药学学报

Pharmacokinetics	Administration route	Drug	Detail	Ref.
Absorption	Oral administration	CMLP-CS	After oral administration of CMLP-CS to mice with a dose of 45.0 mg·kg^-1, the AUC_{0-72 h} value of CM was 606.20 ± 93.58 μg·L^-1·h^-1, while pure CM was 67.76 ± 22.12 μg·L^-1·h^-1 in the same situation.	[34]
	Subcutaneous administration	PEG-G-CSF	After subcutaneous injection of hG-CSF and to cynomolgus monkeys with a dose of 100 μg·kg^-1, AUC_{0-240 h} of hG-CSF was 2 165 ± 552 ng·h·mL^-1, while PEG-G-CSF in the same situation, the AUC_{0-240 h} of hG-CSF was 3 794 ± 1 300 ng·h·mL^-1.	[35]
Distribution	Intravenous injection	PVP-NCTD-NPs	After intravenous injection of PVP-NCTD-NPs to mice with a dose of 5 mg·kg^-1, the concentrations of NCTD in mice tissues were as follows: cholecyst > kidney > liver > other organs, while the pure NCTD were lung > heart > kidney > other organs.	[39]
	Intravenous injection	Polyethylene glycol interferon α2b	After intravenous injection of polyethylene glycol interferon α2b to mice with a dose of 2 mL per 100 kg, the total distribution of unmodified interferon: stomach > kidney > lung > spleen > liver > heart > brain, while polyethylene glycol interferon α2b distribution: stomach > liver > kidney > spleen > lung > heart > brain.	[40]
Metabolism	Intravenous injection	PEG-PLGA	After intravenous injection of PEG-PLGA to mice, the bond between PEG and PLGA will break in vivo. PEG-PLGA is metabolized into PEG, lactic acid and glycolic acid under the action of esterase.	[44]
	Intravenous injection	mPEG2K-DOX	After intravenous injection of mPEG2K-DOX to mice with a dose of 2.5 mg·kg^-1, it can be metabolized into DOX and free PEG in the body, which can be discharged in the form of DOX, free PEG and mPEG2K-DOX.	[46]
	Intravenous injection	PEG modified DOX·HCl-PLI	After intravenous injection of PEG modified DOX·HCl-PLI to tumor bearing mice with a dose of 7 mg·kg^-1, DOX is mainly released, and DOX will be metabolized into a variety of metabolites, mainly doxorubicin alcohol, doxorubicin ketone, doxorubicin alkone, 7-deoxidodoxorubicin aglycone, 7-deoxidodoxorubicin aglycone, etc. Compared with ordinary preparations, DOX·HCl-PLI significantly changed the excretion of drugs through the liver and kidney, and the total excretion of drugs in urine and bile decreased significantly.	[47]
Excretion	Intravenous injection	PVP-NCTD-NPs	After intravenous injection of PVP-NCTD-NPs to mice with a dose of 5 mg·kg^-1, the cumulative excretion rates of NCTD in urine and feces were 17.80% ± 3.32% and 4.51% ± 0.89%, respectively. Eight metabolites were detected in rat urine, but only two in feces.	[39]
	Subcutaneous administration	Polyethylene glycol interferon α-1b (PEG-IFNα-1b)	After subcutaneous administration of PEG-IFN α-1b to macaque with a dose of 7.5 μg·kg^-1, radioactivity is mainly excreted from urine, and a small amount is excreted from bile and feces.	[51]
	Intravenous injection	Polyethylene glycol interferon α2b	After intravenous injection of polyethylene glycol interferon α2b to mice with a dose of 0.2 mL per 100 kg, the total amount of excretion in bile was (4.18 ± 0.80)% of the dose, in urine was (48.20 ± 3.24)%, and in feces was (4.72 ± 1.25)%.	[40]

