水性随烷基侧链长度的增加而降低, 即PMOZ的亲水性最强, 并通过巯基(sulfhydryl, -SH) 将3种聚合物共价修饰在硫醇化二氧化硅纳米粒表面, 功能化后的纳米粒施用在新鲜的猪胃黏膜上, 观察到PMOZ修饰的纳米粒渗透能力最强。研究证实, 提高POZ亲水性可有效增加颗粒在黏液中的扩散速率。

然而, 目前聚(2-烷基-2-恶唑啉) 还未被美国食品药品监督管理局(Food and Drug Administration, FDA) 批准, 因此也限制了其临床应用。

2.2.3 两性离子聚合物

两性离子聚合物是一种同时具有阳离子和阴离子基团, 但整体呈电中性的聚电解质, 如羧酸甜菜碱(carboxybetaine, CB)、磺基甜菜碱(sulphobetaine, SB) 和磷酰胆碱(phosphorylcholine, PC) 等。两性离子具有极强的亲水性、生物惰性和生物相容性^[69], 且已有研究证实两性离子可以产生柔软、可逆的蛋白质电晕^[70], 可降低非特异性蛋白的吸附^[71]。因此, 包覆有两性离子涂层的纳米粒将具有优异的亲水性和中性表面, 获得优越的黏液穿透能力。

Shan等^[48]将二月桂酰基磷脂酰胆碱(dilauroylphosphatidylcholine, DLPC) 包覆在纳米粒表面, 实验发现, 仅3.4% DLPC NPs被黏液捕获, 在黏液中扩散迅速, 96%可穿透黏液层到达下层细胞。Gao等^[49]首次用磺基甜菜碱12 (sulfobetaine 12, SB12) 包被以脱氧胆酸(deoxycholic acid, DC) 改性的介孔二氧化硅纳米粒(mesoporous silica nanoparticles, MSNs) 获得具有两性离子涂层的纳米粒(MSN-DC@SB12), 以改善其黏液穿透性。结果表明, MSN-DC@SB12具有中性和亲水性表面, 在黏液中具有良好的穿透能力。

两性离子涂层不仅赋予纳米粒优越的黏液穿透能力, 且因与细胞磷脂膜具有相似的表面性质可提高细胞摄取, 提高生物利用率, 但目前仍缺乏对两性离子聚合物材料在药物递送方面的深入研究。

2.3 肽类

2.3.1 噬菌体展示的黏液穿透肽

除了聚合物之外, Leal等^[72]在噬菌体展示所得肽库中通过囊性纤维化(cystic fibrosis, CF) 黏液模型扩散筛选出26种具有黏液穿透能力的肽, 这些黏液穿透肽在氨基酸序列上均以柔性序列“-甘氨酸-甘氨酸-甘氨酸-丝氨酸(-GGGS)”接枝到N端, 表 4^[72]陈列了这26种由噬菌体展示技术筛选的具有黏液穿透能力的短肽的氨基酸序列及其表面电位, 可见各黏液穿透肽显示出电中性且高亲水性。与野生型对照相比, 噬菌体展示肽与黏蛋白的结合少, 在CF黏液中的扩散性提高了2.6倍。

2.3.2 类多肽

类多肽(polypeptoids) 是一类在氮原子上有一些取代的以脂族聚酰胺为主链的伪肽聚合物^[73]。人工合成的类多肽模拟了天然蛋白质的结构, 是可生物降解的生物聚合物^[74]。聚肌氨酸(polysarcosine, PSAR) 是一种非离子水溶性和生物相容性多肽, 已被用于表面和纳米粒的功能化^[75-77]。Lau等^[78]证明TiO₂表面接枝毛刷状的PSAR后对非特异性蛋白质吸附和细胞附着具有出色的抵抗力, 且其抑制蛋白质吸附的能力对PSAR链长和接枝密度有依赖性。但是目前没有关于以PSAR或任何其他类多肽进行颗粒功能化以促进其黏液扩散的报道, 但这些材料有望用于跨黏膜药物递送。

