药学学报

Drug carrier	Drug	Disease	Characteristic	Ref.
Lipid nanoparticles	Naringenin	Nonalcoholic fatty liver	Improving intestinal absorption, and the elevated oral bioavailability by loading nano-structured lipid carrier	[31]
	Doxorubicin	Liver cancer	Improving liver targeting by modifying cholic acid ligands	[32]
	Asiatic acid (AA)	Liver fibrosis	Enhancing targeting and improving efficacy by linking to ursodeoxycholic acid (UA) and utilizing it to modify AA nanostructured lipid carriers	[33]
	Adefovir dipivoxil	Hepatitis B virus	Improving intestinal permeability with efficient liver-targeted delivery	[34]
	Sorafenib	Liver fibrosis	Improving the oral bioavailability and liver-targeting properties of sorafenib solid lipid nanoparticles	[35]
	Silibinin	Nonalcoholic fatty liver	Increasing in the oral bioavailability of silibinin	[36]
Micelle	6-Shogaol	Hepatic injury	Improving 6-shogaol's solubility and bioavailability by 6-shogaol loaded in micelles	[37]
	Silybin	Acute liver injury	Enhancing oral bioavailability and liver targeting delivery of silybin by hyaluronic acid-glycyrrhetinic acid micelles possessed glycyrrhetinic acid	[38]
	Baicalein	Acute liver injury	Improving bioavailability and hepatoprotective activity of baicalein	[39]
	Dasatinib	Hepatocellular carcinoma	Enhancing dasatinib solubility, stability, and therapeutic impact	[40]
	Vismodegib (GDC-0449)	Liver fibrotic	To maximize GDC-0449 delivery to hepatic stellate cells (HSCs)	[41]
Polymer nanoparticles	Short-chain fatty acid (SCFA)	Non-alcoholic steatohepatitis	Alleviating non-alcoholic steatohepatitis (NASH) and liver fibrosis by self-assembled polymer-based SCFA prodrugs Nano^{propionic acid (PA)} and Nano^{butyric acid (BA)}	[42]
	Sorafenib	Hepatocar cinoma	Exploiting the presence of carbohydrate receptors, asialoglycoprotein receptor by the preparation of liver-targeted polymeric micelles	[43]
Inorganic nanoparticles	TiO₂	Fatty liver in genetic and high-fat-diet obese	Revealing an unusual enterohepatic antioxidant response responsible for detoxifying low concentrations of reactive oxygen species (ROS) at the cost of elevated levels of hepatic lipolysis	[44]
	Sorafenib	Liver fibrosis	Moieting in the core formed a crosslink between the self-assembling block copolymers to afford stable drug absorption	[45]
Bionic delivery systems	Fucoxanthin	Nonalcoholic fatty liver disease	Offering the system liver-targeting capacity by modifying with glycyrrhetinic acid	[46]
	Quercetin	Nonalcoholic fatty liver disease	Binding to triglycerides and releases the drug in an affinity-driven reaction	[47]
	Mulberry leaf	Hepatocellular carcinoma	Exhibiting negligible adverse effects and superior anti-liver tumor outcomes through direct tumor killing and intestinal microbiota modulation	[48]

Drug carrier	Drug	Disease	Characteristic	Ref.
Lipid nanoparticles	Naringenin	Nonalcoholic fatty liver	Improving intestinal absorption, and the elevated oral bioavailability by loading nano-structured lipid carrier	[31]
	Doxorubicin	Liver cancer	Improving liver targeting by modifying cholic acid ligands	[32]
	Asiatic acid (AA)	Liver fibrosis	Enhancing targeting and improving efficacy by linking to ursodeoxycholic acid (UA) and utilizing it to modify AA nanostructured lipid carriers	[33]
	Adefovir dipivoxil	Hepatitis B virus	Improving intestinal permeability with efficient liver-targeted delivery	[34]
	Sorafenib	Liver fibrosis	Improving the oral bioavailability and liver-targeting properties of sorafenib solid lipid nanoparticles	[35]
	Silibinin	Nonalcoholic fatty liver	Increasing in the oral bioavailability of silibinin	[36]
Micelle	6-Shogaol	Hepatic injury	Improving 6-shogaol's solubility and bioavailability by 6-shogaol loaded in micelles	[37]
	Silybin	Acute liver injury	Enhancing oral bioavailability and liver targeting delivery of silybin by hyaluronic acid-glycyrrhetinic acid micelles possessed glycyrrhetinic acid	[38]
	Baicalein	Acute liver injury	Improving bioavailability and hepatoprotective activity of baicalein	[39]
	Dasatinib	Hepatocellular carcinoma	Enhancing dasatinib solubility, stability, and therapeutic impact	[40]
	Vismodegib (GDC-0449)	Liver fibrotic	To maximize GDC-0449 delivery to hepatic stellate cells (HSCs)	[41]
Polymer nanoparticles	Short-chain fatty acid (SCFA)	Non-alcoholic steatohepatitis	Alleviating non-alcoholic steatohepatitis (NASH) and liver fibrosis by self-assembled polymer-based SCFA prodrugs Nano^{propionic acid (PA)} and Nano^{butyric acid (BA)}	[42]
	Sorafenib	Hepatocar cinoma	Exploiting the presence of carbohydrate receptors, asialoglycoprotein receptor by the preparation of liver-targeted polymeric micelles	[43]
Inorganic nanoparticles	TiO₂	Fatty liver in genetic and high-fat-diet obese	Revealing an unusual enterohepatic antioxidant response responsible for detoxifying low concentrations of reactive oxygen species (ROS) at the cost of elevated levels of hepatic lipolysis	[44]
	Sorafenib	Liver fibrosis	Moieting in the core formed a crosslink between the self-assembling block copolymers to afford stable drug absorption	[45]
Bionic delivery systems	Fucoxanthin	Nonalcoholic fatty liver disease	Offering the system liver-targeting capacity by modifying with glycyrrhetinic acid	[46]
	Quercetin	Nonalcoholic fatty liver disease	Binding to triglycerides and releases the drug in an affinity-driven reaction	[47]
	Mulberry leaf	Hepatocellular carcinoma	Exhibiting negligible adverse effects and superior anti-liver tumor outcomes through direct tumor killing and intestinal microbiota modulation	[48]

口服肝靶向纳米递药系统的研究进展

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张雅文 ¹^,² , 郑正 ³ , 奉建芳 ¹^,⁴ , 涂亮星 ¹^,^* , 范武发 ²^,³^,^*

药学学报 | 综述 2025,60(6): 1661-1670

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药学学报 |综述 2025 , 60 (6) : 1661 -1670

口服肝靶向纳米递药系统的研究进展

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张雅文¹^,², 郑正³, 奉建芳¹^,⁴, 涂亮星¹^,^*, 范武发²^,³^,^*

作者信息

¹江西中医药大学, 中药固体制造技术国家工程研究中心, 江西南昌 330006

²中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050

³中国医学科学院、北京协和医学院药物研究所, 药物传输技术及新型制剂北京市重点实验室, 北京 100050

⁴广西中医药大学药学院, 广西南宁 530200

通讯作者:

涂亮星, Tel: 86-791-87119650, E-mail: tufrankie@163.com

范武发, Tel: 13693524103, E-mail: fanwufa@imm.ac.cn

作者简介:

作者贡献:

张雅文、涂亮星负责文章资料收集与初稿撰写; 张雅文、郑正、奉建芳和范武发负责文章的选题建议与修改; 涂亮星和范武发为该文章的共同负责人。所有作者阅读并认可终稿。

Research progress of oral liver targeting nano-drug delivery system

Ya-wen ZHANG¹^,², Zheng ZHENG³, Jian-fang FENG¹^,⁴, Liang-xing TU¹^,^*, Wu-fa FAN²^,³^,^*

Affiliations

¹National Engineering Research Center for Solid Preparation Technology of Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang 330006, China

²State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China

³Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China

⁴College of Pharmaceutical Sciences, Guangxi University of Chinese Medicine, Guangxi University, Nanning 530200, China

出版时间: 2025-06-12 doi: 10.16438/j.0513-4870.2024-1311

文章导航

摘要

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口服肝靶向纳米递药系统具有给药依从性好、不良反应低和安全性高等优点, 是最有潜力的给药方式。然而, 胃肠道和肝脏的生物及生理学屏障严重阻碍药物载体的口服吸收及在肝脏病变部位的分布。本文首先总结了口服肝靶向纳米递药系统在给药过程中遇到的主要生物和生理学屏障; 同时, 概括了近年来用于口服肝靶向递送的药物载体; 另外, 介绍了口服肝靶向纳米递药系统治疗肝脏相关疾病的研究进展, 为口服肝靶向纳米递药系统治疗肝脏相关疾病的研究提供思路。

关键词

口服 / 肝靶向 / 口服屏障 / 药物递送 / 药物载体

Abstract

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Oral liver-targeting nano-drug delivery system is the most potential drug delivery method which has the advantages of good drug compliance, low side effects, and high safety. However, the biological and physiological barriers in the gastrointestinal tract and liver severely hinder the oral absorption and accumulation of drug carriers in the liver lesions. This review first describes the main biological and physiological barriers encountered by the oral liver-targeted nano-drug delivery system during the drug delivery period. Meanwhile, this article summarizes oral liver-targeting drug carriers in recent years. In addition, the research progress of oral liver-targeted nano-drug delivery system in the treatment of liver-related diseases is introduced, which provides ideas for the development of oral liver-targeting nano-drug delivery system in the liver-related disease treatment.

Key words

oral administration / liver-targeting / oral barrier / drug delivery / drug carrier

引用本文

张雅文, 郑正, 奉建芳, 涂亮星, 范武发. 口服肝靶向纳米递药系统的研究进展. 药学学报, 2025 , 60 (6) : 1661 -1670 . DOI: 10.16438/j.0513-4870.2024-1311

Ya-wen ZHANG, Zheng ZHENG, Jian-fang FENG, Liang-xing TU, Wu-fa FAN. Research progress of oral liver targeting nano-drug delivery system[J]. Acta Pharmaceutica Sinica, 2025 , 60 (6) : 1661 -1670 . DOI: 10.16438/j.0513-4870.2024-1311

正文

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肝脏疾病是全球重大健康问题之一, 每年造成200万人死亡, 占全球所有死亡人数的4%^[1]。目前, 药物治疗、肝切除术和肝移植是肝病的常用治疗方法^[2], 其中, 药物治疗的主要缺点是无法向患者肝脏病变部位输送足够浓度的治疗剂量, 且往往有严重的毒副作用。因此, 开发肝脏靶向的药物递送系统对肝脏疾病的治疗具有重大意义。

口服给药是常用的给药方式之一, 与其他方式相比, 口服给药具有更好的安全性和患者依从性^[3]。其中, 口服肝靶向纳米递药系统是指纳米载体通过口服给药后能特异性地靶向肝脏, 将药物有效地递送至肝病变部位, 从而提高药物疗效和安全性^[4]。近年来, 研究人员对口服肝靶向纳米递药系统在肝脏疾病靶向方面进行了大量研究。例如, 有人利用肠细胞和肝细胞过表达的受体或转运体, 将相应的特异性配体修饰在纳米载体表面, 实现这些载体的高效口服肝靶向递送^[5]。如图1所示, 口服肝靶向纳米递药系统也面临一系列困难, 在胃肠道的低pH和酶环境下, 药物载体容易聚集或降解, 其稳定性遭遇挑战; 同时, 胃肠道黏膜和肠上皮细胞紧密连接也对纳米载体的口服吸收造成了严重的阻碍; 另外, 在口服吸收后, 如何实现肝靶向也是一个重大的难题。因此, 为构建高效的口服肝靶向纳米递药系统, 有必要对目前的给药系统进行归纳和总结, 指出目前面临的挑战, 并对未来进行展望。

1　胃肠道屏障

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1.1　稳定性屏障

药物载体稳定性是指载体及所包封药物保持其物理和化学性质的能力。药物载体口服后的吸收始于胃, 其稳定性易受胃内环境的影响^[6]。胃内环境主要由胃酸和消化酶等物质组成。胃酸pH值在1.5~3.5之间, 药物载体在该环境下容易发生结构降解, 这会导致所包封的药物泄漏及失活等; 同时, 胃内消化酶也会导致药物载体的稳定性降低, 如脂质类载体被胃内的脂肪酶脂解^[7]; 另外, 小肠等吸收部位分布着丰富的脂肪酶和蛋白酶等, 这些酶对载体及药物的稳定性也造成影响。目前, 一些胃酸调节剂和酶抑制剂分别用于改善胃内低pH值环境和抑制胃肠道酶活性, 以增加药物载体的稳定性; 同时, 一些耐酸及酶稳定性材料存在一定的胃肠道稳定性, 可用于口服药物递送系统。总的来说, 药物载体在增加药物稳定性方面具有显著优势, 但口服后胃肠道的稳定性仍然是一个挑战, 将来还应进行细致的研究^[8]。

1.2　黏液屏障

肠黏液主要由杯状细胞分泌的黏蛋白构成, 本质上是由蛋白质、碳水化合物、脂质、盐，以及细胞碎片等混合组成的一种水凝胶^[9]。黏液通过黏附和空间位阻作用迅速捕捉肠容物, 可防止病原体及毒素渗透并侵入黏膜上皮细胞, 但同时也影响了药物载体的扩散和吸收, 对口服给药造成严重的阻碍^[10]。黏蛋白包含富有半胱氨酸的结构区域, 整体呈负电荷。表面疏水性或带正电荷的药物载体易通过静电、范德华力等与黏蛋白相互作用, 这会导致药物困在黏液中, 减少在黏液中的扩散和渗透^[11]。因此, 常在药物载体表面修饰一层亲水性材料, 如聚乙二醇和两性离子聚合物, 减少与黏蛋白的相互作用, 以利于在黏液中的有效渗透。目前, 黏液渗透仍然是制约药物载体口服吸收的关键屏障, 未来应该在载体材料设计上加大研究, 以解决口服药物载体在黏液中渗透难问题。