Pharmacokinetics	Administration route	Drug	Detail	Ref.
Absorption	Oral administration	CMLP-CS	After oral administration of CMLP-CS to mice with a dose of 45.0 mg·kg^-1, the AUC_{0-72 h} value of CM was 606.20 ± 93.58 μg·L^-1·h^-1, while pure CM was 67.76 ± 22.12 μg·L^-1·h^-1 in the same situation.	[34]
	Subcutaneous administration	PEG-G-CSF	After subcutaneous injection of hG-CSF and to cynomolgus monkeys with a dose of 100 μg·kg^-1, AUC_{0-240 h} of hG-CSF was 2 165 ± 552 ng·h·mL^-1, while PEG-G-CSF in the same situation, the AUC_{0-240 h} of hG-CSF was 3 794 ± 1 300 ng·h·mL^-1.	[35]
Distribution	Intravenous injection	PVP-NCTD-NPs	After intravenous injection of PVP-NCTD-NPs to mice with a dose of 5 mg·kg^-1, the concentrations of NCTD in mice tissues were as follows: cholecyst > kidney > liver > other organs, while the pure NCTD were lung > heart > kidney > other organs.	[39]
	Intravenous injection	Polyethylene glycol interferon α2b	After intravenous injection of polyethylene glycol interferon α2b to mice with a dose of 2 mL per 100 kg, the total distribution of unmodified interferon: stomach > kidney > lung > spleen > liver > heart > brain, while polyethylene glycol interferon α2b distribution: stomach > liver > kidney > spleen > lung > heart > brain.	[40]
Metabolism	Intravenous injection	PEG-PLGA	After intravenous injection of PEG-PLGA to mice, the bond between PEG and PLGA will break in vivo. PEG-PLGA is metabolized into PEG, lactic acid and glycolic acid under the action of esterase.	[44]
	Intravenous injection	mPEG2K-DOX	After intravenous injection of mPEG2K-DOX to mice with a dose of 2.5 mg·kg^-1, it can be metabolized into DOX and free PEG in the body, which can be discharged in the form of DOX, free PEG and mPEG2K-DOX.	[46]
	Intravenous injection	PEG modified DOX·HCl-PLI	After intravenous injection of PEG modified DOX·HCl-PLI to tumor bearing mice with a dose of 7 mg·kg^-1, DOX is mainly released, and DOX will be metabolized into a variety of metabolites, mainly doxorubicin alcohol, doxorubicin ketone, doxorubicin alkone, 7-deoxidodoxorubicin aglycone, 7-deoxidodoxorubicin aglycone, etc. Compared with ordinary preparations, DOX·HCl-PLI significantly changed the excretion of drugs through the liver and kidney, and the total excretion of drugs in urine and bile decreased significantly.	[47]
Excretion	Intravenous injection	PVP-NCTD-NPs	After intravenous injection of PVP-NCTD-NPs to mice with a dose of 5 mg·kg^-1, the cumulative excretion rates of NCTD in urine and feces were 17.80% ± 3.32% and 4.51% ± 0.89%, respectively. Eight metabolites were detected in rat urine, but only two in feces.	[39]
	Subcutaneous administration	Polyethylene glycol interferon α-1b (PEG-IFNα-1b)	After subcutaneous administration of PEG-IFN α-1b to macaque with a dose of 7.5 μg·kg^-1, radioactivity is mainly excreted from urine, and a small amount is excreted from bile and feces.	[51]
	Intravenous injection	Polyethylene glycol interferon α2b	After intravenous injection of polyethylene glycol interferon α2b to mice with a dose of 0.2 mL per 100 kg, the total amount of excretion in bile was (4.18 ± 0.80)% of the dose, in urine was (48.20 ± 3.24)%, and in feces was (4.72 ± 1.25)%.	[40]

聚合物纳米药物制剂生物分析方法及药动学研究进展

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崔雨琪 ¹^,^# , 雷芳彬 ¹^,^# , 张霖茜 ² , 尤建嵩 ² , 尹磊 ¹^,^* , 史美云 ¹^,²^,^*

药学学报 | 专题报道: 纳米药物药代动力学研究 2023,58(4): 844-851

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药学学报 | 专题报道: 纳米药物药代动力学研究 2023, 58(4): 844-851