关于噬菌体展示的黏液穿透肽和人工合成的类多肽的在黏液穿透方面的研究工作还很少, 且这些肽类在体内活性、稳定性及噬菌体在体内的生存能力都有待深入探索。

2.4 破坏黏蛋白结构

2.4.1 以蛋白酶降解黏蛋白

在黏液穿透策略方面不仅可以使用黏液惰性材料, 还可以将常规颗粒功能化, 如以蛋白酶修饰, 常用的蛋白酶如胰蛋白酶、木瓜蛋白酶和菠萝蛋白酶等, 这些蛋白酶可以切割黏蛋白的交联网络结构, 充当黏液溶解剂, 从而能够局部破坏黏液层, 间接增强黏液穿透性。

Müller等^[79]将木瓜蛋白酶(papain, PAP) 和聚丙烯酸(polyacrylate, PAA) 共价连接, 并制备成纳米粒(PAP-PAA NPs), 研究发现酶功能化纳米粒在黏液层的扩散程度比没有酶的相同纳米粒高出3倍。随后, 将PAP和菠萝蛋白酶(bromelain, BROM) 分布与PAA共价连接, 分别制备木瓜蛋白酶功能化纳米粒(PAP-PAA NPs) 和菠萝蛋白酶功能化纳米粒(BROM-PAA NPs), 结果表明, 用蛋白酶功能化的纳米粒表现出更强的黏液穿透, 并且发现BROM-PAA NPs比PAP-PAA NPs穿透能力更强^[80]。

蛋白酶功能化策略能有效增强递药系统的黏液穿透能力, 但目前酶偶联纳米载体的技术还处于起步阶段, 只有少数聚合物可用作基质载体, 该策略在未来几年可能会得到进一步发展。而黏蛋白的破坏可能减弱黏液对病毒等外来物质的防御作用, 此外酶活性可能随时间而降低将导致酶功能化递药系统在长期稳定性方面存在潜在问题。

2.4.2 以还原剂预处理

黏蛋白束富含二硫键, 增加其网络结构的黏弹性, 破坏二硫键在一定程度上可减少黏蛋白纤维束的交联, 降低黏液对外来物质的束缚作用。Suk等^[81]将PEG_10K与聚-L-赖氨酸组成DNA载体(DNA-loaded poly-L-lysine conjugated polyethylene glycol 10 kDa, CK₃₀PEG_10K/DNA), 向囊性纤维化小鼠模型递送基因进行治疗, 以二硫键的还原剂N-乙酰基-L-半胱氨酸(N-acetyl-L-cysteine, NAC) 预处理模型小鼠以破坏黏蛋白间的二硫键, 预处理后吸入给药, 有效提高了基因向呼吸系统的递送, 小鼠气道基因的表达提高7~12倍。除NAC外, 还有还原型谷胱甘肽和二硫苏糖醇作为二硫键还原剂, 4-巯基苯甲酸作为高活性黏液溶解化合物及半胱氨酸作为二硫化物交换剂等都可以用于黏液预处理的有效物质。

还原剂预处理策略可以与多种递药系统配合使用, 使用范围广泛, 但是此策略改变了黏液的机械完整性, 降低了对外来有毒物质的防御能力, 且长期给药存在潜在问题。

综上所述, 黏液穿透策略的实现无疑是削弱载体与黏液之间相互作用; 或从载体出发, 选择中性-亲水性材料, 减少与黏液间相互作用加强渗透; 或从黏液出发, 破坏黏蛋白以促进颗粒的渗透。

3 黏膜黏附与黏液穿透的结合策略

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近年来, 也有一些研究工作^[82-84]开发了结合黏膜黏附和黏液穿透的双重功能平台, 有效地改善黏膜药物输送。

Hauptstein等^[82]合成了带有PEG的硫醇化壳聚糖, 与未修饰的壳聚糖相比, 含PEG的硫醇化壳聚糖显示出更大的黏膜黏附强度, 且与硫醇化壳聚糖的黏膜黏附性相当。此外, 含PEG的硫醇化壳聚糖在大鼠肠黏膜和Caco2细胞单层展示出强穿透能力。Krogstad等^[84]以黏膜黏附聚合物PVA或聚乙烯吡咯烷酮[poly (vinyl pyrrolidone), PVP] 为骨架的亲水性纳米纤维, 并装载具有穿透黏液功能的聚乙二醇化聚乳酸-羟基乙酸[poly (lactic-co-glycolic acid), PLGA] 纳米粒, 构建了黏附及穿透双功能递药系统, 在阴道模拟液中, 纳米纤维迅速水合, 释放出黏液穿透性的纳米粒。与纳米粒悬浮液相比, 阴道内给药的纳米纤维在阴道内滞留时间更长, 纳米粒在生殖道内的保留率提高了30倍。