1.3　肠上皮屏障

肠组织主要由肠上皮细胞构成, 还包含少量的杯状细胞和M细胞^[12]。肠上皮细胞之间存在紧密连接, 主要作用是避免肠道内容物(如细菌、毒素) 进入血液系统, 但同时对药物或药物载体的口服吸收也造成了阻碍^[13]。由于紧密连接的存在, 只有疏水性小分子能通过细胞旁路途径吸收, 而亲水性小分子或大分子则难于跨越这道屏障。由于尺寸的限制, 口服药物载体难以通过细胞旁路进行有效吸收^[14]。目前, 一些化学促渗剂被用于改善药物或药物载体的口服吸收, 其口服后能瞬间打开肠上皮细胞之间的紧密连接, 进而增加药物或药物载体通过细胞旁路途径吸收^[15]。然而, 这些化学促渗剂在增加药物和药物载体口服吸收时, 也同样增加了肠道内容物的摄入, 容易造成感染。但是, 借助肠上皮细胞的转胞吞特性, 对药物载体进行合理的表面性质设计, 如配体修饰等, 能促进它们依赖细胞转胞吞途径进行有效的吸收; 另外, 借助M细胞的优良吞噬性能, 可设计靶向M细胞的药物载体, 通过M细胞途径能增加口服吸收。目前, 肠上皮屏障仍然是制约口服药物载体有效吸收的重要原因, 将来应该在药物载体设计和吸收机制上面进行更深入的研究。

1.4　肝靶向屏障

肝脏具有复杂的解剖结构——肝小叶、肝窦、汇管区及中央静脉等^[16]; 同时存在多种细胞类型, 如肝实质细胞、肝窦内皮细胞(hepatic sinus endothelial cells, LSEC)、星状细胞和Kupffer细胞等, 使得靶向肝脏的药物递送面临着诸多挑战^[17]。口服药物载体吸收途径主要有两种, 分别是肝门静脉途径和淋巴途径。在肝门静脉途径中, 药物载体口服吸收后首先通过门静脉系统进入肝脏, 并在肝窦中与肝脏相关细胞直接接触。在淋巴途径中, 药物载体口服后通过肠系膜淋巴管并最终经胸导管进入系统循环。由于肝脏的独特生理结构, 肝脏疾病主要发生在肝实质细胞, 药物载体如何靶向肝脏病变部位面临一系列挑战^[18]。

肝窦内高效筛选机制是药物载体靶向肝脏的重要的生理屏障之一^[19]。肝窦作为肝脏重要的通透性结构, 是血流与其他肝细胞之间物质交换的主要场所^[20]。LSEC是肝窦的主要组成部分, 细胞之间存在空隙, 约50~200 nm之间, 这种结构可以促进肝窦之间的物质交换, 允许血液中的小分子和合适粒径的纳米药物通过内皮细胞间隙进入肝实质细胞^[21]。然而, 这种粒径筛选机制在保护肝细胞免受有害物质侵害的同时, 也会阻碍药物载体的有效递送^[22]。

肝靶向递药系统面临的另一重要屏障是网状内皮系统——Aschoff将吞噬细胞(除粒细胞外) 和血液内的单核细胞以及骨髓和淋巴器官内的网状细胞和内皮细胞归纳为一个系统, 称为网状内皮系统(reticuloendothelial system, RES)^[23]。RES是药物载体在肝脏病变部位靶向分布的主要生物学屏障^[24], 其包括肝脏中的Kupffer细胞, 脾脏中的巨噬细胞以及骨髓中的单核细胞等^{[25, 26]}。口服吸收的药物载体在血液中可被调理素化, 接着被RES识别并吞噬, 分布在肝脏的Kupffer细胞, 而非肝脏病变部位^[27]。为了有效克服RES对肝靶向药物载体的屏障, 研究者们提出了一系列策略^[28]。例如, 将亲水性材料修饰在药物载体的表面, 以减少调理素化, 增加载体的血液循环时间, 进而被动靶向至肝脏病变部位^[29]。在亲水性材料修饰的同时, 还可根据肝病变部位细胞过表达的受体或转运体, 在药物载体表面修饰相应的配体等, 以增加它们在肝病变部位的靶向^[30]。

2　口服肝靶向纳米递药系统的分类

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近年来, 口服肝靶向纳米递药系统在肝脏疾病靶向方面进行了大量的研究, 在提高药物在肝脏相关疾病靶向和疗效方面具有显著的优势。作者主要针对口服肝靶向剂型的研究进展进行综述(图2, 表1^[31-48])。

2.1　脂质纳米粒

脂质纳米粒由一个或几个脂质双层组成, 大小在20~1 000 nm之间, 亲水性药物可以封闭在脂质纳米粒的水性内部区域, 而疏水性药物可以包裹在脂双层的烃链区域中^[49]。脂质纳米粒因其与生物膜的相似结构, 表现出良好的生物相容性和低毒性, 广泛地应用于口服肝靶向递送研究。研究人员利用脂质纳米粒包封药物, 可增加细胞对药物的摄取, 从而提高药物的口服生物利用度和在肝脏中的分布^[50]。Hu等^[31]制备了负载柚皮素的脂质纳米粒。与相同剂量的游离柚皮素相比, 脂质纳米粒增加了柚皮素细胞内转运, 提高了跨肠上皮细胞转运和肠道吸收, 结果表明脂质纳米粒显著提高了柚皮素的口服生物利用度, 达到3.7倍, 并且明显提高了对非酒精性脂肪性肝病的抑制作用。通过利用肝细胞上过表达的受体, 在脂质纳米粒表面修饰相应的配体, 可实现肝脏的精确靶向递送, 增加口服生物利用度和相应的治疗效果^[51]。Li等^[32]构建了一种改性的二硬脂酰磷脂酰乙醇胺-聚乙二醇-胆酸修饰的脂质纳米粒并负载多柔比星, 与多柔比星溶液相比, 多柔比星脂质纳米粒在Caco-2细胞中的转运效率提高了6.65倍。更重要的是, 脂质纳米粒利用肝细胞特异性结合的天然配体——胆酸, 极大增加了药物在肝细胞的靶向分布, 为口服多柔比星的抗肝癌治疗提供了可能。Zhang等^[33]制备了一种聚乙二醇和熊去氧胆酸修饰的积雪草酸脂质体, 与积雪草酸混悬液相比, 聚乙二醇修饰脂质体增加了积雪草酸的口服生物利用度。另外, 利用熊去氧胆酸修饰能够靶向肝细胞, 实现了积雪草酸的肝靶向分布, 在肝脏中药物浓度提高了6.2倍, 最终显著降低了小鼠的肝纤维化和功能损伤。脂质纳米粒在口服肝靶向递送过程中展现出了良好的应用前景, 但它依然面临着口服生物利用度和肝靶向效率低的挑战。因此, 未来的研究需要进一步优化脂质体的制备工艺和配方设计, 以提高其在口服肝靶向纳米递药系统中的应用^[52]。

2.2　胶束

胶束是由两亲性分子(如表面活性剂或两亲性聚合物) 在水中自发形成的纳米级胶体颗粒, 具有疏水核心和亲水外壳结构。这种特殊结构使胶束能够有效包封疏水性药物, 并在体内长时间循环, 提高药物的生物利用度。Zhang等^[37]开发了一种新型mPEG2000胶束, 装载了疏水性化合物6-shogaol, 与游离的6-shogaol相比, mPEG2000胶束增加了6-shogaol的溶解度, 口服生物利用度提高了3.2倍, 最终显著增强了6-shogaol在肝脏中的分布和对肝炎和肝癌的治疗作用。利用肝细胞过表达的受体, 胶束可以通过修饰相应配体, 实现更好的肝脏靶向。Han等^[38]合成了双亲性透明质酸衍生物——透明质酸-甘草次酸偶联物, 包载水飞蓟宾。由于水飞蓟宾极低的水溶性, 其静脉给药受到限制。与水飞蓟宾混悬液相比, 该胶束通过肠上皮细胞旁路途径吸收, 口服生物利用度增加了4.38倍。胶束还利用肝细胞上的甘草次酸受体, 获得了更高的肝靶向分布和肝炎治疗效果。然而, 胶束在口服肝靶向纳米递药系统中也面临一些困境。胶束在胃肠道中的稳定性较差, 在口服给药后胶束容易发生解体, 导致药物释放^[53]。尽管如此, 胶束作为口服肝靶向药物递送载体, 凭借其独特的结构和功能, 具有广阔的发展前景。

