Surface design of nanocarriers: Key to more efficient oral drug delivery systems

doi:10.1016/j.cis.2023.102848

Advances in Colloid and Interface Science
进展在胶体与界面科学领域

Volume 313, March 2023, 102848
卷 313，2023 年 3 月，102848

EI检索SCI升级版化学1区SCI基础版化学2区IF 15.9

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Highlights 高亮

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The fate of oral NCs (SEDDS, SLN, NLC, liposomes, polymeric/inorganic nanoparticles) depends on their surface chemistry.
口腔非溶剂型纳米载体（SEDDS、SLN、NLC、脂质体、聚合物/无机纳米颗粒）的命运取决于其表面化学。
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Bioinert surfaces limit interactions with GI content and mucus guaranteeing that NCs can reach the absorption membrane.
生物惰性表面限制与胃肠道内容物和粘液的相互作用，确保纳米晶体能够到达吸收膜。
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Adhesive surfaces provide an intimate contact with the GI mucosa and a prolonged residence time.
粘附表面与胃肠道黏膜紧密接触，并具有较长的停留时间。
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Absorption enhancing surfaces guarantee an improved drug permeation of the epithelial cell layer.
吸收增强表面确保了上皮细胞层的药物渗透性得到改善。
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Surfaces that shift their zeta potential from negative to positive at the absorption membrane improve cellular uptake.
表面在吸收膜处将ζ电位从负变为正的细胞改善细胞摄取。

Abstract 摘要

As nanocarriers (NCs) can improve the solubility of drugs, prevent their degradation by gastrointestinal (GI) enzymes and promote their transport across the mucus gel layer and absorption membrane, the oral bioavailability of these drugs can be substantially enhanced. All these properties of NCs including self-emulsifying drug delivery systems (SEDDS), solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), liposomes, polymeric nanoparticles, inorganic nanoparticles and polymeric micelles depend mainly on their surface chemistry. In particular, interaction with food, digestive enzymes, bile salts and electrolytes, diffusion behaviour across the mucus gel layer and fate on the absorption membrane are determined by their surface. Bioinert surfaces limiting interactions with gastrointestinal fluid and content as well as with mucus, adhesive surfaces providing an intimate contact with the GI mucosa and absorption enhancing surfaces can be designed. Furthermore, charge converting surfaces shifting their zeta potential from negative to positive directly at the absorption membrane and surfaces providing a targeted drug release are advantageous. In addition to these passive surfaces, even active surfaces cleaving mucus glycoproteins on their way through the mucus gel layer can be created. Within this review, we provide an overview on these different surfaces and discuss their impact on the performance of NCs in the GI tract.
纳米载体（NCs）可以提高药物的溶解度，防止其被胃肠道（GI）酶降解，并促进其穿过粘液凝胶层和吸收膜，从而显著提高这些药物的口服生物利用度。NCs 的所有这些特性，包括自乳化药物递送系统（SEDDS）、固体脂质纳米颗粒（SLNs）、纳米结构脂质载体（NLCs）、脂质体、聚合物纳米颗粒、无机纳米颗粒和聚合物胶束，主要取决于其表面化学。特别是，与食物、消化酶、胆盐和电解质的相互作用、穿过粘液凝胶层的扩散行为以及在吸收膜上的命运都是由其表面决定的。可以设计生物惰性表面，限制与胃肠道液体和内容的相互作用以及与粘液的相互作用；粘附表面提供与 GI 粘膜的紧密接触；以及吸收增强表面。此外，电荷转换表面可以将ζ电位从负值直接转换为正值，在吸收膜上提供靶向药物释放的表面是有利的。除了这些被动表面外，甚至可以在通过粘液凝胶层的过程中切割粘液糖蛋白的活性表面也可以被创造。在本综述中，我们概述了这些不同的表面，并讨论了它们对肠道内纳米晶体性能的影响。

Graphical abstract 图形摘要

Key words 关键词

Oral drug delivery

Nanoparticles

Nanocarriers

Surface decoration

Absorption enhancement

口服药物递送纳米颗粒纳米载体表面修饰吸收增强

1. Introduction 1. 引言

Orally administered nanocarriers (NCs) have been shown to improve the solubility of encapsulated drugs [1] [2] and to prevent them from being degraded by gastrointestinal (GI) enzymes on the way to the absorption membrane [2] [3]. Furthermore, NCs can shuttle drugs efficiently across the mucus gel layer and can prolong GI residence times [4]. In addition, they are able to deliver drugs in a sustained manner and to promote drug transport across the absorption membrane [3]. Due to these properties they can substantially improve oral bioavailability of numerous drugs. Although the variety of NCs including self-emulsifying drug delivery systems (SEDDS), solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), liposomes, polymeric nanoparticles, inorganic nanoparticles and polymeric micelles is huge, their potential depends mainly on surface properties determining their fate in the GI tract. Via the surface chemistry of NCs their interaction with food, digestive enzymes, bile salts and electrolytes is controlled, their diffusion behaviour in the mucus gel layer defined and their fate on the absorption membrane determined. The design of their surface plays therefore a key role for the development of highly efficient oral drug delivery systems. Within this review article we describe the impact of different surfaces on the performance of NCs in the GI tract. We highlight the most suitable surfaces in order to overcome each single barrier with that NCs are confronted in the GI tract and discuss the likely best compromises to overcome all of them.
口服纳米载体（NCs）已被证明可以提高封装药物的溶解度[1][2]，并防止它们在到达吸收膜的过程中被胃肠道（GI）酶降解[2][3]。此外，NCs 可以有效地将药物穿梭过粘液凝胶层，并延长 GI 停留时间[4]。此外，它们能够以持续的方式递送药物并促进药物穿过吸收膜[3]。由于这些特性，它们可以显著提高多种药物的口服生物利用度。尽管包括自乳化药物递送系统（SEDDS）、固体脂质纳米颗粒（SLNs）、纳米结构脂质载体（NLCs）、脂质体、聚合物纳米颗粒、无机纳米颗粒和聚合物胶束在内的 NCs 种类繁多，但它们的潜力主要取决于决定其在胃肠道中命运的表面性质。通过 NCs 的表面化学，它们的与食物、消化酶、胆盐和电解质的相互作用得到控制，其在粘液凝胶层中的扩散行为得到定义，其在吸收膜上的命运得到确定。他们的表面设计因此对高度高效的口服药物递送系统的发展起着关键作用。在本综述文章中，我们描述了不同表面在胃肠道中纳米晶体（NCs）性能上的影响。我们强调了最合适的表面，以克服 NCs 在胃肠道中遇到的每个单独的障碍，并讨论了可能的最佳折衷方案以克服所有这些障碍。

2. Bioinert surfaces 2. 生物惰性表面

The interaction of NCs with GI contents can cause their destabilization, degradation or can lead to an unintended coating with them that masks favoured surface properties. Liposomes were shown to exhibit limited stability in simulated GI media releasing their payload in an uncontrolled manner [5]. Lipid based NCs such as NLCs or SEDDS that can be penetrated by lipases were shown to be lipolysed [6]. In case of liquid NCs such as SEDDS it was shown that fatty acids and bile salts can be incorporated in these NCs causing a shift in their zeta potential [7]. Zhang et al. provided evidence for the formation of a protein corona on the surface of NCs in the GI tract [8]. Cationic NCs were shown to interact with mucus making it more viscous [9]. In order to avoid such unintended interactions that are detrimental to efficiency, bioinert surface properties of orally given NCs are advantageous. The main strategies to achieve bioinertness are based on zwitterionic, polyethylene glycol (PEG), poloxamer/poloxamine and polyglycerol (PG) surfaces.
纳米晶体（NCs）与胃肠道（GI）内容物的相互作用可能导致其不稳定、降解，或导致与它们的不期望的涂层，从而掩盖有利的表面特性。研究表明，脂质体制剂在模拟 GI 介质中表现出有限的稳定性，以非控制方式释放其有效载荷[5]。研究表明，可被脂肪酶渗透的脂质基 NCs，如 NLCs 或 SEDDS，会发生脂解[6]。对于液体 NCs，如 SEDDS，研究表明脂肪酸和胆汁酸盐可以融入这些 NCs，导致其ζ电位发生改变[7]。张等人提供了胃肠道中 NCs 表面形成蛋白质冠的证据[8]。阳离子 NCs 被发现与粘液相互作用，使其更加粘稠[9]。为了避免这种对效率有害的不期望相互作用，口服 NCs 的生物惰性表面特性是有利的。实现生物惰性的主要策略基于两性离子、聚乙二醇（PEG）、聚氧乙烯/聚氧丙烯共聚物/聚氧乙烯胺（poloxamer/poloxamine）和聚甘油（PG）表面。

2.1. Zwitterionic surfaces
2.1. 两性离子表面

The zwitterionic surfaces of many viruses allow them to overcome various biological barriers like the mucus gel layer or cellular membranes. Certain viruses such as Hepatitis B, Norwalk and human papilloma virus exhibit in mucus and saline the same diffusion coefficient [10]. Decorating the surface of NCs with both anionic and cationic charges mimics the surface of viruses and provides bioinert properties. Zwitterionic surfaces bind water by Coulomb forces such as ion-dipole interactions, whereas most other surfaces interact via H-bonds with the surrounding water molecules. Bioinert NCs are able to immobilize water on their surface forming a stable solvation shell as interface shielding from interactions with GI compounds. As illustrated in Fig. 1 one zwitterionic sulfobetaine unit can bind up to eight water molecules, whereas one ethylene oxide unit can bind just one water molecule [11]. A high density of zwitterionic substructures on the surface of NCs leads consequently to super-hydrophilic shells that prevent interactions with the GI environment. In addition, because of the high proximity of opposite charges to each other on the surface, the interaction with ionic substructures found in the GI tract is marginal. Interactions with the ionic head group of bile salts, fatty acids, electrolytes and anionic substructures of mucus glycoproteins can be avoided.
许多病毒的偶极离子表面使它们能够克服各种生物屏障，如粘液凝胶层或细胞膜。某些病毒，如乙型肝炎病毒、诺如病毒和人类乳头瘤病毒，在粘液和盐水中表现出相同的扩散系数[10]。在 NCs 表面装饰阴离子和阳离子电荷，模仿病毒表面并提供生物惰性。偶极离子表面通过库仑力（如离子-偶极相互作用）结合水，而大多数其他表面通过与周围水分子形成氢键相互作用。生物惰性 NCs 能够在其表面固定水，形成稳定的溶剂化壳，作为界面屏蔽，防止与 GI 化合物的相互作用。如图 1 所示，一个偶极离子磺基胆碱单元可以结合多达八个水分子，而一个乙二醇单元只能结合一个水分子[11]。NCs 表面偶极子亚结构的密集分布导致超亲水壳层，从而防止与 GI 环境的相互作用。此外，由于表面正负电荷之间的距离很高，与胃肠道中发现的离子亚结构的相互作用微乎其微。可以避免与胆盐、脂肪酸、电解质和粘蛋白糖蛋白的阴离子亚结构的离子头部团的相互作用。

Amphoteric surfactants display such zwitterionic properties. Phospholipids are likely the most prominent amphoteric surfactants designed by nature that are used in NCs and in particular in liposomes [12]. As phospholipids are the basic building blocks of cell membranes, NCs can be directly coated with cell membranes to generate zwitterionic surfaces [13]. Dilauroyl phosphatidylcholine-coated NCs showed minimal interaction with mucins and high diffusivity [14] [15]. Furthermore, zwitterionic polymers such as polycarboxybetaine, polysulfobetaine, polyphosphorylcholine or polydopamine can be utilized as coating material for NCs [16] [17]. Also designed by nature are betaines being widely distributed in humans, animals and plants [18]. In fact, polycarboxybetaine coated NCs showed a 6.7 times higher diffusivity in mucus than PEG-coated NCs. After injection in the ileum these zwitterionic NCs provided a 4-fold higher biological activity of encapsulated insulin than PEG-coated NCs [19]. These results are in good agreement with various other studies showing that zwitterionic surfaces can compete with PEG surfaces in their bioinert properties [20 21]. Wu et al. used a different approach in order to analyse bioinert properties of coating materials. Instead of analysing the diffusion behaviour of NCs with different coatings in mucus or protein gels, they reversed the experimental setup and investigated the diffusion of proteins in zwitterionic and PEG hydrogels. Their results showed relatively lower interactions between protein-zwitterionic than protein-PEG hydrogels [22]. In Table 1 a comparison of the bio-/mucoinert properties of NCs with zwitterionic and PEG surfaces is provided. Apart from the use of zwitterionic compounds, zwitterionic properties can be provided by the combination of anionic and cationic surfactants or polymers. To which extent the combination of anionic and cationic surfactants leads to the formation of hydrophobic ion pairs that likely tend to concentrate in the inner lipophilic core, however, deserves further investigations. At least in case of polymers this is not an issue at all. As numerous anionic polymers such as polyacrylates, hyaluronic acid, alginate, pectin and carrageenan and a few cationic polymers including polymethacrylates with amino or ammonium substructures and protamine are listed in the inactive ingredient list of approved products [https://www.accessdata.fda.gov/scripts/cder/iig/index.cfm] and others such as chitosan have at least a monograph in the pharmacopoeia, the variety of different combinations for the design of polymeric zwitterionic surfaces is sheer endless. These NCs exhibit high mucus permeating properties [23] [24] [25]. Chitosan/chondroitin sulfate NCs, for instance, were shown to display 3-fold higher diffusion ability compared to PLGA NCs serving as reference [24] and similar results were obtained for chitosan/polyacrylic acid and chitosan/alginate NCs [23] [26]. Furthermore, chitosan/carboxymethyldextran NCs showed comparatively low protein adhesion depending on the ratio of anionic to cationic polymer in these delivery systems [27].
两性表面活性剂表现出这样的两性离子特性。磷脂可能是自然界设计的最突出的两性表面活性剂，用于纳米囊（NCs）中，尤其是在脂质体中[12]。由于磷脂是细胞膜的基本构建块，NCs 可以直接涂覆细胞膜以生成两性离子表面[13]。二硬脂酰磷脂酰胆碱涂覆的 NCs 与粘蛋白的相互作用最小，扩散性高[14] [15]。此外，两性离子聚合物如多羧基甜菜碱、多磺基甜菜碱、多磷酸胆碱或多多巴胺可以用作 NCs 的涂层材料[16] [17]。胆碱也由自然界设计，在人类、动物和植物中广泛分布[18]。实际上，多羧基甜菜碱涂覆的 NCs 在粘液中的扩散性比聚乙二醇涂覆的 NCs 高 6.7 倍。在回肠注射后，这些两性离子 NCs 提供的封装胰岛素的生物活性比聚乙二醇涂覆的 NCs 高 4 倍[19]。这些结果与各种其他研究的结果一致，表明两性离子表面可以在生物惰性特性上与 PEG 表面竞争[2021]。吴等人采用了一种不同的方法来分析涂层材料的生物惰性特性。他们不是分析不同涂层 NCs 在粘液或蛋白凝胶中的扩散行为，而是反转了实验装置，研究了蛋白质在两性离子和 PEG 水凝胶中的扩散。他们的结果表明，蛋白质-两性离子水凝胶之间的相互作用相对较低[22]。在表 1 中提供了 NCs 与两性离子和 PEG 表面的生物/粘性惰性特性的比较。除了使用两性离子化合物外，阴离子和阳离子表面活性剂或聚合物的组合也可以提供两性离子特性。然而，阴离子和阳离子表面活性剂的组合在多大程度上导致形成可能倾向于集中在亲脂性核心内的疏水性离子对，这需要进一步研究。至少在聚合物的情况下，这根本不是问题。众多阴离子聚合物如聚丙烯酸、透明质酸、藻酸盐、果胶和角叉菜胶以及一些阳离子聚合物，包括具有氨基或铵基亚结构的聚甲基丙烯酸和精蛋白，列在批准产品的非活性成分清单中[https://www.accessdata.fda.gov/scripts/cder/iig/index.cfm]和其他如壳聚糖至少在药典中有一个单方，聚合物两性离子表面的设计组合种类繁多。这些 NCs 表现出高粘液渗透性[23] [24] [25]。例如，壳聚糖/硫酸软骨素 NCs 显示出比作为参考的 PLGA NCs 高 3 倍的扩散能力[24]，对于壳聚糖/聚丙烯酸和壳聚糖/藻酸盐 NCs 也获得了类似的结果[23] [26]。此外，壳聚糖/羧甲基壳聚糖 NCs 在这些给药系统中，根据阴离子聚合物与阳离子聚合物比例，表现出相对较低蛋白质粘附性[27]。

Table 1. Comparison of the bio-/mucoinert properties of NCs with zwitterionic and PEG/poloxamer surface.
表 1. 比较 NCs 与两性离子和 PEG/泊洛沙姆表面的生物/疏水性。