聚合物纳米药物制剂生物分析方法及药动学研究进展

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崔雨琪¹^,^#, 雷芳彬¹^,^#, 张霖茜², 尤建嵩², 尹磊¹^,^*, 史美云¹^,²^,^*

作者信息

1.大连理工大学生命科学与药学学院, 辽宁盘锦 124221

2.艾美诚信生物制药有限公司, 辽宁大连 116600

通讯作者:

*尹磊, E-mail: leiyin@dlut.edu.cn;

史美云, E-mail: shimy@dlut.edu.cn

Advances in bioanalysis methods and pharmacokinetics of polymer nanopharmaceuticals

Yu-qi CUI¹, Fang-bin LEI¹, Lin-qian ZHANG², Jian-song YOU², Lei YIN¹^,^*, Mei-yun SHI¹^,²^,^*

Affiliations

1. School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin 124221, China

2. Aim Honesty Biopharmaceutical Co. Ltd., Dalian 116600, China

出版时间: 2023-04-12 doi: 10.16438/j.0513-4870.2022-1086

文章导航

摘要

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聚合物纳米药物制剂因其具有长循环、可降低免疫原性、不良反应小等优点, 得到了越来越多的关注, 已经成为纳米药物制剂研究的热点。然而, 真正成功应用于临床的聚合物纳米药物制剂的数量非常少, 药代动力学行为不理想是导致这一现象的主要原因之一。聚合物纳米制剂作为载药粒子进入体内之后, 会释放出游离药物和聚合物辅料, 游离药物是发挥药效的物质基础, 而聚合物辅料则有可能会引起辅料-药物相互作用, 因此, 聚合物纳米药物制剂药代动力学研究的关注点不应该仅仅局限于游离药物本身, 应该同时关注载药粒子、游离药物、聚合物辅料及其代谢物在体内的动态变化, 这就为聚合物纳米药物制剂的生物分析方法提出了新的要求和挑战。基于此, 本文简要介绍了聚合物纳米药物制剂的常用生物分析方法色谱分析法的特点及适用范围, 概述了聚合物纳米药物制剂在体内的吸收、分布、代谢和排泄, 希望能够为聚合物纳米药物制剂的药代动力学研究、安全性和有效性评价提供借鉴和参考。

关键词

聚合物 / 纳米制剂 / 生物分析方法 / 药动学 / 纳米载体

Abstract

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Polymer nanomaterials have been attracted more and more attention because of their advantages such as long circulation, reduced immunogenicity and less side effects, and have become a hot research topic in nanomaterials. However, the number of polymer nanomedicines successfully applied in clinical application is very limited, and the unsatisfactory pharmacokinetic behavior is one of the main reasons for thisresult. After polymer nanoparticles enter the body, they will release free drugs and polymer excipients. Polymer nanoparticles are the loaded drugs and free drugs are the active chemicals for efficacy, while polymer excipients may cause excipient drug interactions. Therefore, the focus of the pharmacokinetics study of polymer nanoparticles should not be only limited to the free drugs themselves, but should also focus on the loaded drugs, free drugs and polymer excipients. The dynamic changes of polymer excipients and their metabolites pose new requirements and challenges for the bioanalysis of polymer nanomedicines. The characteristics and application scope of common analytical methods for detection polymer nanomedicines including chromatographic assay will be discussed in this paper. Moreover, this review will also summarize the absorption, distribution, metabolism and excretion of polymer nanomedicines. We hope this review will provide reference for the pharmacokinetics study, safety and effectiveness evaluation of polymer nanomedicines.