2.3　聚合物纳米粒

聚合物纳米粒是由天然或合成的高分子材料通过自组装或交联形成的纳米级颗粒, 广泛用于药物递送系统中^[54]。由于聚合物材料的多样性和可调节性, 聚合物纳米粒展现出良好的生物相容性和功能可调等优点。在口服肝靶向纳米递药系统中, 聚合物纳米粒的粒径和表面电荷会影响载体在体内的转运。一般来说, 粒径较小的聚合物纳米粒更容易通过胃肠道屏障, 可以提高药物载体的口服生物利用度和肝靶向。Shashni等^[42]设计了短链脂肪酸(short-chain fatty acid, SCFA) 的前药——通过酯键与丙酸或丁酸偶联, 自组装成直径几十纳米的两亲性稳定聚合物(Nano^SCFA)。SCFA的分子质量小且为水溶性药物, 会迅速从体内清除, 且静脉注射丙酸钠和丁酸钠的半衰期只有6 min左右, 静脉注射途径的疗效较差。为提高SCFA的治疗效果, 需要增加剂量或连续给药, 而口服方式便于给药。Nano^SCFA口服给药后在肠黏膜中积累, 且被酯酶成功裂解时可持续释放几个小时的SCFA, 还可以通过避免被单核吞噬细胞系统吸收和清除来提高生物利用度, Nano^SCFA可以持续地将SCFA靶向到肝脏并缓解非酒精性脂肪性肝炎和肝纤维化的症状。聚合物纳米粒还可以通过黏膜黏附来延长在胃肠道中的停留时间实现更高的口服生物利用度。Pawar等^[55]开发了一种聚甲基丙烯酸-壳聚糖-聚乙二醇聚合物纳米颗粒, 通过提高链的流动性和柔韧性增加聚合物系统的黏膜黏附性能, 通过制剂的黏附可以增加药物口服生物利用度和在肝脏的分布。利用肝细胞过表达的受体, 聚合物纳米粒修饰相应特异性配体同样能够增加肝脏的分布^[56]。Wang等^[57]针对肝细胞过表达的受体, 制备了一种由胆汁酸转运蛋白与单甲氧基聚和脱氧胆酸共轭聚(2-乙基-2-恶唑啉)-聚(D, L-丙交酯) 的聚合物纳米粒(图3)。与未修饰的纳米粒相比, 胆汁酸修饰的制剂在Caco-2细胞中的转运效率增加了1.6倍, 并且增强了药物的肝脏靶向分布。聚合物纳米粒在口服肝靶向纳米递药系统中的应用也存在一些挑战, 在胃肠道中的稳定性容易受胃酸和消化酶的影响, 导致药物提前释放和降解。此外, 部分聚合物材料可能存在潜在的生物相容性问题^[58]。

2.4　无机纳米粒

无机纳米粒是通过物理或化学方法合成、尺寸在10~100 nm的无机纳米粒子。因其具有良好的稳定性、可调控性以及独特的物理化学性质(如磁性、光学特性等), 在口服肝靶向纳米递药系统中展示了良好的应用潜力^[59]。另外, 低剂量无机纳米颗粒已被证实有可能诱导活性氧(reactive oxygen specie, ROS) 的适度增加, 并诱导生物系统的适应性反应。Cai等^[44]报道了各种无机纳米颗粒的重复口服给药, 可促进小鼠肝脏中的脂质降解并缓解脂肪变性, 并且发现极低剂量的无机纳米颗粒便可触发对肝细胞脂质代谢诱导的ROS的低水平抗氧化防御, 而这种非常规的抗氧化反应导致脂质积累减少并减轻肝脏脂肪变性, 且没有明显的不良反应, 可预防和治疗肥胖和非酒精性脂肪肝疾病(图4)。通过肠道黏膜, 无机纳米粒能够实现特异性靶向, 提高药物在体内的累积^[60]。Tran等^[45]开发了一种载有索拉菲尼的二氧化硅纳米粒(Sorafenib@siRNP), 由于载体具有小干扰RNA核糖核蛋白复合体(small interfering ribonucleoprotein, siRNP) 的交联核心和聚乙二醇化外壳, 提高了索拉菲尼的稳定性和增加了索拉菲尼在肠黏膜中的停留, 索拉菲尼的口服生物利用度提高了约2倍, 且增加了其在肝脏中的积累, 对肝纤维化有显著疗效。无机纳米颗粒在口服肝靶向纳米递药系统中的应用也存在一些挑战, 例如多数无机材料存在生物降解性差、长期滞留等问题。

2.5　仿生递送系统

仿生递药系统的一个关键策略是利用生物膜或囊泡的生物相容性和归巢特性等, 能够有效逃避免疫系统的识别清除, 延长药物载体在体内的循环时间和疾病部位的靶向富集。Wu等^[46]从副干酪乳杆菌(Lactobacillus paracei, LpEVs) 中提取了细胞外囊泡, 然后通过酰胺反应获得甘草次酸(glycyrrhetinic acid, GA) 修饰, 随后包载岩藻黄质(fucoxanthin, FX), 最后构建了具有肝脏靶向性的GA-LpEVs-FX。该制剂利用肝细胞上的甘草次酸受体, 显著增加了FX的肝脏分布。与岩藻黄质溶液相比, 该制剂显著提高了岩藻黄质的口服生物利用度, 并有效减轻非酒精性脂肪肝疾病中脂质积累和活性氧诱导的损伤。Wen等^[47]通过沉淀聚合获得了与甘油三酯的空间结构和分子极性匹配的分子印迹聚合物(molecularly imprinted polymer, MIP), 并将自噬激活剂槲皮素(quercetin, QUE) 装载到其印迹腔中, 获得MIP@QUE。MIP@QUE作为甘油三酯的仿生转运蛋白, 具有良好的生物稳定性和相容性, 通过模拟甘油三酯的自然运输, 促进其细胞转运和增强口服生物利用度, 结果表明, 在非酒精性脂肪性肝炎(non-alcoholic steatohepatitis, NAFLD) 模型中, 口服MIP@QUE通过细胞旁路途径吸收进入血循环, 随后靶向肝脏, 并通过激活细胞内的自噬-溶酶体途径, 显著减少NAFLD的脂滴积累, 增加了对NAFLD的治疗效果(图5)。虽然仿生递药系统展现出很好的应用前景, 但是其还面临着口服后肠道相关淋巴组织非特异性摄取风险和肝靶向精准性不足的挑战。

3　口服肝靶向纳米递药系统用于肝脏疾病

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口服肝靶向纳米递药系统在多种肝脏相关疾病, 如肿瘤、肝炎、糖尿病及其他可能受益于肝靶向治疗的疾病中具有重要的应用(图6)。