Type of NC 类型 NC	Surface decorations 表面装饰	Bio-/mucoinert properties 生物/μ-共轭特性	Reference 参考文献
Zwitterionic surfaces providing higher bio-/mucoinert properties than PEG surfaces 两性离子表面提供比聚乙二醇表面更高的生物/疏水性
Polymeric nanoparticles 聚合物纳米颗粒	Zwitterionic surface: Polystyrene latex (PS) particles with poly(sulfobetaine)methacrylate (polySBMA) 两性离子表面：聚苯乙烯乳胶（PS）颗粒与聚（磺基甜菜碱）甲基丙烯酸甲酯（polySBMA） PEG surface: PS particles with 5 kDa PEG 聚乙二醇表面：5 kDa 聚乙二醇 PS 粒子	Faster mucus penetration with polySBMA-PS, similar stability within protein solution 聚 SBMA-PS 使粘液渗透更快，在蛋白溶液中稳定性相似	[28]
Polymeric nanoparticles 聚合物纳米颗粒	Zwitterionic surface: Gold nanoparticles with poly(carboxybetaine acrylamide) (polyCBAA) 两性离子表面：聚（羧基甜菜碱丙烯酰胺）（聚 CBAA）金纳米粒子 PEG surface: Gold nanoparticles coated with 5 kDa PEG 聚乙二醇表面：5 kDa 聚乙二醇包覆的金纳米粒子	PolyCBAA NCs showed lower interaction with proteins PolyCBAA NCs 与蛋白质的相互作用较低	[29]
Polymeric micelles/nanogels 聚合物胶束/纳米凝胶	Zwitterionic surface: 1,2-Distearoyl-sn-glycero-3-phosphorylethanolamine (DSPE) with polycarboxybetaine (PCB) of 5 kDa 两性离子表面：1,2-二硬脂酰基-sn-甘露醇-3-磷酸乙醇胺（DSPE）与 5 kDa 的多羧基甜菜碱（PCB） PEG surface: Polysorbate 80 containing PEG with unspecified chain length 聚乙二醇表面：含有未指定链长的聚乙二醇 80	Zwitterionic PCB particles diffuse 5-fold faster than PEG particles 两性离子 PCB 颗粒比 PEG 颗粒扩散速度快 5 倍	[19]
Polymeric micelles 聚合物胶束	Zwitterionic surface: Poly[2-(N-oxide-N,N-diethylamino)ethyl methacrylate] (OPDEA) 两性离子表面：聚[2-(N-氧化物-N,N-二乙基氨基)乙基甲基丙烯酸酯]（OPDEA） PEG surface: 5 kDa PEG 聚乙二醇表面：5 kDa 聚乙二醇	3-fold higher permeability for OPDEA- poly(ε-caprolactone) micelles 3 倍更高的 OPDEA-聚(ε-己内酯)胶束渗透率	[30]
Model test with grafted poly(ether sulfone) (PES) membrane 模型测试与嫁接的聚醚砜（PES）膜	Zwitterionic surface: [2-(Acryloyloxy)ethyl]trimethylammonium chloride 两性离子表面：[2-(丙烯氧基)乙基]三甲基氯化铵 PEG surface: PEG-22 聚乙二醇表面：PEG-22	Zwitterionic surface displayed the lowest binding affinity to mucus 两性离子表面显示出对粘液的最低结合亲和力	[31]

Zwitterionic and PEG/poloxamer surfaces providing similar bio-/mucoinert properties 两性离子和 PEG/泊洛沙姆表面提供相似的生物/粘蛋白惰性特性
Liposomes 脂质体	Zwitterionic surface: Poly(carboxybetaine) (PCB) 两性离子表面：聚（羧基甜菜碱）(PCB) PEG surface: 5 kDa PEG 聚乙二醇表面：5 kDa 聚乙二醇	Similar in vivo characteristics, higher stability provided by zwitterionic surface 与体内特性相似，两性离子表面提供了更高的稳定性	[32]
Liposomes and polymeric nanoparticles 脂质体和聚合物纳米颗粒	Zwitterionic surface: Liposomes containing 1,2-dioleoyl-sn-glycero-3-phosphocholine 两亲表面：含有 1,2-二油酰基-sn-甘油-3-磷酸胆碱的脂质体 PEG surface: Latex particles coated with PEG (no specified chain length) 聚乙二醇表面：涂覆有聚乙二醇（未指定链长）的乳胶颗粒	Similar diffusion behaviour of both particles in matrigel; however, PEG coated particles were 7-fold larger in size 两种粒子在 Matrigel 中的相似扩散行为；然而，PEG 包覆的粒子大小是未包覆粒子的 7 倍	[33]
Polymeric nanoparticles 聚合物纳米颗粒	Zwitterionic surface: dilauroyl phosphatidylcholine (DLPC) 两性离子表面：二硬脂酰磷脂酰胆碱（DLPC） PEG surface: Pluronic F127 聚乙二醇表面：泊洛沙姆 F127	Zwitterionic surface showed similar mucus permeation but a 3.17-fold higher uptake for DLPC nanoparticles 两性离子表面显示出相似的粘液渗透性，但对 DLPC 纳米粒子的吸收量高出 3.17 倍。	[34]
	Zwitterionic surface: Polydopamine 两性离子表面：聚多巴胺 PEG surface: Pluronic F127 聚乙二醇表面：泊洛沙姆 F127	Similar mucus penetrability, cellular uptake enhanced for zwitterionic surface 相似粘液渗透性，两性离子表面增强细胞摄取	[35]
	Zwitterionic surface with PEG: Cationic octa-arginine (R8) peptide and anionic phosphoserine moiety combined with 2 kDa PEG 两性离子表面与 PEG：阳离子八精氨酸（R8）肽和阴离子磷酸丝氨酸基团与 2 kDa PEG 结合 PEG surface: 2 kDa PEG 聚乙二醇表面：2 kDa PEG	Addition of zwitterionic structures to PEG coated PLGA NCs did not improve overall mucus permeability, however, the zwitterionic surface exhibited 3.4-fold higher uptake by mucus-secreting E12 cells 聚乙二醇包覆的 PLGA 纳米晶体中添加两性离子结构并未提高整体粘液通透性，然而，两性离子表面表现出比粘液分泌 E12 细胞 3.4 倍更高的摄取率	[36]
Polyplexes 多聚物	Zwitterionic surface: Phosphorylcholine-based polymers (PMPC) 两性离子表面：磷酸胆碱基聚合物（PMPC） PEG surface: 5 and 20 kDa linear PEG polyplexes 聚乙二醇表面：5 和 20 kDa 线性聚乙二醇聚复合物	20 kDa PEG and PMPC corona exhibited similar protein adsorption blocking, whereas PMPC showed higher cellular uptake in vivo 20 kDa PEG 和 PMPC 冠层表现出相似的蛋白质吸附阻断，而 PMPC 在体内表现出更高的细胞摄取	[20]
Silica nanoparticles 二氧化硅纳米颗粒	Zwitterionic surface: Sulfobetaine 12 (N-dodecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate) 两性离子表面：磺基甜菜碱 12（N-十二烷基-N,N-二甲基-3-氨基-1-丙烷磺酸盐） PEG surface: Pluronic P123 聚乙二醇表面：泊洛沙姆 P123	Similar permeability in porcine intestinal mucus 猪肠道粘液的相似渗透性	[37]

PEG surfaces providing higher bio-/mucoinert properties than zwitterionic surfaces 聚乙二醇表面提供比两性离子表面更高的生物/疏水性特性
Polymeric nanoparticles 聚合物纳米颗粒	Zwitterionic surface: polyacrylic acid/chitosan 两性离子表面：聚丙烯酸/壳聚糖 PEG surface: 5 kDa mPEG PEG 表面：5 kDa mPEG	NCs with PEG coating showed higher mucus diffusion than zwitterionic NCs 聚乙二醇涂层的 NCs 比两性离子 NCs 表现出更高的粘液扩散性	[23]
Liposomes 脂质体	Zwitterionic surface: 1,2-disteoroyl-sn-glycero-3-phosphatidylcholine (DSPC) 两亲性表面：1,2-二硬脂酰基-sn-甘油-3-磷脂酰胆碱（DSPC） PEG surface with DSPC: 2 kDa PEG 聚乙二醇（PEG）表面与 DSPC：2 kDa PEG	PEGylated liposomes diffused faster in mucus PEG 修饰的脂质体在粘液中扩散更快	[38]

2.2. Polyethylene glycol (PEG) surfaces
2.2. 聚乙二醇（PEG）表面

Polyethylene glycol (PEG) surfaces are broadly used to provide bioinert properties in the GI tract. PEG chains can form a dense hydrated brush on the surface of NCs shielding them from interactions with GI fluids and mucus. Generally, the capability of PEG to form hydrogen bonds with GI compounds is low [39]. Poor protein binding has been correlated with improved mucus permeating properties [40]. High mucoinert and mucus permeating properties of PEG coated NCs were demonstrated in numerous studies [41] [42] [43]. Density, chain length and architecture of PEG brushes have an essential impact on protein adhesion [44]. Dense PEG coatings are beneficial but cannot fully evade protein adsorption [45 46]. PLGA NCs that were coated with a dense PEG brush showed higher mucus permeating properties than those coated with a loose brush [47]. To provide sufficient mucoinert properties, a PEG chain length of 0.3-0.5 kDa seems to be sufficient as comparatively high mucus permeating properties were shown for SEDDS containing PEGylated surfactants such as polysorbates or polyoxyl hydrogenated castor oils (PEG 35 castor oil and PEG 40 castor oil) forming a dense PEG surface [43]. Nonetheless, a PEG chain length of ≥2 kDa is frequently used [48] [49] [50] [51]. Inchaurraga et al. showed that the mucus permeating properties of NCs prepared from the copolymer of methyl vinyl ether and maleic anhydride are higher when these NCs are coated with 2 kDa or 6 kDa PEG than with 10 kDa. Excessive PEG densities were even shown to decrease mucus-permeating properties. Furthermore, NCs coated with 2 kDa or 6 kDa PEG displayed a more prolonged intestinal residence time than those coated with 10 kDa PEG [52]. Long PEG chains seem to entangle with the mucus network limiting mucus penetrating properties. The combination of short and long PEG chains [53] and the architecture of bottle [54], loop [55], branched [56] or cross-linked PEG brushes [57] have also been utilized to improve bioinertness of NCs. In contrast to PEG coverage-density, however, these differences in PEG architecture seem to be of minor relevance. “Hetero-brush” PEG surfaces and in particular those exhibiting a short “underbrush” layer of PEG combined with long PEG have shown higher bioinert properties than “homo-brush” PEG surfaces [58].
聚乙二醇（PEG）表面广泛应用于提供胃肠道（GI）的生物惰性特性。PEG 链可以在纳米晶体（NCs）表面形成致密的亲水刷，从而保护它们免受胃肠道流体和粘液的相互作用。通常，PEG 与胃肠道化合物形成氢键的能力较低[39]。蛋白质结合不良与粘液渗透性能的提高相关[40]。许多研究表明，PEG 包覆的 NCs 具有高粘液惰性和粘液渗透性能[41][42][43]。PEG 刷的密度、链长和结构对蛋白质吸附有重要影响[44]。致密的 PEG 涂层有益，但不能完全避免蛋白质吸附[4546]。涂有致密 PEG 刷的 PLGA NCs 比涂有疏松刷的 NCs 具有更高的粘液渗透性能[47]。为了提供足够的粘液惰性特性，0.3-0.5 kDa 的 PEG 链长度似乎足够，因为含有 PEG 化表面活性剂（如聚山梨酯或聚氧乙烯氢化蓖麻油，如 PEG 35 蓖麻油和 PEG 40 蓖麻油）的 SEDDS 显示出较高的粘液渗透性能，形成致密的 PEG 表面[43]。尽管如此，≥2 kDa 的 PEG 链长度经常被使用[48] [49] [50] [51]。Inchaurraga 等人表明，从甲基乙烯基醚和顺丁烯二酸酐共聚物制备的纳米颗粒（NCs）的粘液渗透性能，当这些 NCs 被涂覆 2 kDa 或 6 kDa PEG 时，比涂覆 10 kDa PEG 时更高。甚至过高的 PEG 密度还被证明会降低粘液渗透性能。此外，涂覆 2 kDa 或 6 kDa PEG 的 NCs 比涂覆 10 kDa PEG 的 NCs 在肠道中的停留时间更长[52]。长 PEG 链似乎会与粘液网络纠缠，限制粘液渗透性能。短和长 PEG 链[53]以及瓶[54]、环[55]、分支[56]或交联 PEG 刷[57]的结构也被用来提高 NCs 的生物惰性。然而，与 PEG 覆盖密度相比，这些 PEG 结构的不同似乎影响不大。“异质刷”PEG 表面，尤其是那些具有短“底层”层 PEG 与长 PEG 结合的表面[58]，比“同质刷”PEG 表面显示出更高的生物惰性。

2.3. Poloxamer/poloxamine surfaces
2.3. 泊洛沙姆/泊洛沙明表面

Poloxamers such as Pluronic® F-127 are polyoxyethylene–polyoxypropylene block copolymers. In contrast to PEGs they contain also hydrophobic domains because of the polyoxypropylene blocks. Due to this property, they can be incorporated into hydrophobic NCs such as PLGA nanoparticles, SEDDS, NLCs, SLNs and liposomes. The surface decoration with Pluronic® F-127 significantly improved the mucus diffusing properties of PLGA nanoparticles and liposomes [59 60]. Hu et al. compared the mucus permeating properties of PLGA NCs coated with Pluronic F-127, a zwitterionic polymer and PEG. Their results showed the highest mucus permeating properties for the zwitterionic polymer coating followed by the PEG and Pluronic F-127 coating that were in the same range [35].
聚氧乙烯-聚氧丙烯嵌段共聚物，如 Pluronic® F-127。与 PEGs 相比，它们还含有疏水基团，因为含有聚氧丙烯嵌段。由于这一特性，它们可以与疏水性纳米载体如 PLGA 纳米颗粒、SEDDS、NLCs、SLNs 和脂质体结合。Pluronic® F-127 的表面修饰显著提高了 PLGA 纳米颗粒和脂质体的粘液扩散性能[5960]。Hu 等人比较了 Pluronic F-127、两性聚合物和 PEG 涂覆的 PLGA 纳米载体的粘液渗透性能。他们的结果表明，两性聚合物涂覆的粘液渗透性能最高，其次是 PEG 和 Pluronic F-127 涂覆，它们的性能处于同一水平[35]。

In contrast to poloxamers (Pluronic©), poloxamines (Tetronic©) exhibit a cationic charge because of amine groups. Self-aggregation of these block polymers due to hydrophobic substructures results in the formation of polymeric micelles. The core of these micellar systems formed by hydrophobic polymer chains enable incorporation of lipophilic drugs, whereas the hydrophilic blocks build an outer shell [61] [62]. By the combination of poloxamers and poloxamines mixed polymeric micelles can be formed [63] [64] [65].
与泊洛沙姆（Pluronic©）不同，泊洛沙明（Tetronic©）由于含有胺基团而表现出阳离子电荷。这些嵌段聚合物由于疏水亚结构而发生的自聚集导致聚合物胶束的形成。由疏水性聚合物链形成的这些胶束系统的核心能够容纳亲脂性药物，而亲水性块则构建外层壳[61] [62]。通过泊洛沙姆和泊洛沙明的组合，可以形成混合聚合物胶束[63] [64] [65]。

2.4. Polyglycerol (PG) surfaces
2.4. 多甘醇（PG）表面

The additional hydroxyl functions of polyglycerols (PGs) in comparison to PEGs provide a more pronounced hydrophilic character and superior hydration. It enables also the synthesis of both linear and branched PG chains [66]. Friedl et al. evaluated the association of bile salts on SEDDS with PG and PEG surfaces revealing that PEG surfaces hamper bile salt fusion to a higher extent than PG surfaces [67]. Similar to PEGs the chain length of PG has a significant impact on its bioinert properties. A chain length of 1.5 kDa was shown to be sufficient to prevent surface interactions with proteins, whereas a chain length below 0.75 kDa resulted already in protein-surface interactions [66 68]. Zou et al. compared the bioinert character of PG- and PEG-coated NCs with each other showing that it increases in the following order: unmodified < low PEG < medium PEG < low PG < medium PG < high PG [69]. Furthermore, PGs were shown to form less reactive oxygen species (ROS) than PEGs [70] that are responsible for the oxidation of various drugs [71] and for allergic reactions [72].
聚甘油（PGs）相较于聚乙二醇（PEGs）具有更多的羟基官能团，这赋予了其更明显的亲水特性和更优越的保湿性能。它还使得线性及分支 PG 链的合成成为可能[66]。Friedl 等人评估了胆盐与 PG 和 PEG 表面的 SEDDS 之间的关联，发现 PEG 表面比 PG 表面更阻碍胆盐的融合[67]。与 PEGs 类似，PG 的链长对其生物惰性特性有显著影响。研究表明，1.5 kDa 的链长足以防止与蛋白质的表面相互作用，而低于 0.75 kDa 的链长已经导致蛋白质-表面相互作用[6668]。Zou 等人比较了 PG 和 PEG 涂覆的 NCs 的生物惰性特性，发现其增加顺序为：未修饰 < 低 PEG < 中等 PEG < 低 PG < 中等 PG < 高 PG[69]。此外，PGs 比 PEGs 形成更少的活性氧（ROS）[70]，这些 ROS 是各种药物氧化[71]和过敏反应[72]的原因。