结合黏膜黏附和黏液穿透为装载不相容药物或具有不同溶解性药物提供了可能, 该组合系统的潜力巨大, 值得进一步研究。

4 总结与展望

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黏膜黏附和黏液穿透两类递送策略在黏膜给药系统中是相辅相成的, 增强黏膜黏附性是为了向黏液内渗透提供足够的时间, 最终达到上皮细胞层, 穿透黏膜, 提高靶组织部位的药物浓度, 改善生物利用度。本文综合介绍了应对黏液屏障的相关递送策略, 并分析了其应用价值及局限性, 引发了一些值得思考的问题: ①针对PEG化纳米粒细胞内化差, 将配体(如细胞穿膜肽) 与PEG联用是否影响其黏液穿透能力？其影响程度与细胞内化效率的综合作用结果又如何？②黏膜黏附或黏液穿透过程药物的释放问题如何把握？③结合黏液更新速度, 如何设计黏膜黏附与黏液穿透二者的完美结合的智能化递药系统？④黏膜递药系统对黏液微生物稳态是否存在影响等。随着现代医药科技的进步和黏膜递药理论的不断完善, 更为合理有效的黏膜递药系统将会逐步实现临床转化, 为广大人民群众的生命健康带来福音。

作者贡献: 吕风梅构思了综述框架并负责文献查找分析及综述撰写; 随力进行内容评估; 刘哲鹏审核并修改。

利益冲突: 所有作者均声明不存在利益冲突。

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2022年第57卷第3期

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doi: 10.16438/j.0513-4870.2021-0935

接收时间：2021-06-25
首发时间：2025-12-22
出版时间：2022-03-12

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收稿日期：2021-06-25
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上海理工大学医疗器械与食品学院, 上海 200093

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*刘哲鹏, Tel: 13917505026; E-mail: zhepengliu@126.com

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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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TxT

Strategy	Brand name	Matrix material	Active pharmaceutical ingredient	Delivery system	Adminis- tration site	Company
Mucosal adhesion	Pilopine HS	Carbopol 940	Pilocarpine	Gel	Ocular	Alcon Laboratories, Inc.
Advantage-S	Polycarbophil and carbopol	Nonoxinol	Gel	Vaginal	Columbia Laboratories, Inc.
CRINONE	Polycarbophil and carbopol	Progesterone	Gel	Vaginal	Columbia Laboratories, Inc.
Mucus penetration	INVELTYS	Pluronic F127 (modified with PEG in a non-covalent fashion)	Loteprednol etabonate 1%	Suspension	Ocular	Kala Pharmaceuticals, Inc.
EYSUVIS	Pluronic F127 (modified with PEG in a non-covalent fashion)	Loteprednol etabonate 0.25%	Suspension	Ocular	Kala Pharmaceuticals, Inc.

Strategy

Brand name

Matrix material

Active pharmaceutical
ingredient

Delivery system

Adminis- tration site

Company

Mucosal adhesion

Pilopine HS

Carbopol 940

Pilocarpine

Gel

Ocular

Alcon Laboratories, Inc.

Advantage-S

Polycarbophil and carbopol

Nonoxinol

Gel

Vaginal

Columbia Laboratories, Inc.

CRINONE

Polycarbophil and carbopol

Progesterone

Gel

Vaginal

Columbia Laboratories, Inc.

Mucus penetration

INVELTYS

Pluronic F127 (modified with PEG in a non-covalent fashion)

Loteprednol etabonate 1%

Suspension

Ocular

Kala Pharmaceuticals, Inc.

EYSUVIS

Pluronic F127 (modified with PEG in a non-covalent fashion)

Loteprednol etabonate 0.25%

Suspension

Ocular

Kala Pharmaceuticals, Inc.