3.1　肿瘤

肝脏是许多原发性和转移性肿瘤的常见部位, 主要有肝细胞癌。肝细胞癌患者临床表现为肝区疼痛、黄疸、消化道症状等, 且早期诊断困难、治疗方法局限和术后高复发率, 所以亟需开发有效的治疗方法。Gao等^[48]从黑桑叶中提取了天然外泌体样脂质纳米颗粒, 这些天然纳米粒富含糖脂、功能性蛋白和活性小分子。纳米粒通过半乳糖受体介导的内吞作用, 增加在肝肿瘤细胞的摄取, 脂质纳米颗粒口服后通过空肠和结肠进入循环系统, 可以获得优良的生物利用度, 且通过直接肿瘤杀伤和肠道微生物群调节表现出卓越的抗肝肿瘤结果。此外, Craparo等^[43]制备了一种载有索拉菲尼的半乳糖基化聚合物胶束, 相对于索拉菲尼溶液, 该纳米粒有着更高的口服生物利用度, 更重要的是, 利用半乳糖配体与内源性凝集素受体的高度特异性相互作用, 获得了很好的肝靶向和肝癌治疗效果。

3.2　肝炎

肝炎是由于某些原因引起肝脏细胞受到破坏, 肝脏的功能受到损害, 引起身体一系列疾病症状, 分为急性肝炎和慢性肝炎等。通过口服肝靶向纳米递药系统, 能够更高效地治疗这些疾病。

3.2.1　急性肝炎

急性肝炎通常由药物使用过量引起, 其特征是肝细胞的急性炎症和损伤。在药物性肝炎的治疗中, N-乙酰半胱氨酸是一种常用的解毒药物, 通过增加谷胱甘肽水平, 帮助肝细胞排出毒素。有研究人员通过口服递送N-乙酰半胱氨酸, 可以增强其在肝脏中的浓度, 从而更有效地防止肝细胞损伤^[61]。Han等^[38]合成了两种双亲性透明质酸衍生物——透明质酸-脱氧胆酸和透明质酸-甘草次酸偶联物, 装载水飞蓟宾胶束, 与水飞蓟宾混悬液相比, 这两种胶束通过肠上皮细胞旁路途径获得了更好的口服生物利用度, 更重要的是, 透明质酸衍生物——透明质酸-脱氧胆酸胶束利用肝细胞上的甘草次酸受体, 获得了更高的肝靶向和肝炎治疗效果。此外, Lu等^[62]构建了一种由奥贝胆酸(obecholic acid, OCA) 和阿托伐他汀(atorvastatin, AHT) 自组装形成的纳米晶(OCAHT), 这种纳米晶不仅提高了胃肠道环境中的稳定性和口服生物利用度, 而且利用肝脏过表达的奥贝胆酸受体实现了肝脏蓄积, OCAHT在改善急性肝炎和非酒精性脂肪性肝炎方面优于OCA和AHT的简单组合, 且毒性较小。

3.2.2　慢性肝炎

3.2.2.1　酒精性肝炎

酒精性肝炎是由于长期大量饮酒导致的肝脏损伤, 其特征为肝细胞变性、坏死以及纤维化的形成。酒精性肝炎患者通常面临着肝脏功能下降和肝纤维化的双重威胁, 因此亟需有效的治疗方法来缓解肝脏损伤。Gu等^[63]开发了一种益生菌鼠李糖乳杆菌(Lactobacillus rhamnosus probiotics, LGG) 来源的外泌体样纳米粒, 该纳米粒可以增加肠上皮细胞紧密连接蛋白的表达, 并保护巨噬细胞免受脂多糖诱导的炎症反应。口服该纳米粒可保护肠道免受酒精引起的屏障功能障碍, 并保护肝脏免受脂肪变性和损伤。

3.2.2.2　非酒精性脂肪性肝炎

NAFLD是一种与肥胖和代谢综合征密切相关的肝病, 其特征为肝脏内脂肪的异常积累。水飞蓟宾是NAFLD常见的治疗药物, 但其口服生物利用度不高。Liang等^[64]制备了一种壳聚糖修饰载有水飞蓟素的脂质纳米粒, 利用壳聚糖在弱酸条件下带正电, 使制剂可以打开小肠上皮细胞之间的紧密连接, 增加了药物的口服生物利用度, 同时还可以增加水飞蓟宾在肝脏的分布和减少脂肪在肝脏中的沉积, 防止脂肪性肝炎及肝纤维化发生。Chen等^[65]开发了一种二乙基氨基乙基葡聚糖包被的胆小体——胆盐修饰的脂质体, 封装小檗碱和姜黄素, 由于二乙氨基乙基葡聚糖是一种阳离子聚合物, 可通过黏附在肠壁黏液中实现药物在肠道的长时间滞留, 显著增加药物的口服生物利用度和在肝脏中的分布, 改善NAFLD的症状。由于NAFLD与肝脏代谢失调有关, 可以通过调节脂质相关的代谢来治疗这种疾病。

3.2.2.3　糖尿病肝病(diabetic liver disease, DLD)

DLD是一种罕见的肝病, 多发生于1型和2型糖尿病, 是糖尿病的常见并发症, 表现为脂肪在肝脏中的过度积累和肝脏功能的下降。目前, 通过胰岛素控制血糖以减轻肝脏负担是DLD的标准治疗手段, Banerjee等^[66]开发了一种由胆碱和香叶酸(geranolic acid, CAGE) 构成的离子液体, 用于胰岛素的口服递送。CAGE提高了口服胰岛素在胃肠道的稳定性, 同时增加了细胞旁路途径的吸收, 显著增强胰岛素的口服生物利用度, 对治疗DLD有着极大的促进作用。

3.3　胆道梗阻(梗塞)

胆道梗阻是指胆汁从肝脏通过胆囊进入肠道的胆汁排出道的任何一段导管堵塞。如果不及时治疗, 这种堵塞会导致严重的并发症。胆道梗阻可能由结石、肿瘤、炎症或狭窄等引起, 且在术后容易复发。在术后, 口服肝靶向药物递送系统可以辅助减少复发并促进肝功能的恢复。Ma等^[67]开发了熊去氧胆酸(ursodeoxycholic acid, UDCA) 修饰的两性离子纳米粒(UC-CMs@ins), 与非UDCA修饰的制剂相比UC-CMs@ins表现出优异的溶酶体逃逸能力和良好的口服生物利用度。UC-CMs@ins可防止胰岛素在胃肠道中降解, 利用肝脏表面配体——UDCA实现肝靶向分布, 有效降低胆汁的毒性, 并通过调节胆汁酸的分泌, 减轻胆汁淤积引发的肝细胞损伤。

4　展望与挑战

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本文总结了口服肝靶向纳米递药系统的生物与生理学屏障、口服肝靶向剂型的研究进展。随着生物材料和纳米技术领域的持续发展, 越来越多新型的递送载体和靶向机制将被应用于口服肝靶向纳米递药系统中。大分子药物, 如多肽、蛋白、核酸等, 在肝脏疾病的治疗中具有显著优势, 但其口服递送仍然存在较大的挑战。将来, 更多的大分子递送载体应被设计和开发, 解决它们在口服递送过程中的稳定性等问题, 突破口服递送屏障, 提高生物利用度和肝靶向效率。个性化医疗的发展也为口服肝靶向纳米递药系统带来了新的机会。通过对患者进行基因组学、蛋白质组学和代谢组学分析, 可以实现对疾病特征和患者个体差异的精确分析, 从而设计出更加个性化的口服肝靶向药物治疗方案。目前, 尚未有口服肝靶向纳米递药系统进入临床试验或使用, 但随着具有更高递送效率的载药系统开发, 相信在不久的将来能突破口服肝靶向“最后一公里”障碍, 为肝脏相关疾病提供精准治疗。

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Devarbhavi H, Asrani SK, Arab JP, et al. Global burden of liver disease: 2023 update [J]. J Hepatol, 2023, 79: 516-537.