2.5. Comparison of bioinert surfaces
2.5. 生物惰性表面的比较

By comparing the bioinert properties of these different surfaces with each other likely the following rank order can be established: zwitterionic > PEG = PG. High bioinert properties are advantageous to avoid interactions of NCs with GI fluids and the mucus gel layer. As soon as NCs have reached the absorption membrane, however, bioinert properties are a hindrance, since they strongly limit interactions of NCs with cellular membranes. Cellular uptake of PEG-coated NCs and in particular that of NCs coated with long PEG chains was shown to be limited in most non-phagocytic and phagocytic cell lines because of a steric hindrance, reduced surface charge and hydrophilic-hydrophobic repulsion [73] [74]. SEDDS exhibiting a PEGylated surface showed lower SEDDS-cell interactions than SEDDS with a PG surface [67]. Furthermore, the partial substitution of a PEG-surfactant with various PG-surfactants resulted in enhanced cellular internalization of SEDDS [75]. Nonetheless, a direct correlation between the bioinert properties of NCs and their cellular uptake does not exist. As illustrated in Fig. 2 zwitterionic surfaces exhibit both: relatively high bioinert properties and relatively high cellular interactions. Dilauroyl-phosphatidlycholine coated NCs showed for example a 4.5-fold increase in cellular uptake on a mucus secreting colon carcinoma cell line, whereas PEGylated NCs were unable to improve cellular uptake although both surfaces exhibited similar mucoinert properties [76]. Zwitterionic surfaces are therefore likely the current best compromise between these two opposing surface properties. In order to avoid even this compromise NCs that are able to convert their surface charge from negative to positive directly at the absorption membrane have been developed. Such systems are described in detail in section 5.
通过比较这些不同表面的生物惰性特性，可以建立以下排序：两性离子 > PEG = PG。高生物惰性特性有利于避免纳米晶体（NCs）与胃肠道（GI）流体和粘液凝胶层的相互作用。然而，一旦 NCs 达到吸收膜，生物惰性特性就成为一种阻碍，因为它们强烈限制了 NCs 与细胞膜之间的相互作用。研究表明，PEG 包覆的 NCs 的细胞摄取，尤其是长 PEG 链包覆的 NCs，在大多数非吞噬性和吞噬性细胞系中受到限制，这是由于空间位阻、表面电荷减少和亲水-疏水排斥[73] [74]。具有 PEG 化表面的 SEDDS 与具有 PG 表面的 SEDDS 相比，表现出较低的 SEDDS-细胞相互作用[67]。此外，将 PEG 表面活性剂部分替换为各种 PG 表面活性剂，导致 SEDDS 的细胞内化增强[75]。尽管如此，NCs 的生物惰性特性与其细胞摄取之间存在直接相关性。如图所示两性离子表面同时表现出：相对较高的生物惰性特性和相对较高的细胞相互作用。例如，二硬脂酰磷脂酰胆碱包覆的纳米晶体（NCs）在分泌粘液的结肠癌细胞系中显示出细胞摄取量增加了 4.5 倍，而聚乙二醇化 NCs 尽管两种表面表现出相似的粘液惰性特性，却无法提高细胞摄取量[76]。因此，两性离子表面可能是目前在这两种对立表面特性之间最佳折衷的选择。为了避免这种折衷，已经开发出能够在吸收膜处直接将表面电荷从负变为正的 NCs。这类系统在第 5 节中详细描述。

3. Adhesive surfaces

The design of adhesive instead of bioinert surfaces can also be beneficial. For oral drug delivery, in particular the adhesion of NCs to the mucus gel layer covering GI epithelia is of interest. Evidence for the potential of both strategies – mucoinert and mucoadhesive surfaces of NCs – is provided by numerous in vivo studies and has already been reviewed extensively [77]. The concept of mucoinert NCs aims to bring NCs in close contact with the absorption membrane where they can interact with epithelial cells providing enhanced drug uptake, whereas mucoadhesive NCs are supposed to remain within the mucus gel layer for a prolonged time releasing the drug in a concentrated manner close to the absorption membrane. As illustrated in Fig. 3 mucoadhesive properties can be provided by chain entanglements of mucoadhesive polymers with mucins and by either non-covalent interactions of the surface of NCs with the mucus gel layer including H-bonding or the formation of covalent bonds such as disulfide bonds that are formed between thiolated polymers and cysteine-rich subdomains of mucus glycoproteins. In Table 2 excipients that are used for the design of mucoadhesive NCs are listed.
粘附性表面而非生物惰性表面的设计也可能有益。特别是对于口服药物递送，NCs 与覆盖胃肠道上皮的粘液凝胶层的粘附性引起了人们的兴趣。通过许多体内研究提供了关于这两种策略——NCs 的粘液惰性和粘附性表面——的潜力证据，并且已经被广泛审查[77]。粘液惰性 NCs 的概念旨在使 NCs 与吸收膜紧密接触，在那里它们可以与上皮细胞相互作用，提供增强的药物摄取，而粘附性 NCs 则应保持在粘液凝胶层内一段时间，以浓缩的方式在吸收膜附近释放药物。如图 3 所示，粘附性可以通过粘附性聚合物的链缠结与粘蛋白以及 NCs 表面与粘液凝胶层之间的非共价相互作用（包括氢键）或形成共价键（如硫醇化聚合物与粘液糖蛋白富含半胱氨酸的亚结构域之间形成的二硫键）来提供。在表 2 中列出了用于设计粘附性 NCs 的辅料。

Table 2. Mucoadhesive polymers used for the design of NCs; representative in vivo studies highlighting the potential of such delivery systems.
表 2. 用于设计纳米载体的粘附性聚合物；突出此类递送系统潜力的代表性体内研究。

Mode of adhesion 粘附方式	Material 材料	Mechanism of mucoadhesion 粘附机理	Representative in vivo studies 代表性体内研究	References 参考文献
Entanglements/ H-bonding 纠缠/氢键	Alginate 褐藻酸盐	Physical entanglements of the polymer with mucin result in mucoadhesive properties; H-bond formation with mucus glycoproteins 聚合物与粘蛋白的物理交联导致其具有粘附性；与粘液糖蛋白形成氢键	Intestinal mucoadhesion of alginate coated core-shell chitosan nanoparticles was shown for oral delivery of naringenin 肠粘附的藻酸盐包覆核壳型壳聚糖纳米粒子被用于橙皮苷的口服递送	[78]
	Carbomer 卡波姆		Acyclovir-loaded spheres with carbomer as mucoadhesive polymer exhibited prolonged residence time and significantly increased bioavailability compared to acyclovir suspension 阿昔洛韦载药微球以羧甲基纤维素钠为粘附性聚合物，与阿昔洛韦悬浮液相比，表现出更长的滞留时间和显著提高的生物利用度	[79]
	Carboxymethyl cellulose sodium salt 羧甲基纤维素钠盐		Carboxymethyl cellulose coated gliadin nanoparticles showed increased bioaccessibility of encapsulated phloretin with controlled release behaviour 羧甲基纤维素包覆的大麦醇提取物纳米颗粒提高了包封的儿茶素的可生物利用度，并表现出可控的释放行为	[80]
	Hyaluronic acid 透明质酸		In vivo studies showed 2 to 10-fold higher mucoadhesion and bioavailability for cross-linked hyaluronic acid nanoparticles compared to free hyaluronic acid 体内研究显示，与游离透明质酸相比，交联透明质酸纳米粒子的粘附性和生物利用度高出 2 至 10 倍	[81]
	Hydroxy ethyl cellulose 羟乙基纤维素		Clarithomycin loaded hydroxyl ethyl cellulose nanoparticles proved rapid H. pylori clearance attributed to strong mucoadhesion of nanoparticles to Hep-2 cell surface 克拉霉素载药羟乙基纤维素纳米颗粒表现出快速清除幽门螺杆菌，归因于纳米颗粒与 Hep-2 细胞表面的强粘附性。	[82]
	Pectin 果胶		Pectin-liposome nanoplexes demonstrated strong mucoadhesion remaining in the intestinal tract even 6 h after administration 果胶-脂质体纳米复合物在给药后 6 小时仍表现出强烈的肠道粘附性	[83]
	Polycarbophil 聚卡波非钙		Amoxicillin loaded polycarbophil nanoparticles interacted with mucus but less pronounced than thiolated polycarbophil nanoparticles 阿莫西林载药聚卡波非钙纳米粒子与粘液相互作用，但程度不如巯基化聚卡波非钙纳米粒子明显	[84]
	Polyethylene glycol (PEG) 聚乙二醇（PEG）		7.3-fold improvement of oral bioavailability of cabazitaxel was achieved for surface polyethylene oxide (PEO) decorated positively charged polymer-lipid hybrid nanoparticles 7.3 倍提高卡巴他赛口服生物利用度，实现了表面聚乙二醇（PEO）修饰的带正电荷聚合物-脂质杂化纳米粒子的效果	[85]
	Poly(vinyl pyrrolidone) 聚乙烯吡咯烷酮		3-fold enhancement in oral bioavailability of alendronate was achieved for complex hydrogels formed with chitosan and ring-opened polyvinyl pyrrolidone 阿仑膦酸钠在口服生物利用度方面实现了 3 倍提升，这是通过壳聚糖和开环聚乙烯吡咯烷酮形成的复合水凝胶实现的	[86]
Ionic interactions / entanglements / H-bonding 离子相互作用/纠缠/氢键	Chitosan 壳聚糖	Cationic charges of mucoadhesive polymers interact strongly with negative charges of mucus glycoproteins; H-bond formation with mucus glycoproteins; physical entanglements of the polymer with mucus glycoproteins further improve mucoadhesive properties 阳离子粘附性聚合物的电荷与粘液糖蛋白的负电荷强烈相互作用；与粘液糖蛋白形成氢键；聚合物与粘液糖蛋白的物理缠结进一步改善粘附性	Nanoparticles of amphiphilic chitosan derivatives exhibited improved oral bioavailability of scutellarin 纳米级两亲性壳聚糖衍生物的纳米颗粒提高了穿心莲内酯的口服生物利用度	[87]
	Poly(aspartic acid)-chitosan 聚天冬氨酸-壳聚糖		Poly(aspatic acid)-chitosan nanoparticles showed enhanced bioavailability of 5-fluoruracil 聚（天冬氨酸）-壳聚糖纳米粒子提高了 5-氟尿嘧啶的生物利用度	[88]
	N-Trimethyl chitosan N-三甲基壳聚糖		Prolonged gastrointestinal residence time and enhanced oral bioavailability of harmine was shown for N-trimethyl chitosan coated liposomes 延长胃肠道停留时间和提高 harmine 的口服生物利用度在 N-三甲基壳聚糖包覆脂质体中得到证实	[89]
Disulfide bridges 二硫键	Thiolated chitosan 硫醇化壳聚糖	Formation of disulfide bridges with cysteine-rich subdomains of mucus glycoproteins 二硫键与粘蛋白糖蛋白富含半胱氨酸亚基的形成	Combination of a self-emulsifying drug delivery system containing insulin with thiolated chitosan provided a significant increase in oral bioavailability 胰岛素与巯基化壳聚糖自乳化药物递送系统的组合显著提高了口服生物利用度	[90]
	Poly(lysine) modified thiolated chitosan 聚赖氨酸修饰的硫醇化壳聚糖		Polylysine modified thiolated chitosan nanoparticles resulted in strong mucoadhesion in vitro and showed improved oral bioavailability and accumulation of paclitaxel in tumors 聚赖氨酸修饰的硫醇化壳聚糖纳米颗粒在体外表现出强烈的粘附性，并显示出提高的口服生物利用度和肿瘤中紫杉醇的积累	[91]
	Per-6-thiolated cyclodextrin 6-硫醇化环糊精		Per-6-thiolated cyclodextrin resulted in a 4.9-fold improvement in oral bioavailability of furosemide 6-硫醇化环糊精使呋塞米的口服生物利用度提高了 4.9 倍	[92]
	S-protected chitosan-thioglycolic acid S-保护壳聚糖-巯基乙酸		S-protected chitosan-thioglycolic acid coated liposomes containing calcitonin showed decrease in blood calcium level down to 65% S-保护壳聚糖-巯基乙酸包覆的含降钙素的脂质体显示出降低血液钙水平至 65%的效果	[93]
	Mucin 粘蛋白		Insulin-loaded mucin-chitosan nanoparticles containing insulin provided prolonged hypoglycaemic effect 胰岛素负载的粘蛋白-壳聚糖纳米颗粒含有胰岛素，提供了长效降血糖作用	[94]

Polymeric excipients are either directly used for the formation of NCs or as coating material. When NCs are formed via in situ gelation of anionic mucoadhesive polymers such as polyacrylic acid, hyaluronic acid, alginate or carboxymethyl cellulose (CMC) with cationic polymers or multivalent cations such as Ca ²⁺, Mg²⁺ or Fe³⁺, however, the mucoadhesive properties of these polymers are quenched and because of the zwitterionic character a mucoinert instead of a mucoadhesive surface is obtained. The same counts also for cationic mucoadhesive polymers such as chitosan that adhere to negatively charged mucins via electrostatic interactions [95]. By the formation of NCs with a combination of cationic and anionic polymers mucoinert surfaces are obtained. In order to achieve high mucoadhesive properties either exclusively anionic or exclusively cationic polymers have to be used. Optionally polymers can be thiolated to further improve their mucoadhesive properties. As thiolated polymers form also disulfide bonds within NCs, multivalent counterions are not needed for their stabilization. Furthermore, thiolated polymers provide more stable coatings of NCs due to disulfide bond formation within the coating material. Orally administered liposomes containing salmon calcitonin (sCT) that were coated with a thiolated chitosan showed for instance in rats an 8.2-fold higher decrease in blood calcium level than a sCT solution [93]. Furthermore, thiolated surfactants such as thiolated palmitic acid [96] or thiolated polyoxyethylene (10) stearyl ether [97] can be anchored with their lipophilic tail in the oily core of lipid-based NCs with the thiolated polar head on the surface. In fact, NLCs decorated with thiolated polyoxyethylene (10) stearyl ether showed 3-fold higher mucoadhesive properties than NLCs decorated with the corresponding non-thiolated surfactant [97].
聚合物助剂可以直接用于形成纳米囊（NCs），或作为涂层材料。当通过阴离子粘附性聚合物（如聚丙烯酸、透明质酸、藻酸盐或羧甲基纤维素（CMC））与阳离子聚合物或多价阳离子（如 Ca ²⁺ 、Mg ²⁺ 或 Fe ³⁺ ）的原位凝胶化形成 NCs 时，然而，这些聚合物的粘附性被淬灭，由于两性离子特性，得到的是黏膜惰性表面而不是粘附性表面。同样适用于通过静电相互作用附着在带负电荷的粘蛋白上的阳离子粘附性聚合物，如壳聚糖[95]。通过阳离子和阴离子聚合物的组合形成 NCs，可以得到黏膜惰性表面。为了实现高粘附性，必须使用纯阴离子或纯阳离子聚合物。可选地，聚合物可以通过巯基化进一步改善其粘附性。由于巯基化聚合物在 NCs 内也形成二硫键，因此不需要多价反离子来稳定它们。此外，硫醇化聚合物由于涂层材料中形成二硫键，为 NCs 提供了更稳定的涂层。例如，在老鼠身上，含有鲑鱼降钙素（sCT）的口服脂质体，其表面涂有硫醇化壳聚糖，与 sCT 溶液相比，血钙水平降低了 8.2 倍[93]。此外，硫醇化表面活性剂，如硫醇化棕榈酸[96]或硫醇化聚氧乙烯（10）硬脂醚[97]，可以通过其亲脂性尾部锚定在基于脂质的 NCs 的油性核心中，而硫醇化极性头部位于表面。实际上，装饰有硫醇化聚氧乙烯（10）硬脂醚的 NLCs 比装饰有相应非硫醇化表面活性剂的 NLCs 表现出 3 倍的粘附性[97]。