Key words

polymer / nanoparticles / bioanalysis method / pharmacokinetic / nanovehicle

引用本文

崔雨琪, 雷芳彬, 张霖茜, 尤建嵩, 尹磊, 史美云. 聚合物纳米药物制剂生物分析方法及药动学研究进展. 药学学报, 2023 , 58 (4) : 844 -851 . DOI: 10.16438/j.0513-4870.2022-1086

Yu-qi CUI, Fang-bin LEI, Lin-qian ZHANG, Jian-song YOU, Lei YIN, Mei-yun SHI. Advances in bioanalysis methods and pharmacokinetics of polymer nanopharmaceuticals[J]. Acta Pharmaceutica Sinica, 2023 , 58 (4) : 844 -851 . DOI: 10.16438/j.0513-4870.2022-1086

正文

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纳米药物制剂指的是通过运用纳米载体技术将原料药制成的纳米尺度的颗粒, 可以通过静电吸附、共价或非共价等连接方式将药物结合在载体表面或直接将药物包裹在载体内部^[1]。相比于其他的剂型, 纳米药物制剂在稳定性、延长药物循环时间、靶向给药等方面具有显著优势。纳米药物制剂包括脂质体、胶束、纳米晶体、蛋白质纳米粒、胶体铁、聚合物纳米粒等。截止到2020年7月, 全球有35种纳米药物制剂已获批准上市^[2], 其中碳酸司维拉姆、盐酸司维拉姆为聚合物纳米制剂。

本文重点关注聚合物纳米药物制剂的生物分析方法及其药代动力学研究进展。聚合物纳米制剂指的是使用纳米技术生产的具有纳米大小的药物输送系统, 使用天然或合成的聚合物材料作为载体。它们具有生物相容性好、可生物降解的优点, 是良好的递送载体, 可以通过调节修饰以实现对纳米材料特征的精准控制。例如通过表面靶点修饰以达到递送药物到靶组织的目的。

聚合物纳米药物制剂包括脂质体、胶囊、聚合物胶束、纳米球、聚合物纳米胶囊和树枝状聚合物, 具体结构见图 1。药物可以被物理包埋或以化学方式纳入到聚合物纳米载体中, 以制成纳米药物制剂^[3]。通过改变载体的组成、稳定性、反应性和表面电荷, 可以调控纳米药物制剂在体内的药代动力学行为。

虽然大量的聚合物纳米药物制剂在临床前研究中取得了一定的成功, 但是仅有极少数能够成功转化到临床上使用^[4], 药代动力学研究不彻底, 安全性和有效性评价不全面是导致这一现象的主要原因之一。聚合物纳米药物制剂相对于小分子化合物而言, 药代动力学行为更复杂, 给药后体内会同时存在多种不同尺度的成分, 如载药粒子、游离药物和聚合物辅料。因此, 聚合物纳米药物制剂药代动力学研究应该同时关注载药粒子、游离药物和聚合物辅料, 这也就为其系统药代动力学研究带来了新的困难和挑战, 对生物分析方法选择性和灵敏度提出了更高的要求。本文归纳总结了聚合物纳米制剂的常用生物分析方法及其药代动力学进展, 从聚合物纳米药物制剂载药粒子、游离药物和聚合物辅料等多个方面系统阐释聚合物纳米制剂在体内的吸收、分布、代谢和排泄, 分析了目前聚合物纳米药物制剂药代动力学研究的不足和未来发展方向, 希望能够为聚合物纳米药物制剂的研究和安全有效性评价提供参考。

1 不同类型的聚合物纳米药物制剂

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1.1 脂质体

脂质体是由磷脂双分子层组成的中空球囊结构。脂质体药物由于具有包载水溶性药物和脂溶性药物、改变给药途径、避免耐受性、能减少不良反应、易于在生物体内降解等优势, 得到人们的高度重视和应用, 在临床转化和应用上取得了较大的进展。例如多柔比星脂质体在临床上已经有一些应用^[5], 但早期应用的多柔比星不够稳定、进入肿瘤组织能力较差, 聚乙二醇修饰的多柔比星脂质体通过聚乙二醇在脂质体周围产生屏障, 减少了游离多柔比星的不良反应, 还延长了药物的血液循环时间, 降低了心脏毒性, 并加强了抗癌能力。

1.2 聚合物胶囊

聚合物胶囊是一种纳米尺度的中空球体, 由聚合物的膜和空心的壳组成^[6]。聚合物胶囊内部极大的空间结构使其可以将药物封装在空核区域。作为纳米反应器, 聚合物胶囊可以封装活性物质, 例如酶、蛋白质等。聚合物胶囊可以保护药物免受蛋白酶水解攻击的同时, 为反应进行提供场所^[7]。