Yamada T, Iwasaki Y, Tada H, et al. Nanoparticles for the delivery of genes and drugs to human hepatocytes [J]. Nat Biotechnol, 2003, 21: 885-890.

Elz AS, Trevaskis NL, Porter CJH, et al. Smart design approaches for orally administered lipophilic prodrugs to promote lymphatic transport [J]. J Control Release, 2022, 341: 676-701.

Liu Y, Yang HS, Zhu JH, et al. Novel albendazole-glucan particles for enhancing intestinal absorption and improving hepatic targeting [J]. Ann Transl Med, 2022, 10: 1312.

Liu Y, Wang XQ, Ren WX, et al. Novel albendazole-chitosan nanoparticles for intestinal absorption enhancement and hepatic targeting improvement in rats [J]. J Biomed Mater Res B Appl Biomater, 2013, 101: 998-1005.

Salaheldin TA, Godugu K, Bharali DJ, et al. Novel oral nano-hepatic targeted anti-PCSK9 in hypercholesterolemia [J]. Nanomedicine, 2022, 40: 102480.

Date T, Paul K, Singh N, et al. Drug-lipid conjugates for enhanced oral drug delivery [J]. AAPS PharmSciTech, 2019, 20: 41.

Wang J, Yadav V, Smart AL, et al. Toward oral delivery of biopharmaceuticals: an assessment of the gastrointestinal stability of 17 peptide drugs [J]. Mol Pharm, 2015, 12: 966-973.

Zhang Z, Lu Y, Qi JP, et al. An update on oral drug delivery via intestinal lymphatic transport [J]. Acta Pharm Sin B, 2021, 11: 2449-2468.

Perez-Lopez A, Behnsen J, Nuccio SP, et al. Mucosal immunity to pathogenic intestinal bacteria [J]. Nat Rev Immunol, 2016, 16: 135-148.

McGuckin MA, Lindén SK, Sutton P, et al. Mucin dynamics and enteric pathogens [J]. Nat Rev Microbiol, 2011, 9: 265-278.

Gieryńska M, Szulc-Dąbrowska L, Struzik J, et al. Integrity of the intestinal barrier: the involvement of epithelial cells and microbiota—a mutual relationship [J]. Animals (Basel), 2022, 12: 145.

Lin DJ, Yang LS, Wen LL, et al. Crosstalk between the oral microbiota, mucosal immunity, and the epithelial barrier regulates oral mucosal disease pathogenesis [J]. Mucosal Immunol, 2021, 14: 1247-1258.

Choonara BF, Choonara YE, Kumar P, et al. A review of advanced oral drug delivery technologies facilitating the protection and absorption of protein and peptide molecules [J]. Biotechnol Adv, 2014, 32: 1269-1282.

Wang D, Jiang Q, Dong ZF, et al. Nanocarriers transport across the gastrointestinal barriers: the contribution to oral bioavailability via blood circulation and lymphatic pathway [J]. Adv Drug Deliv Rev, 2023, 203: 115130.

Boyer TD, Lindor KD. Zakim and Boyer's Hepatology: A Textbook of Liver Disease E-Book [M]. 7th ed. Philadelphia: Elsevier Health Sciences, 2018: 1029-1052.

Israel J, London WT. Liver structure, function, and anatomy: effects of hepatitis B virus [J]. Curr Top Microbiol Immunol, 1991, 168: 1-20.

Cheng ML, Nakib D, Perciani CT, et al. The immune niche of the liver [J]. Clin Sci (Lond), 2021, 135: 2445-2466.

Kubes P, Jenne C. Immune responses in the liver [J]. Annu Rev Immunol, 2018, 36: 247-277.

Taylor KJ, Richman TS. Diseases of the liver [J]. Semin Roentgenol, 1983, 18: 94-101.

Fan QQ, Zhang CL, Qiao JB, et al. Extracellular matrix-penetrating nanodrill micelles for liver fibrosis therapy [J]. Biomaterials, 2020, 230: 119616.

Goltz D, Fischer HP. Liver sinusoids: pathology of endothelial findings [J]. Pathologe, 2020, 41: 471-477.

Li Z, Zhu YB, Zeng HW, et al. Mechano-boosting nanomedicine antitumour efficacy by blocking the reticuloendothelial system with stiff nanogels [J]. Nat Commun, 2023, 14: 1437.

Tang YX, Wang XY, Li J, et al. Overcoming the reticuloendothelial system barrier to drug delivery with a "don't-eat-us" strategy [J]. ACS Nano, 2019, 13: 13015-13026.

Pereira F, Petroianu A, Geraldo JM, et al. Megavoltage radiotherapy effects on organs of the reticuloendothelial system [J]. Acta Cir Bras, 2023, 38: e384123.

Böttcher K, Pinzani M. Pathophysiology of liver fibrosis and the methodological barriers to the development of anti-fibrogenic agents [J]. Adv Drug Deliv Rev, 2017, 121: 3-8.

Krenkel O, Tacke F. Liver macrophages in tissue homeostasis and disease [J]. Nat Rev Immunol, 2017, 17: 306-321.

Karlmark KR, Weiskirchen R, Zimmermann HW, et al. Hepatic recruitment of the inflammatory Gr1⁺ monocyte subset upon liver injury promotes hepatic fibrosis [J]. Hepatology, 2009, 50: 261-274.

Ramachandran P, Pellicoro A, Vernon MA, et al. Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis [J]. Proc Natl Acad Sci U S A, 2012, 109: e3186-95.

Svendsen P, Graversen JH, Etzerodt A, et al. Antibody-directed glucocorticoid targeting to CD163 in M2-type macrophages attenuates fructose-induced liver inflammatory changes [J]. Mol Ther Methods Clin Dev, 2016, 4: 50-61.

Hu R, Liu S, Anwaier G, et al. Formulation and intestinal absorption of naringenin loaded nanostructured lipid carrier and its inhibitory effects on nonalcoholic fatty liver disease [J]. Nanomedicine, 2021, 32: 102310.

Li Y, Zhu CY. Mechanism of hepatic targeting via oral administration of DSPE-PEG-cholic acid-modified nanoliposomes [J]. Int J Nanomedicine, 2017, 12: 1673-1684.

Zhang YW, Tu LL, Zhang Y, et al. Liver-targeted delivery of asiatic acid nanostructured lipid carrier for the treatment of liver fibrosis [J]. Drug Deliv, 2021, 28: 2534-2547.

Abd El-Halim SM, Abdelbary GA, Amin MM, et al. Stabilized oral nanostructured lipid carriers of adefovir dipivoxil as a potential liver targeting: estimation of liver function panel and uptake following intravenous injection of radioiodinated indicator [J]. Daru, 2020, 28: 517-532.