Generally, too high mucoadhesive properties are likely not advantageous as NCs adhere already on the surface of the mucus gel layer that is most rapidly eliminated as part of the mucus turnover process. Ideally, NCs increase their mucoadhesive properties the deeper they have penetrated the mucus gel layer. Thiolated NCs, for example, become more reactive the deeper they penetrate into the mucus gel layer. As the pH on the surface of the mucus gel layer is between 1-6 and close to the absorption membrane 7.2, the concentration of thiolate anions representing the reactive form of thiols for disulfide bond formation with mucus glycoproteins is increasing the closer such NCs are getting to the epithelium [98].
一般来说，过高的粘附性可能并不有利，因为纳米晶体（NCs）已经粘附在粘液凝胶层表面，该层作为粘液更新过程的一部分，是最快被消除的。理想情况下，NCs 的粘附性随着其在粘液凝胶层中的深入而增加。例如，巯基化的 NCs 随着其在粘液凝胶层中的深入而变得更加活跃。由于粘液凝胶层表面的 pH 值在 1-6 之间，接近吸收膜的 7.2，因此，代表巯基的活性形式与粘液糖蛋白形成二硫键的巯基酸根离子的浓度随着 NCs 接近上皮层而增加[98]。

4. Absorption enhancing surfaces
4. 吸收增强表面

NCs can enhance drug absorption from the GI mucosa by interacting with epithelial cells in numerous ways. They can open tight junctions, fuse with cellular membranes and enter cells via endocytosis [99 100]. Endocytotic pathways include clathrin-mediated, caveolin-mediated as well as clathrin- and caveolin-independent endocytosis, phagocytosis, and micropinocytosis. Endocytosed NCs are internalized by intra-cellular vesicles such as endosomes, phagosomes, or macropinosomes hindering them to directly access the cytosol [99]. Unless transcytosed, escape from these intracellular vesicles is essential to allow the release of their payload into the cytoplasm from where drugs can reach the systemic circulation by crossing the basolateral cell membrane more easily. Apart from size and shape, the surface of NCs is mainly responsible for their mode of interaction with enterocytes.
纳米颗粒可以通过与上皮细胞以多种方式相互作用，增强药物从胃肠道黏膜的吸收。它们可以打开紧密连接，与细胞膜融合，通过内吞作用进入细胞[99100]。内吞作用途径包括由网格蛋白介导的、由 caveolin 介导的以及网格蛋白和 caveolin 非依赖的内吞作用、吞噬作用和微饮作用。内吞的纳米颗粒被细胞内的囊泡如内体、吞噬体或巨饮泡内化，阻碍它们直接进入细胞质[99]。除非通过跨细胞运输，否则从这些细胞内囊泡逃逸对于将它们的有效载荷释放到细胞质中至关重要，药物可以从那里通过更容易地穿越基底侧细胞膜进入全身循环。除了大小和形状外，纳米颗粒的表面主要对其与肠上皮细胞的相互作用方式负责。

4.1. Anionic surfaces 4.1. 阴离子表面

An anionic surface charge of NCs seems to trigger the opening of tight junctions (TJs). Carboxymethyl chitosan/chitosan nanoparticles with an anionic surface charge triggered more extensive disintegration of TJs and stronger paracellular permeability than the same nanoparticles with positive surface charge. Moreover, oral bioavailability of insulin was significantly higher when being administered with anionic charged nanoparticles than with cationic charged nanoparticles [101 102]. Furthermore, silica nanoparticles with an anionic surface charge were shown to bind to epithelial cells to briefly and reversibly open TJs [103]. In addition, a study by Yu et al. revealed enhanced uptake via the lymphatic pathway using anionic SLNs in comparison to cationic surface charge [104].
阴离子表面电荷的碳纳米管（NCs）似乎会触发紧密连接（TJs）的开放。与带正电荷的相同纳米粒子相比，带阴离子表面电荷的羧甲基壳聚糖/壳聚糖纳米粒子引发了更广泛的 TJs 分解和更强的细胞间通透性。此外，与带阳离子电荷的纳米粒子相比，胰岛素与带阴离子电荷的纳米粒子联合给药时，口服生物利用度显著更高[101102]。此外，研究表明，带阴离子表面电荷的二氧化硅纳米粒子可以与上皮细胞结合，短暂且可逆地开放 TJs[103]。此外，与带阳离子表面电荷相比，Yu 等人的一项研究揭示了使用带阴离子表面电荷的脂质纳米粒（SLNs）通过淋巴途径增强摄取[104]。

4.2. Cationic surfaces 4.2. 阳离子表面

Certain cationic polymers such as chitosan, trimethylated chitosan and polyethyleneimine were also shown to open TJs [105]. This TJs opening property of cationic polymers can be transferred to NCs [106] [107] [108]. Chitosan coated dendritic silica nanoparticles, for instance, enhanced exenatide permeation through Caco-2 monolayer by opening TJs [109]. Also Yu et al. showed that NCs with positive surface charge based on chitosan were able to open TJs between Caco-2 cells and to increase paracellular permeability [110]. In another study surface modification of PEG coated mesoporous silica nanoparticles modified with polyethyleneimine showed enhanced intestinal epithelial absorption of insulin by TJ opening [102]. Nevertheless, permeation of NCs through TJs is in most cases restricted by their size, as fully opened TJs are smaller than 20 nm in diameter [111]. The importance of NC size for permeation enhancement via TJs opening was further evaluated by Lin et al. indicating no increased paracellular transport for larger carriers [112]. According to this, the permeability of small drug molecules can be improved via TJs opening by polycations whereas for larger drugs no increase in drug permeation is observed. A more detailed review summarizing the improvement of oral bioavailability via polycations is provided by Schulz et al. [113].
某些阳离子聚合物，如壳聚糖、三甲基化壳聚糖和聚乙烯亚胺，也被证明可以打开 TJs[105]。这种阳离子聚合物的 TJs 打开特性可以转移到 NCs[106] [107] [108]。例如，壳聚糖包覆的树枝状硅纳米粒子可以增强通过 Caco-2 单层的西尼肽渗透，通过打开 TJs[109]。此外，Yu 等人也表明，基于壳聚糖的带正电荷的 NCs 能够打开 Caco-2 细胞之间的 TJs 并增加细胞旁路通透性[110]。在另一项研究中，聚乙二醇包覆的介孔二氧化硅纳米粒子经过聚乙烯亚胺改性后，其表面改性增强了通过 TJs 打开的肠上皮对胰岛素的吸收[102]。然而，NCs 通过 TJs 的渗透在大多数情况下受到其尺寸的限制，因为完全打开的 TJs 直径小于 20 nm[111]。Lin 等人进一步评估了 NC 尺寸对于通过 TJs 打开增强渗透的重要性，指出较大载体不会增加细胞旁路转运[112]。根据这一发现，通过多价阳离子打开紧密连接，可以改善小分子药物的通透性，而对于大分子药物则没有观察到药物通透性的增加。Schulz 等人[113]提供了一篇更详细的综述，总结了通过多价阳离子提高口服生物利用度的方法。

Since cellular membranes exhibit an anionic charge mainly because of heparan sulfate proteoglycan serving as a cell-surface endocytosis receptor [114], NCs with a cationic surface can ionicly interact with cellular membranes inducing endocytosis as illustrated in Fig. 4. Numerous research groups investigated the use of cationic NCs for drug delivery [115] [116] [117]. An enhanced uptake was observed for positively charged chitosan NCs compared to negatively charged equivalents on non-phagocytic cell lines, whereas phagocytic cell lines showed no differences in cellular uptake indicating a cell-dependent uptake behaviour [118]. The intracellular uptake can be further influenced by varying the surface charge as reported for chitosan NCs, capable of being localized in the peri-nuclear region [119]. Nevertheless, a careful adjustment of the cationic charge is necessary as it is also responsible for cytotoxic effects such as perturbated cellular and nuclear membranes, protein adsorption, release of degrading enzymes from lysosomes, mitochondrial permeabilization and dysfunction, generation of reactive oxygen species, altered cytoplasmatic enzyme functions and DNA damage [120] [121]. Despite the risk of adverse effects, the enhancement in cell penetration of cationic NCs makes them attractive for drug delivery. The potential of cationic liposomes to efficiently overcome the mucus gel and absorption barrier was demonstrated for oral insulin delivery using a protein corona around the cationic liposomes to improve permeation across the mucus layer [122]. The cationic charge proved also to be beneficial for absorption of olanzapine loaded in cationic SLN where higher zeta potential showed enhanced bioavailability [123]. Increased cellular uptake was shown for cationic PLGA nanoparticles that was linked to electrostatic interactions with the cell membrane as the main driving force [124].
由于细胞膜主要由于肝素硫酸蛋白聚糖作为细胞表面内吞受体[114]而表现出阴离子电荷，因此具有阳离子表面的纳米颗粒（NCs）可以离子性地与细胞膜相互作用，诱导内吞作用，如图 4 所示。许多研究小组研究了阳离子 NCs 在药物递送中的应用[115] [116] [117]。与带负电荷的类似物相比，在非吞噬细胞系中观察到正电荷壳聚糖 NCs 的增强摄取，而吞噬细胞系在细胞摄取方面没有差异，表明存在细胞依赖性的摄取行为[118]。细胞内摄取可以进一步通过改变表面电荷来影响，如报道的壳聚糖 NCs，能够在核周区域定位[119]。然而，由于阳离子电荷还负责细胞毒性效应，如细胞和核膜的扰动、蛋白质吸附、溶酶体中降解酶的释放、线粒体通透性和功能障碍、活性氧的产生、细胞质酶功能的改变和 DNA 损伤[120] [121]，因此需要仔细调整阳离子电荷。尽管存在不良影响的危险，阳离子纳米晶体（NCs）在细胞渗透方面的增强使其在药物递送方面具有吸引力。阳离子脂质体的潜力被证明可以有效地克服粘液凝胶和吸收屏障，这在口服胰岛素递送中得到了证实，其中使用围绕阳离子脂质体的蛋白质冠来改善粘液层的渗透性[122]。阳离子电荷也被证明对阳离子固体脂质纳米粒（SLN）中装载的奥氮平的吸收有益，其中较高的 zeta 电位显示出增强的生物利用度[123]。阳离子 PLGA 纳米粒子的细胞摄取增加被证明与细胞膜的静电相互作用有关，这是主要的驱动力[124]。

An additional advantage of cationic NCs is their interaction with the negatively charged mucus layer on the absorption site resulting in a prolonged residence time of the carrier. Chitosan and polymyxin B surface modified rifampicin loaded nanoemulsions showed enhanced mucoadhesion [125]. The interaction of cationic NCs with the mucus layer, however, might also lead to an insufficient cellular uptake [126] [127] [128]. Due to the fast mucus turnover the adhesive interactions could also hinder the carrier to reach its target site at all [129]. The strong mucus interaction of cationic NCs can be overcome by masking the surface charge by a bioinert polymer such as PEG, thereby improving the diffusion rates of cationic NCs [126]. Another strategy for cationic carriers to overcome the mucus gel barrier is the design of charge converting NCs as described in section 5.
阳离子纳米晶体（NCs）的另一个优点是它们与吸收部位的带负电荷粘液层的相互作用，导致载体在吸收部位的停留时间延长。壳聚糖和聚多肽 B 表面修饰的利福平纳米乳液显示出增强的粘附性[125]。然而，阳离子 NCs 与粘液层的相互作用也可能导致细胞摄取不足[126] [127] [128]。由于粘液快速更新，粘附性相互作用也可能阻碍载体到达其目标部位[129]。通过使用如 PEG 的生物惰性聚合物屏蔽表面电荷，可以克服阳离子 NCs 与粘液层强烈的相互作用，从而提高阳离子 NCs 的扩散速率[126]。阳离子载体克服粘液凝胶屏障的另一种策略是设计如第 5 节所述的带电转换 NCs。

A further application of cationic NCs is their use as delivery vectors for nucleic acids. The reason for this is the characteristic negative charge of the nucleic acid phosphate backbone which facilitates association with cationic NCs via electrostatic interactions [116]. The nucleic acids could either be co-precipitated with cationic polymers or complexed with cationic surfactants to form nanoparticles [130]. Lipoplexes with cationic lipids show enhanced cellular uptake of nucleic acids but with the slow escape of the drug from the vesicles due to the strong interaction with the nanocarrier as major drawback [131]. This might be overcome by incorporation of p-DNA-cationic lipid complexes into SEDDS which showed high transfection efficiency [132]. Successful oral gene delivery was shown for a dominant peanut allergen gene encapsulated in chitosan nanoparticles where mice receiving nanoparticles showed higher gene expression [133]. Inorganic cationic nanoparticles prepared from chitosan coated gold nanoparticles loaded with siRNA for colorectal liver metastasis therapy provided facilitated active transport through enterocytes after oral administration [134].
阳离子 NCs 的进一步应用是它们作为核酸的递送载体。这是因为核酸磷酸骨架的特有负电荷，这有利于通过静电相互作用与阳离子 NCs 结合[116]。核酸可以与阳离子聚合物共沉淀，或者与阳离子表面活性剂复合形成纳米颗粒[130]。阳离子脂质体的细胞摄取核酸能力增强，但药物从脂质体中缓慢释放，由于与纳米载体的强相互作用，这是主要缺点[131]。这可以通过将 p-DNA-阳离子脂质复合物加入 SEDDS 中克服，这显示出高转染效率[132]。对于封装在壳聚糖纳米颗粒中的主要花生过敏原基因，成功实现了口服基因递送，接受纳米颗粒的小鼠显示出更高的基因表达[133]。由壳聚糖包覆的金纳米颗粒制备的无机阳离子纳米颗粒，负载 siRNA 用于结直肠癌肝转移治疗，在口服给药后促进了通过肠上皮细胞的主动转运[134]。

4.3. Cell-penetrating peptides
4.3. 细胞穿透肽

Another approach to increase oral drug uptake focuses on the use of NCs that are decorated with cell-penetrating peptides (CPPs). CPPs are typically composed of 5-30 amino acids and can facilitate intracellular transport of various biomolecules and NCs, enabling their function at the target site [135]. CPPs exhibit different uptake mechanisms, depending on their physicochemical properties. These can be divided into energy-independent e.g. membrane lysis and energy-dependent uptake mechanisms including micropinocytosis and clatrin- and caveolin-mediated endocytosis [136]. Furthermore, CPPs can be used to specifically target intracellular organelles [137]. Considering advantages such as multiple uptake pathways as well as minor toxicity of certain CPPs, a major focus lies in combining CPPs with NCs to enhance cellular uptake [138]. They can be attached or imbued to different types of NCs, such as organic (e.g. polymers, lipids, biomolecules), inorganic (e.g. silica, gold) or composite NCs [139 140]. Interconnection can be achieved via electrostatic interactions or via covalent bonds of the CPPs with NCs. The immobilization of CPP on the surface of NCs utilizing electrostatic interactions is simple and does not require chemical modifications of the CPP, whereas covalent bonds provide higher stability and binding site selectivity [141]. Kamei et al. showed an increased insulin uptake into intestinal epidermal mucosa in vitro by co-administration of R8 (D-form arginines) and L-penetratin as CPP, demonstrating suitability even for larger peptide drugs [142]. Shrestha et al. modified porous silicon NCs with chitosan and R9-CPP for oral insulin delivery, revealing a large involvement of energy-dependent uptake processes [143]. In another approach, CPP-PEG-modified silica NCs greatly enhanced oral availability of a model hormone [51]. Hereby, the PEG modification improved mucus permeation, while the CPP facilitated uptake into the cell.
另一种提高口服药物吸收的方法是关注使用修饰有细胞穿透肽（CPPs）的纳米颗粒（NCs）。CPPs 通常由 5-30 个氨基酸组成，可以促进各种生物分子和 NCs 的细胞内转运，使其在靶位点的功能得以实现[135]。CPPs 的摄取机制取决于其物理化学性质，表现出不同的摄取机制，例如能量独立的（如膜溶解）和能量依赖的摄取机制，包括微饮作用和 clatrin-及 caveolin 介导的内吞作用[136]。此外，CPPs 还可以用于特异性靶向细胞内细胞器[137]。考虑到多摄取途径以及某些 CPPs 的轻微毒性等优势，主要关注将 CPPs 与 NCs 结合以增强细胞摄取[138]。它们可以附着或嵌入到不同类型的 NCs 中，如有机的（例如聚合物、脂质、生物分子）、无机的（例如二氧化硅、金）或复合 NCs[139140]。通过静电相互作用或通过 CPPs 与 NCs 的共价键可以实现互连。 CPP 在 NCs 表面的静电相互作用固定简单，无需对 CPP 进行化学修饰，而共价键提供更高的稳定性和结合位点选择性[141]。Kamei 等人通过共给予 R8（D 型精氨酸）和 L-渗透素作为 CPP，在体外证明了胰岛素被肠道表皮黏膜吸收的增加，证明了其甚至适用于较大的肽类药物[142]。Shrestha 等人用壳聚糖和 R9-CPP 对多孔硅 NCs 进行改性，用于口服胰岛素递送，揭示了能量依赖性摄取过程的大量参与[143]。在另一种方法中，CPP-PEG 改性的二氧化硅 NCs 显著提高了模型激素的口服生物利用度[51]。在此，PEG 修饰改善了粘液渗透性，而 CPP 促进了细胞摄取。