Adhesion strategy	Delivery system	Administration site	Mechanism, advantage and disadvantage	Reference
Cationization	Nanogel	Bladder mucosa	Electrostatic effect enhances adhesion and improves the cell internalization, but the effect is unstable due to the presence of electrolytes	[12]
Gel	Vaginal mucosa	[13]
Nanocrystal	Vaginal mucosa	[14]
Lipid nanoemulsion	Nasal mucosa	[15]
Thiolation	Nanoparticles	Intestine	The disulfide bond is covalently bonded, which is a simple modification method, while the sulfhydryl group is easy to oxidize and lead to unsuccessful modification	[16, 17]
Gel	Nasal mucosa	[18]
Microspheres	Nasal mucosa	[19]
Maleimide modification	Liposomes	Bladder mucosa	The thioether bond is covalently bonded, the stronger adhesion results in obvious adhesion effect, but the functional groups are easy to oxidize and lead to failure	[20]
Tables	Oral mucosa	[21]
Prodrugs	Oral mucosa	[22]
Lectinization	Microspheres	Gastric mucosa	Binds specifically to glycosyls improves adhesion. While lectin is easily deactivated, causing immunogenicity or toxic effects in the body	[23]
Nanoparticles	Nasal mucosa	[24]
Micelles	Bladder mucosa	[25]
Thermosensitive gel	Ocular	[26]
Liposomes	Ocular	[27]
Catechol conjugation	Capsule	Intestine	Irreversible covalent binding effectively enhances the affinity of mucin. It is a kind of safe material from a wide range of sources, but its adhesion ability is sensitive to pH	[28]
Gel	Intestine	[29]

Adhesion strategy

Delivery system

Administration site

Mechanism, advantage and disadvantage

Reference

Cationization

Nanogel

Bladder mucosa

Electrostatic effect enhances adhesion and improves the cell internalization, but the effect is unstable due to the presence of electrolytes

[12]

Gel

Vaginal mucosa

[13]

Nanocrystal

Vaginal mucosa

[14]

Lipid nanoemulsion

Nasal mucosa

[15]

Thiolation

Nanoparticles

Intestine

The disulfide bond is covalently bonded, which is a simple modification method, while the sulfhydryl group is easy to oxidize and lead to unsuccessful modification

[16, 17]

Gel

Nasal mucosa

[18]

Microspheres

Nasal mucosa

[19]

Maleimide modification

Liposomes

Bladder mucosa

The thioether bond is covalently bonded, the stronger adhesion results in obvious adhesion effect, but the functional groups are easy to oxidize and lead to failure

[20]

Tables

Oral mucosa

[21]

Prodrugs

Oral mucosa

[22]

Lectinization

Microspheres

Gastric mucosa

Binds specifically to glycosyls improves adhesion. While lectin is easily deactivated, causing immunogenicity or toxic effects in the body

[23]

Nanoparticles

Nasal mucosa

[24]

Micelles

Bladder mucosa

[25]

Thermosensitive gel

Ocular

[26]

Liposomes

Ocular

[27]

Catechol conjugation

Capsule

Intestine

Irreversible covalent binding effectively enhances the affinity of mucin. It is a kind of safe material from a wide range of sources, but its adhesion ability is sensitive to pH

[28]

Gel

Intestine

[29]

Mucus penetration material	Delivery system	Administration site	Mechanism, advantage and disadvantage	Reference
PEG	Nanovesicles	Vaginal	The dense hydrophilic coating makes the particles invisible in the mucus and diffuse quickly, but PEG is easily oxidized and unstable, and the coating leads to poor cell internalization	[38]
Gene nanocarrier	Vaginal	[39]
Nanocages	Lung	[40]
Microspheres	Lung	[41]
Liposomes	Gastrointestinal tract	[42]
Nanoparticles	Vaginal	[43]
PVA	Nanoparticles	Vaginal mucus	PVA enhanced penetration efficiency by destroying hydrophobic interactions and protected the coated particles. PVA with a specific degree of hydrolysis were required, and there were few relatively reports	[44]
Nanoparticles	Cervical mucus	[45]
POZ	Nanoparticles	Gastric mucosa	POZ with high in vivo stability provided hydrophilic neutral coating. But POZ has not been approved by FDA	[46, 47]
Zwitterionic polymer	Nanoparticles	Intestine	Zwitterionic polymers provided hydrophilic neutral surface and the form of protein corona resisted adsorption of proteins, which not only improved mucus penetration but also enhanced cell uptake. However, current lack of studies report the use of zwitterionic polymers in drug delivery	[48, 49]