Wang HP, Wang HY, Yang WL, et al. Improved oral bioavailability and liver targeting of sorafenib solid lipid nanoparticles in rats [J]. AAPS PharmSciTech, 2018, 19: 761-768.

Chen CH, Chen CJ, Elzoghby AO, et al. Self-assembly and directed assembly of lipid nanocarriers for prevention of liver fibrosis in obese rats: a comparison with the therapy of bariatric surgery [J]. Nanomedicine (Lond), 2018, 13: 1551-1566.

Zhang HY, Wang QL, Sun CY, et al. Enhanced oral bioavailability, anti-tumor activity and hepatoprotective effect of 6-shogaol loaded in a type of novel micelles of polyethylene glycol and linoleic acid conjugate [J]. Pharmaceutics, 2019, 11: 107.

Han XF, Wang Z, Wang MY, et al. Liver-targeting self-assembled hyaluronic acid-glycyrrhetinic acid micelles enhance hepato-protective effect of silybin after oral administration [J]. Drug Deliv, 2016, 23: 1818-1829.

Zhang SN, Wang Y, Shan JJ, et al. Improved bioavailability and hepatoprotective activity of baicalein via a self-assembled solutol HS15 micelles system [J]. Curr Drug Deliv, 2024, 21: 461-472.

Shaikh R, Bhattacharya S, Saoji SD. Development, optimization, and characterization of polymeric micelles to improve dasatinib oral bioavailability: Hep G2 cell cytotoxicity and in vivo pharmacokinetics for targeted liver cancer therapy [J]. Heliyon, 2024, 10: e39632.

Dutta R, Kumar V, Peng Y, et al. Pharmacokinetics and biodistribution of GDC-0449 loaded micelles in normal and liver fibrotic mice [J]. Pharm Res, 2017, 34: 564-578.

Shashni B, Tajika Y, Ikeda Y, et al. Self-assembling polymer-based short chain fatty acid prodrugs ameliorate non-alcoholic steatohepatitis and liver fibrosis [J]. Biomaterials, 2023, 295: 122047.

Craparo EF, Sardo C, Serio R, et al. Galactosylated polymeric carriers for liver targeting of sorafenib [J]. Int J Pharm, 2014, 466: 172-180.

Cai J, Peng J, Feng J, et al. Antioxidant hepatic lipid metabolism can be promoted by orally administered inorganic nanoparticles [J]. Nat Commun, 2023, 14: 3643.

Tran HT, Vong LB, Nishikawa Y, et al. Sorafenib-loaded silica-containing redox nanoparticles for oral anti-liver fibrosis therapy [J]. J Control Release, 2022, 345: 880-891.

Wu CY, Xiang SY, Wang HT, et al. Orally deliverable sequence-targeted fucoxanthin-loaded biomimetic extracellular vesicles for alleviation of nonalcoholic fatty liver disease [J]. ACS Appl Mater Interfaces, 2024, 16: 9854-9867.

Wen Y, Weng P, Li YY, et al. Triglyceride-targeted molecularly imprinted polymers activate lipophagy via cargo exchange for nonalcoholic fatty liver disease treatment [J]. ACS Appl Polym Mater, 2024, 6: 7265-7277.

Gao Q, Chen NX, Li BY, et al. Natural lipid nanoparticles extracted from Morus nigra L. leaves for targeted treatment of hepatocellular carcinoma via the oral route [J]. J Nanobiotechnology, 2024, 22: 4.

Feng YS, Sun CY, Yuan YY, et al. Enhanced oral bioavailability and in vivo antioxidant activity of chlorogenic acid via liposomal formulation [J]. Int J Pharm, 2016, 501: 342-349.

Zhang R, El-Mayta R, Murdoch TJ, et al. Helper lipid structure influences protein adsorption and delivery of lipid nanoparticles to spleen and liver [J]. Biomater Sci, 2021, 9: 1449-1463.

Wang J, Huang S. Research progress on novel carrier-modified methods and evaluation of active targeting antitumor preparation [J]. Chin Herb Med, 2014, 6: 22-28.

Shah S, Dhawan V, Holm R, et al. Liposomes: advancements and innovation in the manufacturing process [J]. Adv Drug Deliv Rev, 2020, 154-155: 102-122.

Van Hasselt PM, Janssens GE, Slot TK, et al. The influence of bile acids on the oral bioavailability of vitamin K encapsulated in polymeric micelles [J]. J Control Release, 2009, 133: 161-168.

He CB, Yin LC, Tang C, et al. Size-dependent absorption mechanism of polymeric nanoparticles for oral delivery of protein drugs [J]. Biomaterials, 2012, 33: 8569-8578.

Pawar H, Douroumis D, Boateng JS. Preparation and optimization of PMAA-chitosan-PEG nanoparticles for oral drug delivery [J]. Colloids Surf B Biointerfaces, 2012, 90: 102-108.

Li Y, Yang BH, Zhang XW. Oral delivery of imatinib through galactosylated polymeric nanoparticles to explore the contribution of a saccharide ligand to absorption [J]. Int J Pharm, 2019, 568: 118508.

Wang LQ, Liu Q, Hu XP, et al. Enhanced oral absorption and liver distribution of polymeric nanoparticles through traveling the enterohepatic circulation pathways of bile acid [J]. ACS Appl Mater Interfaces, 2022, 14: 41712-41725.

Araújo F, Shrestha N, Granja PL, et al. Safety and toxicity concerns of orally delivered nanoparticles as drug carriers [J]. Expert Opin Drug Metab Toxicol, 2015, 11: 381-393.

Asad S, Jacobsen AC, Teleki A. Inorganic nanoparticles for oral drug delivery: opportunities, barriers, and future perspectives [J]. Curr Opin Chem Eng, 2022, 38: 100869.

Huang HC, Barua S, Sharma G, et al. Inorganic nanoparticles for cancer imaging and therapy [J]. J Control Release, 2011, 155: 344-357.

Sharieff S, Idrees A, Rafai W, et al. Use of oral N-acetylcysteine (NAC) in non-acetaminophen-induced acute hepatic failure [J]. Cureus, 2023, 15: e35852.

Lu HF, Ban ZL, Xiao K, et al. Hepatic-accumulated obeticholic acid and atorvastatin self-assembled nanocrystals potentiate ameliorative effects in treatment of metabolic-associated fatty liver disease [J]. Adv Sci (Weinh), 2024, 11: e2308866.

Gu ZL, Li FY, Liu YH, et al. Exosome-like nanoparticles from Lactobacillus rhamnosus GG protect against alcohol-associated liver disease through intestinal aryl hydrocarbon receptor in mice [J]. Hepatol Commun, 2021, 5: 846-864.

Liang J, Liu Y, Liu JG, et al. Chitosan-functionalized lipid-polymer hybrid nanoparticles for oral delivery of silymarin and enhanced lipid-lowering effect in NAFLD [J]. J Nanobiotechnology, 2018, 16: 64.

Chen Y, Jiang ZH, Xu JZ, et al. Improving the ameliorative effects of berberine and curcumin combination via dextran-coated bilosomes on non-alcohol fatty liver disease in mice [J]. J Nanobiotechnology, 2021, 19: 230.

Banerjee A, Ibsen K, Brown T, et al. Ionic liquids for oral insulin delivery [J]. Proc Natl Acad Sci U S A, 2018, 115: 7296-7301.