Despite having significant clinical potential CPPs exhibit shortcomings regarding oral application. Enzymatic degradation is a common problem associated with the use of CPPs. It can be prevented by using protease resistant D-form CPPs instead of natural-occurring L-forms, highlighting the importance of CPP structure regarding proteolytic stability and uptake properties [144] [145]. Cyclic CPPs that are also used as drugs such as polymyxin B show increased stability towards proteolytic degradation and cell permeability compared to linear CPPs [146]. Other modifications of CPPs include addition of arginine enhancing cell-penetrating properties or addition of histidine resulting in pH-responsive CPPs. By this approach, advantages of individual sequences can be combined by splicing functional CPPs together creating chimeric CPPs, as is the case for Transportan [147] [148]. Another potential disadvantage of CPPs are increased mucus interactions because of their mostly cationic structure, as described in section 4.2 [149].
尽管具有显著的临床潜力，CPPs 在口服应用方面存在不足。酶解降解是与 CPPs 使用相关的一个常见问题。可以通过使用蛋白酶抗性的 D 型 CPPs 代替天然存在的 L 型形式来预防，这突出了 CPP 结构在蛋白酶稳定性和摄取特性方面的重要性[144] [145]。作为药物使用的环状 CPPs，如多粘菌素 B，与线性 CPPs 相比，在蛋白酶降解和细胞通透性方面表现出更高的稳定性[146]。CPPs 的其他改性包括添加精氨酸以增强细胞穿透性或添加组氨酸以产生 pH 响应性 CPPs。通过这种方法，可以通过拼接功能 CPPs 来结合个别序列的优点，从而创建嵌合 CPPs，如 Transportan[147] [148]。CPPs 的另一个潜在缺点是由于它们主要呈阳离子结构，与第 4.2 节所述，增加了与粘液的相互作用[149]。

The use of ‘smart’ nanocarriers provides a promising approach to circumvent aforementioned limitations [150] [151]. In such systems, CPPs are sterically protected until arrival at the target site, where a local stimulus leads to deprotection of CPPs and thus targeted uptake [138] [152]. The concept of such systems is illustrated in Fig. 5. Local stimuli can include changes in pH and enzymes allowing circumvention of stability- or mucus-related drawbacks of CPPs. Although this area has not been extensively investigated with focus on oral application, orientating studies on possible combinations of CPP and smart NC are already available. Furthermore, CPP-decorated NCs were masked with polyphosphates that are cleaved and released by the brush border membrane bound enzyme intestinal alkaline phosphatase [153]. Such systems are described in more detail in section 5.
智能纳米载体的使用为绕过上述限制提供了一种有希望的方法[150] [151]。在这样的系统中，CPPs 在到达目标位点之前被立体保护，局部刺激导致 CPPs 去保护，从而实现靶向摄取[138] [152]。此类系统的概念如图 5 所示。局部刺激可以包括 pH 值和酶的变化，从而避免 CPPs 的稳定性和粘液相关缺点。尽管这一领域尚未在口腔应用方面进行广泛研究，但关于 CPP 和智能 NC 可能组合的研究已经存在。此外，CPP 修饰的 NCs 被多磷酸盐掩蔽，这些多磷酸盐被刷状缘膜结合的酶肠道碱性磷酸酶切割和释放[153]。此类系统在第 5 节中描述得更详细。

4.4. Surfaces that fuse with cellular membranes
4.4. 与细胞膜融合的表面

The design of lipid NCs that fuse with cellular membranes offers the advantage of a direct drug release into the cytoplasm as illustrated in Fig. 6. As a sufficiently high membrane fluidity of lipid NCs seems necessary for this fusion process mainly liquid lipid NCs such as SEDDS and liposomes with a main phase transition temperature (T_m) below 37°C seem to be advantageous. As biological membranes show virtually no tendency to fuse randomly, however, certain triggers are essential for this process. Inspired by SNARE proteins that trigger the docking of transport vesicles to the plasma membrane [154], peptide subunits of these proteins were conjugated to cholesterol and attached to the surface of liposomes. With these modified liposomes a targeted membrane fusion for drug delivery was achieved [155].
脂质纳米颗粒（NCs）与细胞膜融合的设计，使得药物可以直接释放到细胞质中，如图 6 所示。由于脂质 NCs 的膜流动性足够高似乎是这一融合过程所必需的，因此主要相变温度（T _m ）低于 37°C 的液体脂质 NCs，如 SEDDS 和脂质体似乎具有优势。然而，由于生物膜几乎不具有随机融合的趋势，因此某些触发剂对于这一过程是必不可少的。受 SNARE 蛋白启发，这些蛋白的肽亚基被偶联到胆固醇上并附着到脂质体的表面[154]。通过这些修饰后的脂质体，实现了靶向膜融合以进行药物递送[155]。

Liposomes studded with 0.8-nm-wide carbon nanotube porins were recently shown to function as shuttle for direct cytoplasmic drug delivery by facilitating fusion of lipid membranes and complete mixing of the membrane material and vesicle interior content [158]. Zwitterionic surfaces seem to be advantageous for the fusion of NCs with cellular membranes, as this process is mainly observed for such surfaces. The fusion process starts with dehydration at the interface, close apposition of the oily droplets, protrusion of hydrophobic molecules to the surface of the oily droplets, transient lipid complex formation and absorption [157]. In contrast, PEG-ylated surfaces are likely a hindrance for fusion, as their highly hydrophilic and charge shielding nature limits interactions of NCs with cellular membranes [159]. This is recognized as the PEG-dilemma [160].
脂质体上镶嵌有 0.8 纳米宽的碳纳米管孔道，最近研究表明它们可以作为直接胞浆药物输送的穿梭载体，通过促进脂质膜融合和膜材料与囊泡内部内容的完全混合来实现[158]。两性离子表面似乎有利于与细胞膜的融合，因为这一过程主要观察于此类表面。融合过程始于界面处的脱水，油滴的紧密接触，疏水分子向油滴表面的突出，瞬时的脂质复合物形成和吸收[157]。相比之下，聚乙二醇化表面可能阻碍融合，因为它们高度亲水和电荷屏蔽的性质限制了纳米颗粒与细胞膜的相互作用[159]。这被称为 PEG 困境[160]。

4.5. Thiolated surfaces 4.5. 硫醇化表面

NCs bearing thiol groups on their surface are capable of opening TJs and to induce endocytosis [161].
表面带有巯基的 NCs 能够打开 TJs 并诱导内吞作用[161]。

The responsible mechanism for opening TJs is based on the interaction of thiol groups on the surface of NCs with thiol groups of membrane bound enzymes and proteins [162] [163]. Clausen et al. showed that thiolated polymers are able to inhibit protein tyrosine phosphatase mediated by glutathione. This inhibition blocks the dephosphorylation of the extracellular loops of occludin causing the opening of TJs [162]. Zhang et al. demonstrated also thiol dependent interactions with epidermal growth factor and insulin-like growth factor resulting in the disruption of claudin-4 causing TJ opening [163]. For example a 3- to 5-fold improved permeation of a fluorescence-labelled dextran was achieved on a Caco-2 monolayer by utilizing NCs that were prepared via in situ gelation of thiolated poly(acrylic acid) and thiolated chitosan in comparison to the corresponding unthiolated NCs [164]. Due to S-protection this permeation enhancing effect of thiols can be even further improved [163] [165] [166]. Chitosan nanoparticles containing insulin were coated with poly(acrylic acid)-cysteine-6-mercaptonicotinic acid. With these S-protected thiolated NCs an enhanced paracellular transport of insulin across an intestinal cell layer and an oral bioavailability of insulin up to 16% was obtained [167].
负责开启 TJs 的机制基于 NCs 表面的巯基与膜结合酶和蛋白质的巯基相互作用[162] [163]。Clausen 等人表明，巯基化聚合物能够抑制由谷胱甘肽介导的蛋白酪氨酸磷酸酶。这种抑制阻止了 occludin 细胞外环的去磷酸化，导致 TJs 的开启[162]。Zhang 等人还证明了巯基与表皮生长因子和胰岛素样生长因子依赖的相互作用，导致 claudin-4 的破坏，从而引起 TJs 的开启[163]。例如，通过利用通过原位凝胶化巯基化聚丙烯酸和巯基化壳聚糖制备的 NCs，与相应的非巯基化 NCs 相比，在 Caco-2 单层上实现了荧光标记的右旋糖酐的 3-到 5 倍的渗透改善[164]。由于 S-保护，巯基的这种渗透增强效果甚至可以进一步改善[163] [165] [166]。含有胰岛素的壳聚糖纳米颗粒被涂覆了聚丙烯酸-半胱氨酸-6-巯基烟酸。通过这些 S-保护性硫醇化的 NCs，实现了胰岛素跨肠细胞层的增强旁路转运和高达 16%的口服生物利用度[167]。

As the mechanism for opening TJs seems to be mediated by glutathione, NCs do not need to directly interact with the membrane. Nonetheless, they should get at least close to it. Highly reactive thiol groups on the surface of NCs are therefore likely disadvantageous, as they form already new disulfide bonds with the loose outer mucus gel layer hindering these carriers on their diffusion to the membrane [168].
由于开启 TJs 的机制似乎由谷胱甘肽介导，NCs 不需要直接与膜相互作用。然而，它们至少应该接近膜。因此，NCs 表面的高度反应性硫醇基团可能是不利的，因为它们会与松散的外层粘液凝胶层形成新的二硫键，阻碍这些载体向膜的扩散[168]。

Endocytosis of thiolated NCs is likely also induced by their reaction with cysteine subunits of membrane bound proteins. Exofacial thiols were shown to enhance cellular association and internalization of thiolated NCs [169]. Studies with thiolated NLCs revealed mainly clathrin-mediated endocytosis and just a minor involvement of caveolae-dependent and clathrin- and caveolae-independent uptake. Thiol-dependent uptake was additionally confirmed by the pronounced impact of reducing and oxidizing agents on this mechanism [170]. These results are in agreement with numerous other studies with different types to thiolated NCs. Thiolated chitosan NCs, for example, containing a plasmid encoding for alkaline phosphatase displayed a 5-fold increase in protein expression when compared to unmodified chitosan NCs [171]. In another study thiolated chitosan NCs were designed for oral gene delivery showing a 5-fold enhanced transfection efficacy [172]. Enhanced cellular uptake of thiolated chitosan NCs containing an anticancer drug was also reported by Jiang et al. [173]. Sakloetsakun et al. developed SEDDS containing thiolated chitosan for oral insulin delivery and showed a significant increase in serum insulin compared to oral insulin solution [174].
内吞作用硫醇化 NCs 可能也是由其与膜结合蛋白的半胱氨酸亚基反应引起的。研究表明，外表面硫醇可以增强硫醇化 NCs 的细胞结合和内化[169]。硫醇化 NLCs 的研究主要揭示了网格蛋白介导的内吞作用，以及仅轻微涉及洞穴蛋白依赖性和网格蛋白-洞穴蛋白非依赖性摄取。此外，通过还原和氧化剂对这种机制的影响，硫醇依赖性摄取也得到了证实[170]。这些结果与许多其他关于不同类型硫醇化 NCs 的研究结果一致。例如，含有编码碱性磷酸酶质粒的硫醇化壳聚糖 NCs 与未修饰的壳聚糖 NCs 相比，蛋白质表达量增加了 5 倍[171]。在另一项研究中，设计的硫醇化壳聚糖 NCs 用于口服基因递送，显示出 5 倍的转染效率增强[172]。Jiang 等人还报道了含有抗癌药物的硫醇化壳聚糖 NCs 的细胞摄取增强[173]。Sakloetsakun 等人开发含有巯基化壳聚糖的 SEDDS 口服胰岛素递送系统，与口服胰岛素溶液相比，血清胰岛素水平显著升高[174]。

5. Charge converting surfaces
5. 电荷转换表面

Charge converting NCs rely mainly on the brush border membrane bound enzyme intestinal alkaline phosphatase (ALP) that cleaves and releases phosphates from the surface of NCs [175]. Due to the loss of these anionic phosphate substructures from the surface of NCs they convert their charge to neutral or positive and/or lose their zwitterionic character as almost just positive charges remain on the surface. In Fig. 7 the concept of charge converting NCs is illustrated. The very first charge converting NCs for oral drug delivery were formed by coacervation of polyethylenimine-6-phosphogluconic acid conjugate and a chitosan-phosphotyrosine conjugate with carboxymethylcellulose [176] [177]. Although not all phosphate groups were cleaved because of limited access for phosphatase such NCs could nonetheless convert their zeta potential from negative to positive values. Polyethylenimine-6-phosphogluconic acid NCs were shown to shift their zeta potential from -6 to +3 mV [176]. Alternatively phosphate groups can be enzymatically immobilized on the surface of NCs providing facilitated access for phosphatase [178]. In case of lipid-based formulations such as NLCs, SLNs or SEDDS, phosphorylated lipids are anchored in the lipophilic core of these NCs. The very first charge converting lipid-based NCs shifted their zeta potential from just -1 mV to +1 mV [179]. The formulation contained a cationic surfactant and phosphatidic acid that is cleaved by ALP. Alternatively, flip-flop surfactants bearing phosphate and amine groups such as phosphorylated serine-oleylamine [180] or phosphorylated octadecylamine [181] were incorporated into liquid lipid NCs.
电荷转换纳米颗粒主要依赖于刷状缘膜结合的酶肠道碱性磷酸酶（ALP），该酶从纳米颗粒表面切割并释放磷酸盐[175]。由于这些阴离子磷酸基团从纳米颗粒表面丢失，它们将电荷转换为中性或正电荷，并且/或者失去两性离子特性，因为几乎只剩下正电荷留在表面。图 7 展示了电荷转换纳米颗粒的概念。第一种用于口服药物递送的电荷转换纳米颗粒是通过聚乙烯亚胺-6-磷酸葡萄糖酸共轭物和羧甲基纤维素结合的壳聚糖-磷酸酪氨酸共轭物共凝聚形成的[176][177]。尽管由于磷酸酶的有限可及性，并非所有磷酸基团都被切割，但这些纳米颗粒仍然可以将它们的ζ电位从负值转换为正值。聚乙烯亚胺-6-磷酸葡萄糖酸纳米颗粒被证明可以将它们的ζ电位从-6 mV 转换为+3 mV[176]。或者，磷酸基团可以通过酶固定在纳米颗粒表面，从而为磷酸酶提供便利的接触[178]。在基于脂质的制剂，如 NLCs、SLNs 或 SEDDS 中，磷酸化脂质锚定在这些纳米载体（NCs）的亲脂核心中。第一种电荷转换的基于脂质的 NCs 将它们的ζ电位从仅-1 mV 转变为+1 mV[179]。该制剂含有阳离子表面活性剂和磷脂酸，该磷脂酸被 ALP 裂解。或者，将带有磷酸和胺基团的翻转-翻转表面活性剂，如磷酸化丝氨酸-油胺[180]或磷酸化硬脂胺[181]，纳入液体脂质 NCs 中。

Unintended charge interactions like an ion pairing between anionic and cationic surfactants can be avoided by such flip-flop systems. As PEG surfaces turned out to shield surface charges [182], PEG free NCs are advantageous. Alternatively, phosphate groups can be placed on top of PEG brushes. Phosphorylated lipids with PEG spacer such as N,N′bis(polyoxyethylene)oleylamine bisphosphate (POAP) [183] and polyoxyethylene (9) nonylphenol monophosphate ester [182] showed on the surface of lipid NCs a more pronounced charge conversion than others. Studies comparing the charge conversion of SEDDS containing phosphorylated lipids with PEG spacers of increasing chain length confirm these results [184]. Meanwhile, lipid-based NCs converting their surface charge from around -40 mV to +10 mV are available [185]. The advantage of such charge converting NCs for oral drug delivery are high mucus permeating properties guaranteeing that these carriers can reach the absorption membrane to a high extent as well as an improved cellular uptake. To bring as many NCs as feasible close to the absorption membrane of the gastrointestinal mucosa, mucoinert properties provided by an anionic surface charge are advantageous. Driven by the water flow [186] and the concentration gradient of NCs between the gastrointestinal lumen and the absorption membrane, mucoinert NCs can reach the absorption membrane in high quantities. When no water is absorbed from the gastrointestinal mucosa and a steep concentration gradient towards the absorption membrane is not anymore provided because of their gastrointestinal transit, however, these NCs can also diffuse back out of the mucus layer into the lumen. This back diffusion along with subdiffusive motions in mucus was analyzed with phage particles exhibiting a diameter of ∼20–200 nm [187]. Back diffusion can be hindered by charge converting NCs that are entrapped close to the epithelium after conversion to positive charge due to strong ionic interactions with cell membranes and mucus glycoproteins.
非预期的电荷相互作用，如阴离子和阳离子表面活性剂之间的离子配对，可以通过这种翻转系统避免。由于 PEG 表面被证明可以屏蔽表面电荷[182]，因此无 PEG 的 NCs 具有优势。或者，可以将磷酸基团放置在 PEG 刷的顶部。具有 PEG 间隔基团的磷酸化脂质，如 N,N′双（聚氧乙烯）油胺双磷酸（POAP）[183]和聚氧乙烯（9）壬基苯酚单磷酸酯[182]，在脂质 NCs 表面表现出比其他物质更明显的电荷转换。比较含有不同链长 PEG 间隔基团的磷酸化脂质 SEDDS 电荷转换的研究[184]证实了这些结果。同时，表面电荷从约-40 mV 转换为+10 mV 的脂质基 NCs 也已有报道[185]。这种电荷转换 NCs 在口服药物递送中的优势在于高粘液渗透性，这保证了这些载体可以以高程度到达吸收膜，以及提高细胞摄取。为了尽可能地将尽可能多的 NCs 靠近胃肠道黏膜的吸收膜，由阴离子表面电荷提供的粘蛋白惰性特性是有利的。在水流[186]和胃肠道腔与吸收膜之间 NCs 浓度梯度的驱动下，粘蛋白惰性 NCs 可以大量达到吸收膜。然而，由于它们的胃肠道转运，当没有水从胃肠道黏膜吸收，并且不再提供指向吸收膜的陡峭浓度梯度时，这些 NCs 也可以从粘蛋白层中扩散回腔内。这种反向扩散以及粘蛋白中的亚扩散运动，通过直径约为∼20-200 nm 的噬菌体颗粒[187]进行了分析。反向扩散可以被由于与细胞膜和粘蛋白糖蛋白的强烈离子相互作用而转换为正电荷后，被捕获在接近上皮附近的电荷转换 NCs 所阻碍。