Mucus penetration material

Delivery system

Administration site

Mechanism, advantage and disadvantage

Reference

PEG

Nanovesicles

Vaginal

The dense hydrophilic coating makes the particles invisible in the mucus and diffuse quickly, but PEG is easily oxidized and unstable, and the coating leads to poor cell internalization

[38]

Gene nanocarrier

Vaginal

[39]

Nanocages

Lung

[40]

Microspheres

Lung

[41]

Liposomes

Gastrointestinal tract

[42]

Nanoparticles

Vaginal

[43]

PVA

Nanoparticles

Vaginal mucus

PVA enhanced penetration efficiency by destroying hydrophobic interactions and protected the coated particles. PVA with a specific degree of hydrolysis were required, and there were few relatively reports

[44]

Nanoparticles

Cervical mucus

[45]

POZ

Nanoparticles

Gastric mucosa

POZ with high in vivo stability provided hydrophilic neutral coating. But POZ has not been approved by FDA

[46, 47]

Zwitterionic polymer

Nanoparticles

Intestine

Zwitterionic polymers provided hydrophilic neutral surface and the form of protein corona resisted adsorption of proteins, which not only improved mucus penetration but also enhanced cell uptake. However, current lack of studies report the use of zwitterionic polymers in drug delivery

[48, 49]

Number	Sequence	Net charge at pH 7.4
1	LTAQPSTGGGS	-0.1
2	VNRSSLYGGGS	0.9
3	APTAVSKGGGS	0.9
4	TPHPLRLGGGS	1.1
5	APKQSLEGGGS	-0.1
6	VSTPSTPGGGS	-0.1
7	GGLSSRPGGGS	0.9
8	YPSPWGYGGGS	-0.1
9	TVRTSADGGGS	-0.1
10	TLNRVPNGGGS	0.9
11	GVPTALPGGGS	-0.1
12	QLVYPAPGGGS	-0.1
13	SSQLSRPGGGS	0.9
14	LGTSMQLGGGS	-0.1
15	SLGPSPGGGGS	-0.1
16	ISLPSPTGGGS	-0.1
17	MISSNSSGGGS	-0.1
18	YNSPTHHGGGS	0.4
19	SGTHHKAGGGS	1.4
20	TNTMTRAGGGS	0.9
21	KPFPPMKGGGS	1.9
22	ETTHLTGGGGS	-0.8
23	SPHDVAYDGGGS	-1.8
24	LPLWEVYGGGS	-1.1
25	QLKPLEFGGGS	-0.1
26	GETRAPLGGGS	-0.1

Number

Sequence

Net charge at pH 7.4

LTAQPSTGGGS

-0.1

VNRSSLYGGGS

0.9

APTAVSKGGGS

0.9

TPHPLRLGGGS

1.1

APKQSLEGGGS

-0.1

VSTPSTPGGGS

-0.1

GGLSSRPGGGS

0.9

YPSPWGYGGGS

-0.1

TVRTSADGGGS

-0.1

TLNRVPNGGGS

0.9

GVPTALPGGGS

-0.1

QLVYPAPGGGS

-0.1

SSQLSRPGGGS

0.9

LGTSMQLGGGS

-0.1

SLGPSPGGGGS

-0.1

ISLPSPTGGGS

-0.1

MISSNSSGGGS

-0.1

YNSPTHHGGGS

0.4

SGTHHKAGGGS

1.4

TNTMTRAGGGS

0.9

KPFPPMKGGGS

1.9

ETTHLTGGGGS

-0.8

SPHDVAYDGGGS

-1.8

LPLWEVYGGGS

-1.1

QLKPLEFGGGS

-0.1

GETRAPLGGGS

-0.1