为了提高蛋白质的递送效率, 聚合物纳米胶囊可以快速将目标蛋白质传递到细胞中, 并在细胞内信号的激发下释放出来。2013年, Yan等^[8]选择带有正电荷单体的可降解交联剂, 利用谷胱甘肽(二硫化物) 反应, 通过原位聚合, 制备了融合重组麦芽糖结合蛋白(MBP-APO) 的凋亡蛋白聚合物纳米胶囊。当纳米胶囊进入肿瘤细胞内时, 聚合物外壳被降解, 治疗蛋白被释放出来, 从而实现了快速有效的蛋白质递送。

1.3 聚合物胶束

聚合物胶束是一种由两亲性表面活性剂分子构成的胶束^[9], 其在水溶液中分散时, 能自发形成外壳“头部”亲水, 内核“尾部”疏水的稳定分散胶束。聚合物胶束具备良好的体内稳定性和组织靶向性, 且可达到药物的可控释放, 这些年来受到了广泛的关注。广泛用于抗肿瘤药物的载体, 主要包括小分子药物、核酸和蛋白等物质^[10]。聚合物胶束的重要特质之一是难溶性的药物可被包载在胶束的疏水核中, 亲水性外壳能有效避免微粒集聚, 进而提升难溶性药物的溶解度、保护药物分子避免其在体内失活。Saw等^[11]制备了均匀的、具有高细胞渗透性的超小(直径12 nm) 球形胶束, 这些胶束是通过引入4%~10%的聚乙二醇修饰的磷脂分子制成的。胶束的血液循环时间相对较长, 并迅速被细胞吞噬, 使药物快速释放出来。Xu等^[12]以透析法制备了具有较高载药能力的多柔比星壳聚糖聚合物胶束DOX-OSC, 载药量达35.8%, 包封产率达75.3%。近年来, 针对肿瘤细胞的pH敏感胶束一直是深入研究的对象。大多数实体肿瘤的pH值(pH < 6.5) 低于周围正常组织的pH值(pH 7.4), 而细胞内体和溶酶体的pH值5.0~6.0, 这种pH梯度可以用来开发pH敏感的肿瘤靶向性药物输送系统^{[13, 14]}。

1.4 树枝状聚合物

树枝状聚合物是通过支化基元逐步重复的反应得到的一类具有高度支化结构的大分子, 应用于生物医药、催化剂以及光电功材料等领域。最初, 由于技术受限, 只能合成聚丙烯亚胺。随着合成技术的进步, 如今已经有一百余种树枝状聚合物被合成出来。

树枝状大分子的结构在水溶液中呈球状对称, 其具有黏度低、负载能力高、载药方式多样、纳米尺寸受控的特点。树枝状聚合物的独特结构使其具备抗真菌的药理活性, 成为具有研究价值的抗真菌感染生物材料。Janiszewska等^[15]设计合成并表征了一系列新的阳离子脂肽, 发现具有C12残基的衍生物对念珠菌的抗菌活力明显提升。近年来多种阳离子树枝状聚合物被用于基因转载的研究中, 但实际应用仍面临一个主要障碍, 即显著的非特异性细胞毒性^[16]。为此, 科研工作者做出了许多努力。Shao等^[17]对此进行了研究, 并合成了具有多个氢键修饰和显著的转染效果且细胞毒性低的树枝状大分子。

1.5 聚合物纳米球

聚合物纳米球由高密度聚合物基体组成, 药物可以溶于水中或分散在聚合物中变成聚合物固体粒子, 形成各种药物的有效负载(包埋、吸附或化学偶联)。由于其潜在的药物输送能力, 这类纳米颗粒被广泛用于疾病的诊断和治疗。壳聚糖、聚乳酸-羟基乙酸[poly(lactic-co-glycolic acid), PLGA]、聚乳酸和聚氰基丙烯酸丁酯是构建纳米球最常用的聚合物。其中, 壳聚糖是一种天然的线性多糖, 由几丁质的碱性脱乙酰化获得, 是具有生物相容性和生物可降解性的聚合物, 可以作为纳米药物的自我载药系统^[18]。负载有神经活性物质的壳聚糖纳米颗粒表面经靶向修饰后, 可以通过静脉注射有效地穿过血脑屏障, 在目标部位达到治疗效果^[19]。聚合物纳米球良好的稳定性和药物缓释能力使其具有巨大的药物研发潜力。