Bioinert surfaces hinder interactions with epithelial cells, whereas NCs that are able to convert their surface charge from anionic to neutral or cationic directly at the absorption membrane can address this dilemma [4]. Charge converting NCs bearing phosphorylated tyramine on their surface permeated porcine intestinal mucus to an 8.6-fold higher extent than those from which the phosphate groups were already cleaved off by ALP. On contrary, a 2.4-fold higher uptake by Caco-2 cells was observed for phosphorylated tyramine decorated NCs, when cellular membrane bound ALP was not inhibited [188]. An enhanced mucus permeation and improved cellular uptake after enzymatic cleavage of phosphate groups were also reported for various other charge converting NCs [180] [185]. Charge converting poly(lactic-co-glycolic acid) NCs were loaded with insulin and coated with anionic phosphoserine and cationic octa-arginine. Because of their negative surface charge these NCs exhibited 2.4-fold higher mucus permeating properties than the same NCs without phosphate groups. After phosphate cleavage uptake of these charge converting NCs by Caco-2 cells was 1.5-fold improved and oral bioavailability of insulin in diabetic rats was almost 2-fold higher [189].
生物惰性表面阻碍了与上皮细胞的相互作用，而能够在吸收膜处直接将表面电荷从阴离子转换为中性或阳离子的纳米颗粒（NCs）可以解决这一难题[4]。表面带有磷酸化酪胺的 NCs 比那些磷酸基团已被 ALP 切割的 NCs 更深入地渗透猪小肠粘液，渗透程度高出 8.6 倍。相反，当细胞膜结合的 ALP 未被抑制时，磷酸化酪胺修饰的 NCs 在 Caco-2 细胞中的摄取量比未修饰的 NCs 高出 2.4 倍。据报道，各种其他电荷转换 NCs 在磷酸基团酶解切割后也表现出增强的粘液渗透性和改善的细胞摄取[180] [185]。电荷转换聚乳酸-羟基乙酸共聚物 NCs 被装载胰岛素并涂覆阴离子磷酸丝氨酸和阳离子八精氨酸。由于它们的负表面电荷，这些 NCs 比没有磷酸基团的相同 NCs 表现出 2.4 倍更高的粘液渗透性。磷酸裂解后，这些电荷转换 NCs 被 Caco-2 细胞摄取提高了 1.5 倍，糖尿病大鼠口服胰岛素的生物利用度几乎提高了 2 倍[189]。

6. Surfaces providing a targeted drug release
6. 靶向药物释放的表面

Oral drug delivery systems targeting specific gastrointestinal segments and effectively releasing their payload there can improve bioavailability and reduce local side effects. In particular, enzymes, pH and redox potential can be utilized to achieve such a targeting.
口服靶向特定胃肠道段的药物递送系统，并在此处有效释放其有效载荷，可以提高生物利用度并减少局部副作用。特别是，可以利用酶、pH 值和氧化还原电位来实现这种靶向。

6.1. Enzyme triggered systems
6.1. 酶触发的系统

NCs are able to release their payload in a targeted and controlled manner after structural modification via cleavage of enzymatically labile substructures on their surface by endogenous enzymes [190]. Evidence for targeted transport and payload release of NCs at the intestinal brush border membrane in presence of ALP has already been provided. Leichner et al. developed chitosan/tripolyphosphate nanoparticles providing a targeted release of β-galactosidase within the intestinal mucus gel layer close to the absorption membrane [191]. Once the particles have reached the target site, the tripolyphosphate cross linkers are hydrolysed by ALP causing particle degradation and drug release. In presence of isolated ALP, 58% of β-galactosidase were released after one hour corresponding to a 2.5-fold improvement of drug release compared to the control without ALP. On porcine mucosa, a release of 94% was demonstrated after three hours indicating a retarded payload release in comparison to isolated ALP. This is primarily attributable to the fact that nanoparticles first have to cross the entire mucus layer before reaching the target brush border membrane [191]. Site specific mucosal drug delivery at the epithelial cell surface of the GI tract upon exposure with ALP was also shown by Le-Vinh et al. [192].
纳米颗粒（NCs）通过表面易受酶解的亚结构被内源酶切割进行结构修饰后，能够以靶向和可控的方式释放其有效载荷 [190]。在存在 ALP 的情况下，已提供纳米颗粒在肠道刷状缘膜上的靶向运输和有效载荷释放的证据。Leichner 等人开发了壳聚糖/三聚磷酸盐纳米颗粒，能够在肠道粘液凝胶层中靶向释放β-半乳糖苷酶 [191]。一旦颗粒到达目标部位，三聚磷酸盐交联剂就会被 ALP 水解，导致颗粒降解和药物释放。在存在分离的 ALP 的情况下，一小时后释放了 58%的β-半乳糖苷酶，与无 ALP 的控制组相比，药物释放提高了 2.5 倍。在猪黏膜上，三小时后释放了 94%，与分离的 ALP 相比，有效载荷释放延迟。这主要是由于纳米颗粒首先必须穿过整个粘液层，才能到达目标刷状缘膜 [191]。特定部位的胃肠道粘膜药物递送在暴露于 ALP 后也在 Le-Vinh 等人[192]的研究中得到证实。

Saleh et al. demonstrated protection against enzymatic degradation by lipase via surface shielding of cationic polymyxin B with anionic polyphosphate [193]. Phosphate residues were cleaved off by isolated ALP serving as potential trigger for targeted drug release at the absorption membrane [193].
Saleh 等人通过阳离子多粘菌素 B 的表面屏蔽，利用阴离子多磷酸盐来证明对酶解降解的保护作用[193]。磷酸残基被分离的 ALP 裂解，作为在吸收膜上靶向药物释放的潜在触发因素[193]。

Additionally, NCs have been modified with pH-sensitive substances to protect the API in the upper GI tract for subsequent enzyme-triggered release at the desired site. Huang et al., coated their NCs with chitosan and hyaluronic acid [194]. These NCs were stable up to pH 6.8 whereas at pH 7.4 the protonation degree of chitosan was reduced and electrostatic interactions of oppositely charged molecules were limited. The resulting detachment of chitosan from the surface of NCs revealed the hyaluronic acid residues that specifically carried the vehicle into cancer cells via CD-44 receptors. In presence of hyaluronidase, the integrity of hyaluronic acid-based NCs was destroyed and the drug was released [194].
此外，纳米载体（NCs）已被 pH 敏感物质改性，以保护上消化道中的 API，并在预定部位通过酶触发放出。黄等人用壳聚糖和透明质酸对 NCs 进行包覆[194]。这些 NCs 在 pH 6.8 时稳定，而在 pH 7.4 时，壳聚糖的质子化程度降低，带相反电荷的分子之间的静电相互作用受限。壳聚糖从 NCs 表面脱落的结果揭示了透明质酸残基，这些残基特异性地将载体通过 CD-44 受体带入癌细胞。在透明质酸酶存在下，基于透明质酸的 NCs 的完整性被破坏，药物被释放[194]。

Li et al. recently focused on a novel colon-targeting and enzyme triggered drug delivery system for oral delivery of curcumin [195]. Curcumin-cyclodextrin inclusion complexes were coated with chitosan and sodium alginate. Gel formation at low pH due to strong electrostatic interactions between the carboxyl groups of alginate and the amino groups of chitosan provided protection of the API against the harsh gastric environment. In the stomach (pH 1.2) and the upper part of the small intestine (pH 6.8), only 12% and 27% of the drug were released within 4 h, respectively, indicating that initial burst release of curcumin was effectively prevented. In simulated ileum environment (pH 7.4), 37% of the drug were released after 24 h. However, drug release significantly increased up to 90% within 4 h in presence of α-amylase due to enzymatically cleavage of the cyclodextrin ring structure [195].
李等人最近关注了一种新型的结肠靶向和酶触发的药物递送系统，用于口服递送姜黄素[195]。姜黄素-环糊精包合物被壳聚糖和海藻酸钠包覆。由于海藻酸根的羧基和壳聚糖的氨基之间强烈的静电相互作用，在低 pH 值下形成凝胶，从而保护 API 免受恶劣的胃环境。在胃（pH 1.2）和小肠上部（pH 6.8）中，药物在 4 小时内分别仅释放了 12%和 27%，这表明姜黄素的初始快速释放得到了有效防止。在模拟回肠环境（pH 7.4）中，药物在 24 小时后释放了 37%。然而，由于环糊精环结构的酶解，在α-淀粉酶存在的情况下，药物释放在 4 小时内显著增加至 90%。

Similar approach was reported by Ünal et al. who incorporated the colorectal anticancer drug camptothecin in cyclodextrin for protection against absorption and degradation in the stomach and the intestine. Once having reached the colon, cyclodextrins were dissociated by the colonic microflora and the drug was released. The NCs were additionally coated with positively charged chitosan to increase interactions with negatively charged mucus resulting in prolonged residence time at the desired site of action. Drug release studies under simulated gastrointestinal conditions demonstrated that 52% of encapsulated camptothecin reached the simulated colon followed by a drug release of approximately 90% after 24 h. Microflora-triggered delivery systems as designed by Ünal et al. were identified as highly convenient for oral treatment of gastrointestinal inflammations such as inflammatory bowel disease, Crohn’s disease or ulcerative colitis due to their site-specific drug release [196].
类似的方法由Ünal 等人报道，他们将结直肠癌抗癌药物喜树碱与环糊精结合，以保护其在胃和肠中的吸收和降解。一旦到达结肠，环糊精被结肠微生物群解离，药物被释放。NCs 还额外涂覆了带正电荷的壳聚糖，以增加与带负电荷粘液的相互作用，从而在所需的作用部位延长停留时间。在模拟胃肠道条件下进行的药物释放研究表明，52%的包封喜树碱到达模拟结肠，24 小时后药物释放量约为 90%。Ünal 等人设计的微生物触发递送系统被认定为治疗胃肠道炎症（如炎症性肠病、克罗恩病或溃疡性结肠炎）的口服治疗高度方便，因为这些系统具有部位特异性药物释放[196]。

Cai et al., for example, demonstrated colon-specific drug release based on azo-bond cleavages by enzymes produced of the colonic microflora [197]. Chitosan (CS) was attached to the surface of hollow mesoporous silica spheres (HMSS) via azo-bonds (HMSS-N=N-CS). After enzymatic degradation of chitosan, it detached from the particles’ surface and the drug was released. The potential of this concept was confirmed as in presence of colonic enzymes as around 40% of the drug were released within 24 h, whereas a drug release of only 10% was determined in absence of colonic enzymes. Furthermore, the amount of released drug significantly increased by increasing the concentration of the enzymes [197].
蔡等人，例如，通过结肠微生物产生的酶催化的偶氮键断裂，展示了基于偶氮键的特异性结肠药物释放[197]。壳聚糖（CS）通过偶氮键（HMSS-N=N-CS）附着在空心介孔二氧化硅球（HMSS）的表面。在壳聚糖的酶解降解后，它从颗粒表面脱落，药物被释放。这一概念的可能性在结肠酶存在的情况下得到了证实，大约 40%的药物在 24 小时内被释放，而在没有结肠酶的情况下，药物释放量仅为 10%。此外，随着酶浓度的增加，释放的药物量显著增加[197]。

Song et al. coated their drug carrier with polyacrylic acid as pH sensitive polymer triggering drug release in the colon, as well as with chitosan as enzyme sensitive moiety degradable by β-glycosidase produced of the colonic microflora. Enhanced drug concentration at the target site was proven in tumor-bearing mice [198].
Song 等人将药物载体涂覆上聚丙烯酸作为 pH 敏感聚合物，触发在结肠中的药物释放，同时涂覆上壳聚糖作为酶敏感基团，可被结肠微生物群产生的β-糖苷酶降解。在肿瘤携带小鼠中证实了目标部位的药物浓度增强[198]。

Furthermore, the overexpression of specific enzymes in pathological conditions can be used for enzyme-mediated drug release. Esterases are overexpressed in inflammatory environment [199]. Chen et al. designed lipid NCs via ester bond linkages with chitosan modified surfaces for oral delivery of dexamethasone against ulcerative colitis [200]. In vitro drug release studies showed that in artificial intestinal fluid without esterase only 24% of dexamethasone were released after 48 h, whereas in presence of esterases a drug release of 49% was observed. These esterase-responsive characteristics were attributed to ester-bond cleavages in the NC system resulting in structural disturbance and rapid drug release. Moreover, dexamethasone was released faster in combination with chitosan than without the polymer indicating that the surface modification retarded drug release. Colon targeting and strong retention properties of the developed NCs were confirmed in ulcerative colitis infected mice [200].
此外，在病理条件下特定酶的过表达可用于酶介导的药物释放。酯酶在炎症环境中过表达[199]。Chen 等人通过酯键连接壳聚糖修饰的表面设计脂质纳米颗粒（NCs），用于口服递送地塞米松以治疗溃疡性结肠炎[200]。体外药物释放研究表明，在不含酯酶的人工肠液中，48 小时后只有 24%的地塞米松被释放，而在存在酯酶的情况下，观察到 49%的药物释放。这些酯酶响应特性归因于 NC 系统中酯键的断裂，导致结构破坏和快速药物释放。此外，与未添加聚合物相比，地塞米松与壳聚糖结合时释放速度更快，表明表面修饰延缓了药物释放。在溃疡性结肠炎感染小鼠中，开发的 NCs 的结肠靶向和强保留特性得到了证实[200]。

6.2. pH triggered systems
6.2. pH 触发的系统

The GI tract exhibits a pH gradient increasing from the stomach (pH 1-2) to the small intestine (pH 6-7) and the ileum (pH 7-8) [201]. This property makes pH a perfect trigger for targeted oral drug delivery in case of gastrointestinal diseases such as inflammatory bowel disease, Crohn’s disease, ulcerative colitis and colon cancer. A simple and effective strategy to design pH-sensitive NCs is enteric coating with suitable polymers. The most commonly used coating materials for oral delivery are methacrylic acid copolymers known as Eudragit® [201] [202]. At low pH, the carboxylic groups of the polymer are protonated preventing initial and unspecific drug release in the upper GI tract. From neutral to alkaline media, the carboxylic groups are deprotonated and ionized. The resulting electrostatic repulsion leads to disintegration of the coating material and drug release in colonic pH milieu [203].
胃肠道表现出从胃（pH 1-2）到小肠（pH 6-7）和回肠（pH 7-8）的 pH 梯度增加[201]。这一特性使得 pH 成为针对胃肠道疾病（如炎症性肠病、克罗恩病、溃疡性结肠炎和结肠癌）进行靶向口服药物递送的完美触发器。设计 pH 敏感纳米颗粒（NCs）的一种简单有效策略是使用合适的聚合物进行肠溶包衣。最常用的口服递送包衣材料是称为 Eudragit®的甲基丙烯酸共聚物[201] [202]。在低 pH 下，聚合物的羧基被质子化，防止在胃肠道上部释放药物。从中性到碱性介质，羧基去质子化和电离。由此产生的静电排斥导致包衣材料分解和在结肠 pH 环境中释放药物[203]。

Wang et al. developed PLGA NCs coated with Eudragit® S100 for oral delivery of 5-fluorouracil. In vitro tests demonstrated that the coating effectively prevented drug release in pH conditions < 7. At pH 7.4, the NCs exhibited initial burst release followed by slow and sustained drug release over 120 h based on swelling and erosion of the PLGA polymer [204].
王等人开发了涂覆有 Eudragit® S100 的 PLGA 纳米晶体，用于口服 5-氟尿嘧啶。体外实验表明，该涂层在 pH 值小于 7 的条件下能有效防止药物释放。在 pH 7.4 时，纳米晶体表现出初始的快速释放，随后基于 PLGA 聚合物的膨胀和侵蚀，缓慢且持续地释放药物超过 120 小时[204]。