Ma YH, Wang W, Li CH, et al. Ursodeoxycholic acid-decorated zwitterionic nanoparticles for orally liver-targeted close-looped insulin delivery [J]. Adv Healthc Mater, 2024, 13: e2302677.

2025年第60卷第6期

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doi: 10.16438/j.0513-4870.2024-1311

接收时间：2024-12-31
首发时间：2026-09-20
出版时间：2025-06-12

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收稿日期：2024-12-31
修回日期：2025-03-04

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作者信息

¹江西中医药大学, 中药固体制造技术国家工程研究中心, 江西南昌 330006

²中国医学科学院、北京协和医学院药物研究所, 天然药物活性物质与功能国家重点实验室, 北京 100050

³中国医学科学院、北京协和医学院药物研究所, 药物传输技术及新型制剂北京市重点实验室, 北京 100050

⁴广西中医药大学药学院, 广西南宁 530200

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涂亮星, Tel: 86-791-87119650, E-mail: tufrankie@163.com

范武发, Tel: 13693524103, E-mail: fanwufa@imm.ac.cn

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2种不同金属材料的力学参数

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

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Drug carrier	Drug	Disease	Characteristic	Ref.
Lipid nanoparticles	Naringenin	Nonalcoholic fatty liver	Improving intestinal absorption, and the elevated oral bioavailability by loading nano-structured lipid carrier	[31]
	Doxorubicin	Liver cancer	Improving liver targeting by modifying cholic acid ligands	[32]
	Asiatic acid (AA)	Liver fibrosis	Enhancing targeting and improving efficacy by linking to ursodeoxycholic acid (UA) and utilizing it to modify AA nanostructured lipid carriers	[33]
	Adefovir dipivoxil	Hepatitis B virus	Improving intestinal permeability with efficient liver-targeted delivery	[34]
	Sorafenib	Liver fibrosis	Improving the oral bioavailability and liver-targeting properties of sorafenib solid lipid nanoparticles	[35]
	Silibinin	Nonalcoholic fatty liver	Increasing in the oral bioavailability of silibinin	[36]
Micelle	6-Shogaol	Hepatic injury	Improving 6-shogaol's solubility and bioavailability by 6-shogaol loaded in micelles	[37]
	Silybin	Acute liver injury	Enhancing oral bioavailability and liver targeting delivery of silybin by hyaluronic acid-glycyrrhetinic acid micelles possessed glycyrrhetinic acid	[38]
	Baicalein	Acute liver injury	Improving bioavailability and hepatoprotective activity of baicalein	[39]
	Dasatinib	Hepatocellular carcinoma	Enhancing dasatinib solubility, stability, and therapeutic impact	[40]
	Vismodegib (GDC-0449)	Liver fibrotic	To maximize GDC-0449 delivery to hepatic stellate cells (HSCs)	[41]
Polymer nanoparticles	Short-chain fatty acid (SCFA)	Non-alcoholic steatohepatitis	Alleviating non-alcoholic steatohepatitis (NASH) and liver fibrosis by self-assembled polymer-based SCFA prodrugs Nano^{propionic acid (PA)} and Nano^{butyric acid (BA)}	[42]
	Sorafenib	Hepatocar cinoma	Exploiting the presence of carbohydrate receptors, asialoglycoprotein receptor by the preparation of liver-targeted polymeric micelles	[43]
Inorganic nanoparticles	TiO₂	Fatty liver in genetic and high-fat-diet obese	Revealing an unusual enterohepatic antioxidant response responsible for detoxifying low concentrations of reactive oxygen species (ROS) at the cost of elevated levels of hepatic lipolysis	[44]
	Sorafenib	Liver fibrosis	Moieting in the core formed a crosslink between the self-assembling block copolymers to afford stable drug absorption	[45]
Bionic delivery systems	Fucoxanthin	Nonalcoholic fatty liver disease	Offering the system liver-targeting capacity by modifying with glycyrrhetinic acid	[46]
	Quercetin	Nonalcoholic fatty liver disease	Binding to triglycerides and releases the drug in an affinity-driven reaction	[47]
	Mulberry leaf	Hepatocellular carcinoma	Exhibiting negligible adverse effects and superior anti-liver tumor outcomes through direct tumor killing and intestinal microbiota modulation	[48]

Drug carrier

Drug

Disease

Characteristic

Ref.

Lipid nanoparticles

Naringenin

Nonalcoholic fatty liver

Improving intestinal absorption, and the elevated oral bioavailability by loading nano-structured lipid carrier

[31]

Doxorubicin

Liver cancer

Improving liver targeting by modifying cholic acid ligands

[32]

Asiatic acid (AA)

Liver fibrosis

Enhancing targeting and improving efficacy by linking to ursodeoxycholic acid (UA) and utilizing it to modify AA nanostructured lipid carriers

[33]

Adefovir dipivoxil

Hepatitis B virus

Improving intestinal permeability with efficient liver-targeted delivery

[34]

Sorafenib

Liver fibrosis

Improving the oral bioavailability and liver-targeting properties of sorafenib solid lipid nanoparticles

[35]

Silibinin

Nonalcoholic fatty liver

Increasing in the oral bioavailability of silibinin

[36]

Micelle

6-Shogaol

Hepatic injury

Improving 6-shogaol's solubility and bioavailability by 6-shogaol loaded in micelles

[37]

Silybin

Acute liver injury

Enhancing oral bioavailability and liver targeting delivery of silybin by hyaluronic acid-glycyrrhetinic acid micelles possessed glycyrrhetinic acid

[38]

Baicalein

Acute liver injury

Improving bioavailability and hepatoprotective activity of baicalein

[39]

Dasatinib

Hepatocellular carcinoma

Enhancing dasatinib solubility, stability, and therapeutic impact

[40]

Vismodegib (GDC-0449)

Liver fibrotic

To maximize GDC-0449 delivery to hepatic stellate cells (HSCs)

[41]

Polymer nanoparticles

Short-chain fatty acid (SCFA)

Non-alcoholic steatohepatitis

Alleviating non-alcoholic steatohepatitis (NASH) and liver fibrosis by self-assembled polymer-based SCFA prodrugs Nano^{propionic acid (PA)} and Nano^{butyric acid (BA)}

[42]

Sorafenib

Hepatocar cinoma

Exploiting the presence of carbohydrate receptors, asialoglycoprotein receptor by the preparation of liver-targeted polymeric micelles

[43]

Inorganic nanoparticles

TiO₂

Fatty liver in genetic and high-fat-diet obese

Revealing an unusual enterohepatic antioxidant response responsible for detoxifying low concentrations of reactive oxygen species (ROS) at the cost of elevated levels of hepatic lipolysis

[44]

Sorafenib

Liver fibrosis

Moieting in the core formed a crosslink between the self-assembling block copolymers to afford stable drug absorption

[45]

Bionic delivery systems

Fucoxanthin

Nonalcoholic fatty liver disease

Offering the system liver-targeting capacity by modifying with glycyrrhetinic acid

[46]

Quercetin

Nonalcoholic fatty liver disease

Binding to triglycerides and releases the drug in an affinity-driven reaction

[47]

Mulberry leaf

Hepatocellular carcinoma

Exhibiting negligible adverse effects and superior anti-liver tumor outcomes through direct tumor killing and intestinal microbiota modulation

[48]