2 生物分析方法

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聚合物纳米药物在体内有载药粒子、游离药物和释放的聚合物。目前, 聚合物纳米药物的体内分析过程主要是通过对血浆中不同剂型药物的浓度和组织中药物的总浓度的测定来进行的, 对不同形式的药物在组织中的分布和定量分析较少^[20]。常见的聚合物纳米药物的分析方法包括高效液相色谱法(HPLC), 高效液相色谱串联质谱法(HPLC-MS/MS)。

2.1 高效液相色谱法

HPLC由经典液相柱色谱法发展而来, 具有快速、准确、专属性好、自动化水平高等特点被广泛应用于药物分析中^[21], 在多组分分析和杂质控制方面发挥着重要作用^[22-26]。Wang等^[27]采用单臂聚乙二醇偶联齐墩果酸制备mPEG-OA聚合物, 通过自组装包裹另一种天然产物抗肿瘤药物10-羟基喜树碱[(S)-10-hydroxycamptothecin, HCPT] 合成mPEG-OA/HCPT NPs, 并使用高效液相色谱法测定药物在体外的累计释放量。结果表明, mPEG-OA NPs和mPEG-OA/HCPT NPs在肿瘤微环境中药物释放的时间较长, 药物通过共价键连接在药物载体上比物理包裹在体内的缓释效果更好。

2.2 高效液相色谱串联质谱法

HPLC-MS/MS集色谱和质谱的优点于一身, 具有灵敏度高、专属性强、可对多种样品成分进行定性和定量分析等优点^[28]。例如, Khajavinia等^[29]建立了一种HPLC-MS/MS方法, 定量分析包载在PLGA纳米粒中的多西他赛, 分析结果在15.6~4 000 ng·mL^-1内均有较好的准确度和精密度, 能够为多西他赛负载的聚合物纳米递送系统的分析提供方法支持。

3 聚合物纳米药物药代动力学研究

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聚合物纳米制剂的多尺度效应使得其药代动力学行为比单纯的小分子化合物更加复杂。聚合物纳米制剂在体内会释放出游离药物和高分子辅料, 体内会同时存在载药粒子、游离药物、辅料及其代谢物等多种不同成分。传统的聚合物纳米药物制剂药代动力学研究只针对游离药物本身, 这具有一定的局限性, 并不能够系统地阐述聚合物纳米药物制剂在体内的真实药动学行为, 也会为纳米制剂的药代动力学和药效动力学关联性研究、安全性和有效性研究带来误导。因此, 为了揭示聚合物纳米药物制剂在体内的真实药代动力学行为, 必须同时关注聚合物纳米药物制剂载药粒子、游离药物、游离辅料及代谢物在体内的吸收、分布、代谢、排泄, 从而揭示聚合物纳米制剂在体内的时空命运, 为聚合物纳米制剂的成功研发和临床转化提供数据支持和参考。