Further evidence for site-specific release of 5-fluorouracil in the oral treatment of colorectal cancer was provided by Tummala et al.. Eudragit® L100 coated NCs showed sustained drug release of 82% within 4 h. In comparison, non-enteric coated NCs released > 50% of 5-fluorouracil before even reaching the colon [205].
进一步提供了 5-氟尿嘧啶在结直肠癌口服治疗中局部释放的证据，由 Tummala 等人提供。Eudragit® L100 包衣的 NCs 在 4 小时内持续释放了 82%的药物。相比之下，非肠溶包衣的 NCs 在到达结肠之前就释放了超过 50%的 5-氟尿嘧啶[205]。

Similar observations were made by Ali et al. who incorporated the glucocorticoid budesonide in a PLGA core followed by enteric coating with Eudragit® S100. Results showed that uncoated NCs released > 75% of budesonide after 2 h at pH 1.2, whereas coated PLGA NCs released < 20% of the drug. At pH 7.4, drug release significantly increased up to 80% within 8 h [206].
相似观察由 Ali 等人提出，他们将糖皮质激素布地奈德纳入 PLGA 核心，随后用 Eudragit® S100 进行肠溶包衣。结果显示，未包衣的 NCs 在 pH 1.2 下 2 小时后释放了>75%的布地奈德，而包衣的 PLGA NCs 释放的药物<20%。在 pH 7.4 下，药物释放显著增加，8 小时内可达 80% [206]。

The targeting potential of Eudragit® coated drug delivery systems was also shown by Jain et al. [207]. Oxaliplatin for oral treatment against colon cancer was incorporated in hyaluronic acid-coupled chitosan NCs and coated with Eudragit® S100. Site specificity of the designed NCs was confirmed in tumor bearing mice as hyaluronic acid coupled NCs reached the target site to a higher extent than uncoupled carriers. This was additionally attributable to the fact that most malignant cell types overexpress hyaluronic acid receptors (e.g. CD44 receptors) [208] [209].
Eudragit®包覆药物递送系统的靶向潜力也由 Jain 等人[207]所示。奥沙利铂作为口服治疗结直肠癌的药物被纳入透明质酸偶联的壳聚糖 NCs 中，并涂覆 Eudragit® S100。设计的 NCs 在肿瘤携带小鼠中的位点特异性得到证实，因为透明质酸偶联的 NCs 比未偶联的载体更大幅度地到达目标部位。这还归因于大多数恶性细胞类型过度表达透明质酸受体（例如 CD44 受体）[208] [209]。

Another promising and highly efficient strategy to actively target and release drugs at a specific site is the surface modification of mesoporous silica nanoparticles (MSNs). Mesoporous silica provides abundant silanol groups (Si-OH) on the pore surface that facilitate conjugation with functional groups of polymers to form pH-responsive coatings [210] [211]. Tian et al. capped the surface of MSNs with polyacrylic acid (PAA) [212]. In acidic environment (pH 2), only 20% of the model drug doxorubicin were released within 12 h, whereas in weak basic conditions (pH 7.6) 64% of the API were released. This can be explained by the presence of H-bonds between the carboxylic groups of PAA at low pH preventing drug release. At pH 7.6, however, the functional groups became deionized and repulsive forces opened the pore channels for rapid drug release (Fig. 8) [212]. In comparison, unmodified MSNs demonstrated initial burst release (78%) at pH 2 followed by insufficient drug release (10%) at pH 7.6.
另一种有前景且高效的策略是，通过表面改性介孔二氧化硅纳米粒子（MSNs）来主动靶向并释放药物。介孔二氧化硅在孔表面提供了丰富的硅醇基团（Si-OH），这有助于与聚合物的官能团结合形成 pH 响应性涂层[210] [211]。田等人在 MSNs 表面接枝了聚丙烯酸（PAA）[212]。在酸性环境（pH 2）中，模型药物阿霉素在 12 小时内仅释放了 20%，而在弱碱性条件下（pH 7.6）64%的 API 被释放。这可以解释为在低 pH 下，PAA 羧基团之间的氢键阻止了药物释放。然而，在 pH 7.6 时，官能团去质子化，排斥力打开了孔道，促进了药物的快速释放（图 8）[212]。相比之下，未改性的 MSNs 在 pH 2 时表现出初始的爆发性释放（78%），随后在 pH 7.6 时药物释放不足。

Similar observations were made by Nguyen et al. via surface-modification of MSNs with bifunctional succinylated polylysine for targeted release of prednisolone in colonic pH [213]. The polymeric coating effectively prevented premature drug release at pH 1.9 (< 14% within 2 h) in comparison to uncoated MSNs (> 95% within 2 h). In simulated colonic pH conditions, repulsive forces between the anionic polymeric chains caused swelling followed by steady drug release (> 50% after 8 h).
Nguyen 等人通过表面修饰 MSNs 的双功能琥珀酰化聚赖氨酸，实现了在结肠 pH 值下靶向释放泼尼松[213]。聚合物涂层有效地防止了在 pH 1.9（2 小时内释放率小于 14%）时药物的过早释放，与未包覆的 MSNs（2 小时内释放率大于 95%）相比。在模拟的结肠 pH 条件下，阴离子聚合物链之间的排斥力导致膨胀，随后药物稳定释放（8 小时后释放率超过 50%）。

Another surface-functionalized system based on MSNs was developed by Lee et al.. Positively charged trimethylammonium functional groups on the particles surface enabled the incorporation of anionic drugs such as sulfasalazine. At gastric pH, the silanol groups were protonated and uncharged and thus did not interfere with the electrostatic attraction between the positively charged trimethylammonium groups and the anionic drug. At neutral pH, the silanol groups were deprotonated and strong electrostatic repulsion triggered drug release [210].
基于 MSNs 的另一种表面功能化系统由 Lee 等人开发。粒子表面的正电荷三甲基铵官能团使得阴离子药物如磺胺吡啶得以结合。在胃酸 pH 值下，硅醇基团质子化且不带电，因此不会干扰正电荷三甲基铵官能团与阴离子药物之间的静电吸引。在中性 pH 值下，硅醇基团去质子化，强烈的静电排斥触发了药物释放[210]。

Cheng et al. modified MSNs with pH-sensitive trimethylammonium groups via hydrazone linkages that were easily hydrolyzed in the stomach at acidic pH. The resulting electrostatic repulsion caused rapid release of sulfasalazine (80% after 4 h) in simulated colonic pH (pH 7-8, Fig. 9). The activation of the prodrug sulfasalazine based on azo-bond cleavages by azo-reductases produced of the colonic microflora further raises the targeting potential of this novel drug delivery system [214].
Cheng 等人通过酰胺键合将 pH 敏感的三甲基铵基团引入 MSNs，这些键合在酸性 pH 值下在胃中易于水解。由此产生的静电排斥导致在模拟结肠 pH 值（pH 7-8，图 9）下磺胺噻唑快速释放（4 小时后释放 80%）。基于由结肠微生物群产生的偶氮还原酶通过偶氮键裂解激活前药磺胺噻唑，进一步提高了这种新型药物递送系统的靶向潜力[214]。

pH dependent release of anionic drugs from zirconium-based metal-organic framework was linked to cationic zeta potential at acidic conditions getting reduced at neutral pH and therefore allowing API to be released in the intestine [215]. Modulation of the drug release from clay nanoparticles was obtained by the usage of large cationic polymers leading to controllable release [216].
锆基金属有机框架中阴离子药物的 pH 依赖性释放与酸性条件下的阳离子ζ电位降低有关，在中性 pH 时因此允许 API 在肠道中释放[215]。通过使用大阳离子聚合物调节粘土纳米粒子的药物释放，从而实现可控释放[216]。

6.3. Redox triggered systems
6.3. 氧化还原触发的系统

In patients with intestinal inflammation or cancer, abnormally high levels of glutathione (GSH) and reactive oxygen species (ROS) have been identified. This knowledge has been extensively used for oral delivery of surface modified NCs that specifically release their payload at the desired site in response to redox-gradients.
在患有肠道炎症或癌症的患者中，已发现谷胱甘肽（GSH）和活性氧（ROS）水平异常升高。这一知识已被广泛用于口服递送表面修饰的纳米颗粒（NCs），这些纳米颗粒能够响应氧化还原梯度在目标部位特异性释放其有效载荷。

Du et al., for instance, designed redox-sensitive SLNs for incorporation of disulfide bond linked camptothecin and palmitic acid conjugates (CPT-SS-PA) [217]. It was hypothesized that overexpressed GSH in tumor cells causes degradation of the conjugate and drug release of CPT via disulfide bond cleavages (Fig. 10). Redox-sensitivity studies confirmed this assumption as in reductive dithiotreitol (DTT) solution almost 80% of the conjugate was degraded after 20 min whereas in absence of DTT < 10% was degraded after 24 h [217].
杜等人，例如，设计了具有氧化还原敏感性的脂质纳米粒（SLNs）以结合二硫键连接的喜树碱和棕榈酸共轭物（CPT-SS-PA）[217]。假设肿瘤细胞中 GSH 的高表达导致共轭物降解和 CPT 通过二硫键断裂释放药物（图 10）。氧化还原敏感性研究表明，在还原型二硫苏糖醇（DTT）溶液中，20 分钟后几乎 80%的共轭物被降解，而在无 DTT 的情况下，24 小时后降解率小于 10%[217]。

Following this approach, Dinarvand et al. developed an oral delivery system for colon cancer treatment by encapsulating the antisence hSET1 and the anticancer drug SN38 in NCs based on cysteine trimethyl chitosan (cysTMC) and carboxymethyl dextran (CMD) [218] [219]. In simulated extracellular environment (4.5 M GSH), only 9% and 20-25% of the anticancer drug were released after 8 h from TMC/CMD and cysTMC/CMD nanocarriers, respectively. In simulated intracellular environment (10 mM GSH), however, drug release after 6 h from TMC/CMD nanocarriers was 13% in comparison to 61% in case of cysTMC/CMD nanoparticles. The incorporation of disulfide bonds in TMC was therefore a useful tool to increase GSH responsiveness for targeted drug release [218].
采用该方法，Dinarvand 等人通过将 hSET1 反义寡核苷酸和抗癌药物 SN38 封装在基于半胱氨酸三甲基壳聚糖（cysTMC）和羧甲基葡聚糖（CMD）的纳米载体中，开发了一种用于结直肠癌治疗的口服递送系统[218] [219]。在模拟的细胞外环境中（4.5 M GSH），TMC/CMD 和 cysTMC/CMD 纳米载体在 8 小时后分别只有 9%和 20-25%的抗癌药物释放。然而，在模拟的细胞内环境中（10 mM GSH），TMC/CMD 纳米载体在 6 小时后的药物释放量为 13%，而 cysTMC/CMD 纳米粒子的释放量为 61%。因此，在 TMC 中引入二硫键是提高 GSH 响应性以实现靶向药物释放的有用工具[218]。

Another promising redox-sensitive system for targeted intracellular drug release based on cleavage of disulfide bonds was prepared by Qiao et al. [220]. Results indicated that curcumin linked to PEG via disulfide bonds was released to a significantly higher extent in presence of 10 mM GSH (53% within 24h) than in presence of 10 μM GSH (15% within 24 h) [220].
另一种基于二硫键断裂的靶向细胞内药物释放的氧化还原敏感系统由乔等制备 [220]。结果表明，通过二硫键与 PEG 连接的姜黄素在 10 mM GSH 存在下（24 小时内释放 53%）比在 10 μM GSH 存在下（24 小时内释放 15%）释放得更多 [220]。

Furthermore, a self-assembling amphiphilic inulin polymer (4-aminothiophenol conjugated carboxymethyl inulin, ATP-CMI) was designed for oral budesonide delivery against inflammatory bowel disease. Redox-responsive drug release due to disulfide bond cleavage and subsequent disassembly of ATP-CMI chains was confirmed in vitro. Drug release studies in GSH-free media showed low release of budesonide (45%), whereas significantly higher drug release was observed in media containing 20 mM GSH (80%). Superior therapeutic efficacy of the developed NCs in comparison to budesonide suspension was demonstrated additionally in vivo [221].
此外，设计了一种用于口服布地奈德递送以治疗炎症性肠病的自组装两亲性果聚糖聚合物（4-氨基噻吩酚偶联羧甲基果聚糖，ATP-CMI）。体外证实，由于二硫键断裂和 ATP-CMI 链的后续解聚，发生了氧化还原响应的药物释放。在无 GSH 的培养基中进行的药物释放研究表明，布地奈德的释放量较低（45%），而在含有 20 mM GSH 的培养基中观察到显著更高的药物释放（80%）。此外，与布地奈德悬浮液相比，所开发的 NCs 在体内表现出更优越的治疗效果[221]。

In addition to disulfide bonds, thioketal bonds were used for targeted release of budesonide in response to ROS. Li et al. designed a self-assembled and redox-sensitive Janus-prodrug for oral delivery of budesonide (B-ATK-T) composed of ROS-responsive aromatized thioketal (ATK) and tempol (T) as antioxidant [222] [223]. Rapid hydrolyzation of the thioketal bonds effectively triggered drug release in presence of H₂O₂. The targeting potential of the novel NCs was additionally demonstrated in colitis-induces mice as they markedly accumulated in diseased colonic tissue [222].
除了二硫键外，硫代缩酮键也被用于响应活性氧（ROS）来靶向释放布地奈德。Li 等人设计了一种自组装和氧化还原敏感的 Janus 前药（B-ATK-T），用于口服布地奈德（B-ATK-T）的递送，由响应 ROS 的芳香化硫代缩酮（ATK）和抗氧化剂双（甲基）亚磷酸酯（T）组成[222] [223]。硫代缩酮键的快速水解在存在 H ₂ O ₂ 的情况下有效地触发了药物释放。新型纳米颗粒的靶向潜力还通过在结肠炎诱导的小鼠中进行了验证，因为它们在病变的结肠组织中显著积累[222]。

A similar approach was followed by Wilson et al. [224] who developed thioketal NCs based on a polymer (poly-(1,4-phenyleneacetone dimethylene thioketal)) composed of thioketal linkages [225] that are stable against acid-, base- and protease-catalyzed degradation [225] [226] but trigger ROS-sensitive drug release of siRNA at sites of intestinal inflammation [224].
威尔逊等人[224]采用了类似的方法，他们基于一种聚合物（聚（1,4-苯基乙酮二甲基硫酮））开发了硫酮酮 NCs，该聚合物由硫酮酮键[225]组成，这些键对酸、碱和蛋白酶催化的降解具有稳定性[225] [226]，但在肠道炎症部位触发对 ROS 敏感的 siRNA 药物释放[224]。

Zhang et al. applied a similar strategy for oral delivery of Tempol based on a biocompatible ß-cyclodextrin derivative with oxidative-labile moieties (4-(hydroxymethyl) phenylboronic acid pinacol esters) [227]. In presence of 1 mM H₂O₂ simulating non-physiologically high ROS levels, the NCs were completely hydrolyzed within 6 h resulting in highly redox-sensitive drug release. Additionally, in vivo studies with UC-induced mice showed limited nonspecific distribution but effective colon targeting as well as reduced oxidative stress after oral delivery [227].
张等人采用了一种类似策略，通过一种生物相容性的β-环糊精衍生物（4-（羟甲基）苯硼酸戊二醇酯）进行 Tempol 的口服递送[227]。在 1 mM H ₂ O ₂ 模拟非生理性高 ROS 水平存在的情况下，NCs 在 6 小时内完全水解，导致高度氧化还原敏感的药物释放。此外，在 UC 诱导小鼠的体内研究中，显示出有限的非特异性分布，但有效的结肠靶向以及口服递送后的氧化应激降低[227]。

Despite this obvious great potential of redox-sensitive NCs in the field of oral drug delivery, these systems are often compromised by (1) enzymatic degradation and instability in the harsh conditions of the upper GI tract, (2) premature and unspecific drug release and (3) the possibility of targeting only one or two kinds of ROS [202].
尽管在口腔药物递送领域，红氧敏感型纳米晶体（NCs）具有明显的巨大潜力，但这些系统通常受到以下因素的影响而受损：（1）在上消化道恶劣条件下，酶促降解和不稳定性，（2）过早和不特异性的药物释放，（3）仅针对一种或两种活性氧（ROS）[202]。

7. Mucolytic surfaces 7. 稀释性表面

In contrast to passive surfaces as described above, active surfaces are able to react with the biological environment eliminating compounds that would otherwise interact. In case of oral drug delivery systems in particular active surfaces that are able to cleave mucus glycoproteins are of interest. They cleave the three-dimensional network of the mucus gel layer enabling even higher mucus permeating properties than passive surfaces. As NCs with such surfaces cleave the mucus network just in front of their way through it, they do not entirely destroy the mucus layer and its protective function. Such active mucopenetrating NCs exhibit mucolytic enzymes like papain, bromelain and trypsin on their surface [228] [229]. As these proteases cleave mucus glycoproteins, NCs can permeate the mucus gel layer in an almost unhindered manner. These enzymes are covalently attached to polymers that are used either for particle formation or as coating materials [230] [231]. Papain, for instance, was covalently attached to poly(acrylic acid) that was formulated to nanoparticles by ionic gelation. As these NCs can deeply penetrate the GI mucus gel layer reaching also the firm mucus layer close to the absorption membrane, they exhibited a significantly prolonged intestinal residence time in rats after oral administration [229]. Further in vivo evidence for the potential of mucolytic enzyme decorated NCs to deeply penetrate the intestinal mucus gel layer was provided for papain and bromelain functionalized particles [232]. Alternatively, mucolytic enzymes can be conjugated to lipophilic tails and anchored on the surface of lipid-based NCs. The surface decoration of SEDDS with a papain-palmitate conjugate, for example, increased the mucus permeability of these NCs 3-fold [233]. Hydrophobic ion pairs of mucolytic enzymes with lipophilic counter ions such as sodium dodecylsulfate can be anchored on the surface of lipid NCs as well [234].
与上述被动表面不同，主动表面能够与生物环境发生反应，消除否则会与之相互作用的化合物。特别是在口服药物递送系统中，能够裂解粘液糖蛋白的主动表面引起了人们的兴趣。它们能够裂解粘液凝胶层的三维网络，使粘液渗透性能甚至高于被动表面。作为具有此类表面的纳米颗粒，它们在通过粘液网络之前将其裂解，因此不会完全破坏粘液层及其保护功能。这种主动粘液穿透纳米颗粒在其表面表现出木瓜蛋白酶、菠萝蛋白酶和胰蛋白酶等粘液溶解酶[228] [229]。由于这些蛋白酶裂解粘液糖蛋白，纳米颗粒可以几乎无阻碍地渗透粘液凝胶层。这些酶通过共价键附着在用于粒子形成或作为涂层材料的聚合物上[230] [231]。例如，木瓜蛋白酶通过离子凝胶化共价键附着在聚丙烯酸上，该聚丙烯酸被制成纳米颗粒。这些纳米晶体可以深入穿透胃肠道粘液凝胶层，甚至达到接近吸收膜的坚实粘液层，因此在大鼠口服给药后表现出显著延长的肠道停留时间[229]。进一步体内证据表明，粘液溶解酶修饰的纳米晶体具有深入穿透肠道粘液凝胶层的潜力，例如木瓜蛋白酶和菠萝蛋白酶功能化颗粒[232]。另一方面，粘液溶解酶可以与亲脂性尾巴偶联并锚定在脂质纳米晶体表面。例如，使用木瓜蛋白酶-棕榈酸偶联物对 SEDDS 进行表面修饰，可以将这些纳米晶体的粘液通透性提高 3 倍[233]。粘液溶解酶与亲脂性反离子（如十二烷基硫酸钠）形成的疏水性离子对也可以锚定在脂质纳米晶体表面[234]。

8. Conclusion 8. 结论

The immense potential and effectiveness of nanocarriers including SEDDS, SLNs, NLCs, liposomes, polymeric micelles and polymeric as well as inorganic nanoparticles in the field of oral drug delivery has become more and more evident in recent years. Beneficial features such as enhanced drug solubility, permeation across mucus and mucosa, stability against enzymatic degradation in the GI tract as well as controlled drug release justify their superior role for oral drug delivery systems. Modification of the NCs surface chemistry can even further improve their efficacy in terms of interaction with food, digestive enzymes, bile salts and electrolytes. Bioinert surface properties, for example, prevent interactions with GI compounds due to a stable solvation shell that results from the zwitterionic NC surfaces with both anionic and cationic charges binding water molecules by Coulomb forces. Zwitterionic surfaces can be designed either by amphoteric surfactants such as phospholipids or the combination of anionic and cationic surfactants or polymers. Additionally, PEG- and PG-coatings shield NCs from interactions with GI fluids and mucus via dense hydrated brushes on the NCs surface. Moreover, the design of adhesive surfaces has been found to be suitable for oral drug delivery due to adhesion of NCs to the mucus gel layer covering the GI epithelium. Mucoadhesiveness can be achieved by either non-covalent interactions (H-bonding, ionic- and hydrophobic interactions) or covalent bonds (disulfide bonds) between the NCs surface and the mucus gel layer. Furthermore, surface modified NCs have the capability to enhance drug absorption via tight junctions opening, fusion with cellular membranes and endocytosis. More recently charge converting surfaces based on phosphate moieties that are cleaved by a membrane bound phosphatase and therefore convert their charge from anionic to neutral or cationic were developed. Enzymatic cleavage of surface modified NCs by phosphatase furthermore offers the possibility of targeted and controlled drug release at the brush border membrane. Targeted drug release can additionally be achieved by coating of NCs with polymers that change their structure and release the payload in response to the different pH milieu of the GI tract. NCs that undergo structural changes under reductive environment have also been intensively studied. The cleavage of disulfide bonds by GSH effectively triggers drug release, especially in the cytosol where the GSH concentration is higher than in extracellular compartments. Current research has additionally focused on active surfaces that, in comparison to passive surfaces mentioned above, interact with the biological environment. The cleavage of mucus glycoproteins, for example, increases the permeation behaviour of NCs. In general, the diversity of materials for surface modification as well as the wide range of potential triggers inducing structural changes, offer great flexibility in the surface design of NCs.
纳米载体（包括 SEDDS、SLNs、NLCs、脂质体、聚合物胶束和聚合物及无机纳米颗粒）在口服药物递送领域的巨大潜力和有效性近年来越来越明显。如增强药物溶解度、穿过粘液和粘膜的渗透性、在胃肠道中对抗酶降解的稳定性以及可控药物释放等有益特性，证明了它们在口服药物递送系统中的优越作用。对纳米载体表面化学的修饰甚至可以进一步提高它们与食物、消化酶、胆盐和电解质的相互作用效率。例如，两性表面活性剂（如磷脂）或阴离子和阳离子表面活性剂或聚合物的组合可以设计出两性离子表面。此外，PEG-和 PG 涂层通过纳米载体表面的密集水化刷，保护纳米载体免受胃肠道液体和粘液的相互作用。此外，粘附表面的设计被发现适合口服药物递送，因为纳米晶体（NCs）粘附在覆盖胃肠道上皮的粘液凝胶层上。粘附性可以通过纳米晶体表面和粘液凝胶层之间的非共价相互作用（氢键、离子和疏水相互作用）或共价键（二硫键）来实现。此外，表面修饰的纳米晶体具有通过紧密连接开放、与细胞膜融合和内吞作用增强药物吸收的能力。最近，基于磷酸基团且可被膜结合磷酸酶切割的带电转换表面被开发出来，因此它们的电荷从阴离子转换为中性或阳离子。此外，磷酸酶对表面修饰的纳米晶体的酶解切割还提供了在刷状缘膜上实现靶向和可控药物释放的可能性。通过聚合物涂层实现靶向药物释放，这些聚合物会根据胃肠道不同 pH 环境改变其结构并释放有效载荷。在还原环境下发生结构变化的纳米晶体也已被广泛研究。半胱氨酸巯基化合物（GSH）有效裂解二硫键，从而触发药物释放，尤其是在细胞质中，GSH 浓度高于细胞外间隙。当前研究还关注了与上述被动表面相比，能够与生物环境相互作用的活性表面。例如，裂解粘蛋白糖蛋白可增加纳米晶体（NCs）的渗透行为。总的来说，表面改性材料的多样性和潜在触发结构变化的广泛范围，为纳米晶体（NCs）的表面设计提供了极大的灵活性。

Declaration of Competing Interest
声明利益冲突

None.

Acknowledgements 致谢

This review article was supported by the Austrian Forschungsförderungsgesellschaft (FFG), project: BCS class 3 drugs (No 885650).
这篇综述文章得到了奥地利研究促进协会（Forschungsförderungsgesellschaft，FFG）的支持，项目：BCS 类 3 药物（编号 885650）。

Data availability 数据可用性

No data was used for the research described in the article.
文章中描述的研究未使用任何数据。

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Cell-penetrating peptides for transmucosal delivery of proteins

2024, Journal of Controlled Release
Enabling non-invasive delivery of proteins across the mucosal barriers promises improved patient compliance and therapeutic efficacies. Cell-penetrating peptides (CPPs) are emerging as a promising and versatile tool to enhance protein and peptide permeation across various mucosal barriers. This review examines the structural and physicochemical attributes of the nasal, buccal, sublingual, and oral mucosa that hamper macromolecular delivery. Recent development of CPPs for overcoming those mucosal barriers for protein delivery is summarized and analyzed. Perspectives regarding current challenges and future research directions towards improving non-invasive transmucosal delivery of macromolecules for ultimate clinical translation are discussed.
Oral nanomedicine biointeractions in the gastrointestinal tract in health and disease

2023, Advanced Drug Delivery Reviews
Oral administration is the preferred route of administration based on the convenience for and compliance of the patient. Oral nanomedicines have been developed to overcome the limitations of free drugs and overcome gastrointestinal (GI) barriers, which are heterogeneous across healthy and diseased populations. This review aims to provide a comprehensive overview and comparison of the oral nanomedicine biointeractions in the gastrointestinal tract (GIT) in health and disease (GI and extra-GI diseases) and highlight emerging strategies that exploit these differences for oral nanomedicine-based treatment. We introduce the key GI barriers related to oral delivery and summarize their pathological changes in various diseases. We discuss nanomedicine biointeractions in the GIT in health by describing the general biointeractions based on the type of oral nanomedicine and advanced biointeractions facilitated by advanced strategies applied in this field. We then discuss nanomedicine biointeractions in different diseases and explore how pathological characteristics have been harnessed to advance the development of oral nanomedicine.
Oral drug delivery: Influence of mucus on cellular interactions and uptake of lipid-based nanocarriers in Caco-2 cells

2023, Acta Biomaterialia
Citation Excerpt :
Zwitterionic surfaces use Coulomb forces like ion-dipole interactions to bind water, while most other surfaces rely on H-bonds to interact with water molecules in their environment. As a result, bioinert, zwitterionic NCs can immobilize water on their surface, forming a stable solvation shell that acts as an interface shield against interactions with gastrointestinal (GI) compounds [14]. Moreover, zwitterionic surfactants do not cause an immune response like PEG.
This study aimed to investigate the impact of the mucus gel barrier on intestinal mucosal uptake of lipid-based nanocarriers (NCs). Zwitterionic- (ZW), polyglycerol- (PG) and polyethylene glycol- (PEG) surfactant-based o/w nanoemulsions were developed. NCs were assessed regarding their size and zeta potential, stability in biorelevant media and mucus, mucus permeation behavior, cellular interactions and uptake by Caco-2 cells with and without mucus and by a Caco-2/HT29-MTX co-culture. All NCs were in the size range of 178 – 204 nm and exhibited a zeta potential between -4.2 and +1.2 mV. ZW- and PG-NCs demonstrated mucus permeating properties comparable to PEG-NCs. In contrast, ZW- and PG-NCs showed high cellular uptake, whereas limited cellular uptake was observed in case of PEG-NCs. Furthermore, mucus on Caco-2 cells as well as the mucus secreting co-culture had a significant impact on the cellular uptake of all tested NCs. According to these results, ZW- and PG-NCs are advantageous to overcome the mucus and epithelial barrier of the intestinal mucosa.
Within this study the impact of mucus on cellular uptake of lipid-based nanocarriers (NCs) with different surface decorations was investigated. The potential of NCs with zwitterionic-, polyglycerol- and polyethylene glycol-surfactants on their surface to overcome the mucus and epithelial barrier was evaluated. Zwitterionic- and polyglycerol-NCs showed mucus permeating properties similar to PEG-NCs. In contrast, zwitterionic- and polyglycerol-NCs substantially outperformed PEG-NCs in their cellular uptake properties. According to these findings, zwitterionic- and polyglycerol-NCs have the potential to overcome both the mucus and epithelial barrier of the mucosa.
Posterity of nanoscience as lipid nanosystems for Alzheimer's disease regression

2023, Materials Today Bio
Alzheimer's disease (AD) is a type of dementia that affects a vast number of people around the world, causing a great deal of misery and death. Evidence reveals a relationship between the presence of soluble Aβ peptide aggregates and the severity of dementia in Alzheimer's patients. The BBB (Blood Brain Barrier) is a key problem in Alzheimer's disease because it prevents therapeutics from reaching the desired places. To address the issue, lipid nanosystems have been employed to deliver therapeutic chemicals for anti-AD therapy in a precise and targeted manner. The applicability and clinical significance of lipid nanosystems to deliver therapeutic chemicals (Galantamine, Nicotinamide, Quercetin, Resveratrol, Curcumin, HUPA, Rapamycin, and Ibuprofen) for anti-AD therapy will be discussed in this review. Furthermore, the clinical implications of the aforementioned therapeutic compounds for anti-AD treatment have been examined. Thus, this review will pave the way for researchers to fashion therodiagnostics approaches based on nanomedicine to overcome the problems of delivering therapeutic molecules across the blood brain barrier (BBB).
Effective drug combinations of betulinic acid and ceranib-2 loaded Zn:MnO<inf>2</inf> doped-polymeric nanocarriers against PC-3 prostate cancer cells

2023, Colloids and Surfaces B: Biointerfaces
Citation Excerpt :
The addition of Zn into MnO2 NCs improved their multifunctional properties such as optic, magnetic, hydrophilic and hydrophobic interactions. Furthermore, because of their small size and good dispersion in aqueous solution, the NCs are a promising candidate for biomedical applications such as cancer diagnosis and treatment [51]. The FTIR spectra of all the NCs were given in Fig. 3.
The development of theranostic nanocarriers with synergistic drug combinations has received considerable attention due to their improved pharmaceutical activity. Herein, we reported an investigation about the in-vitro anticancer activity of ceranib-2 (Cer), betulinic acid (BA), and the combination of betulinic acid and ceranib-2 (BA-Cer) against PC-3 prostate cancer cells. For this purpose, first we designed a suitable nanocarrier using a novel Zn:MnO₂ nanocomposite (NCs) and gallic acid (GA)-polylactic acid (PLA)-Alginate polymeric shell with nanoscale particle size and good stability. Chemical statements, morphology, and physicochemical properties of the nanocarrier have been illuminated with advanced characterization techniques. According to the transmission electron microscopy (TEM) results, Zn:MnO₂ NCs had a spherical and monodispersed morphology with a 2.03 ± 0.67 nm diameter. Moreover, vibrating-sample magnetometer (VSM) results showed that Zn:MnO₂ had paramagnetic properties with a saturation magnetization (Ms) value of 1.136 emu/g. Additionally, the in-vitro cytotoxic effects of the single and binary drugs loaded Zn:MnO₂-doped polymeric nanocarriers against PC-3 prostate cancer cells were investigated. According to the results, there was no significant cytotoxic effect of free BA and Cer against PC-3 prostate cancer cells. However, BA/Zn:MnO₂@GA-PLA-Alginate NCs, BA-Cer/Zn:MnO₂ @GA-PLA-Alginate NCs and free BA-Cer had IC₅₀ values of 6.498, 7.351, and 18.571 μg/mL, respectively. Consequently, BA-Cer/Zn:MnO₂@GA-PLA-Alginate is a nanocarrier with good stability, enhanced drug loading and release capacity for hydrophobic drugs, as well as being used as both imaging and treatment agent due to its magnetic properties. Furthermore, BA and Cer drug combination showed great promise in prostate cancer therapy which is known to be resulted high drug resistance. We strongly believed that this work could lead to an investigation of the molecular mechanisms of BA-mediated cancer theapy.
Chitosan in Oral Drug Delivery Formulations: A Review

2023, Pharmaceutics

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Historical Perspective 历史视角Surface design of nanocarriers: Key to more efficient oral drug delivery systems纳米载体表面设计：更高效口服药物递送系统的关键

Highlights 高亮

Abstract 摘要

Graphical abstract 图形摘要

Key words 关键词

1. Introduction 1. 引言

2. Bioinert surfaces 2. 生物惰性表面

2.1. Zwitterionic surfaces2.1. 两性离子表面

2.2. Polyethylene glycol (PEG) surfaces2.2. 聚乙二醇（PEG）表面

2.3. Poloxamer/poloxamine surfaces2.3. 泊洛沙姆/泊洛沙明表面

2.4. Polyglycerol (PG) surfaces2.4. 多甘醇（PG）表面

2.5. Comparison of bioinert surfaces2.5. 生物惰性表面的比较

3. Adhesive surfaces

4. Absorption enhancing surfaces4. 吸收增强表面