3.1 聚合物纳米药物药代动力学研究

3.1.1 吸收

给药途径是影响聚合物纳米药物制剂吸收的重要因素^[30]。通过静脉给药的聚合物纳米药物制剂直接进入血液循环, 经皮下和肌肉途径给药的聚合物纳米药物制剂则大多通过以局部淋巴结为主的淋巴系统吸收, 然后进入体循环^[31]。通过口服给药的聚合物纳米药物制剂, 通常会经历细胞旁路转运、胞吞作用和M细胞摄取后, 在胃肠道中被吸收^{[32, 33]}。聚合物纳米颗粒口服后的黏着性, 增加了其在吸收部位的停留时间和接触面积, 进而提高了生物利用度, 可替代赋形剂改善药物在胃肠道中的分布, 保护多肽类药物免受胃肠道消化酶的降解。Li等^[34]进行了大鼠口服姜黄素(curcumine, CM) 及壳聚糖包覆姜黄素脂质体(chitosan coated curcumin liposomes, CMLP-CS) (给药剂量均为45.0 mg·kg^-1) 的药代动力学研究。结果表明: CMLP-CS和CM的AUC_{0-72 h}分别为606.20 ± 93.58和67.76 ± 22.12 μg·L^-1·h^-1, CMLP-CS的AUC_{0-72 h}值约为CM的8.9倍, CMLP-CS明显提高了CM的口服生物利用度。Ou等^[35]通过对食蟹猴皮下注射100 μg·kg^-1的人粒细胞集落刺激因子(human granulocyte colony stimulating factor, hG-CSF) 及聚乙二醇化重组人粒细胞集落刺激因子(pegylated recombinant human granulocyte colony stimulating factor, PEG-G-CSF) 研究其吸收程度。研究结果表明: 食蟹猴分别皮下注射100 μg·kg^-1 hG-CSF和PEG-G-CSF后, hG-CSF对应的AUC_{0-240 h}分别为2 165 ± 552和3 794 ± 1 300 ng·h·mL^-1。聚乙二醇修饰能够显著提高人粒细胞集落刺激因子皮下注射给药的生物利用度。

3.1.2 分布

聚合物纳米药物在组织中的分布主要取决于粒子大小、所带电荷情况以及表面性质等药物自身性质, 同时也受血清蛋白结合情况、组织供血情况、血管、内皮和单核吞噬细胞系统等因素的影响^{[36, 37]}。载药粒子是载体类纳米药物的运输工具和储存仓库, 靶部位/靶点中的游离药物是发挥药效的物质基础。与其他器官相比, 聚合物纳米药物粒子能更加快速地分布至肝脏、脾脏和骨髓。Zhang等^[38]制备了N-辛基-O-硫酸盐壳聚糖(N-octyl-O-sulfate chitosan, NOSC) 胶束紫杉醇(paclitaxel, PTX) 传递系统, 考察了PIX-NOSC胶束(PIX-M) 的体内分布情况。研究结果显示, PTX通过静脉注射后主要分布在肝、肾、脾和肺中, 其中肺中保留时间最长。Ding等^[39]制备了包衣去甲斑蝥素-壳聚糖纳米粒(PVP-NCTD-NPs), 在对小鼠静脉注射的同时, 以去甲斑蝥素(norcantharidin, NCTD) 为参比制剂进行了药代动力学研究。结果表明: PVP-NCTD-NPs给药后, NCTD在各组织中药物浓度分布趋势为胆囊 > 肾脏 > 肝脏 > 其他脏器, 而NCTD给药后其在个组织中药物浓度分布的趋势为肺脏 > 心脏 > 肾脏 > 其他脏器。Yao等^[40]进行了大鼠静脉给药聚乙二醇-干扰素α2b (0.002 mL·kg^-1) 的药代动力学实验, 结果表明: 给药48 h之后, 未经修饰的干扰素组织分布浓度由高到低的顺序为胃 > 肾 > 肺 > 脾 > 肝 > 心 > 脑, 而聚乙二醇-干扰素α2b给药后组织中干扰素组织分布浓度由高到低的顺序为胃 > 肝 > 肾 > 脾 > 肺 > 心 > 脑。聚乙二醇修饰改变了干扰素α2b在组织中的分布情况。聚乙二醇修饰多柔比星脂质体(doxil) 是一种通过静脉注射将多柔比星递送至肿瘤组织的有效载体。由于此脂质体的被动靶向作用, 可有效降低多柔比星对心脏的毒性, 但其抗肿瘤活性未见明显改善^[41], 而doxil较普通多柔比星制剂给药后会出现新的不良反应, 如手足综合征等^[42], 可能是由于脂质体制剂改变了多柔比星组织分布。因此, 全面了解不同组织中的聚合物纳米药物的载药粒子、游离药物、游离辅料及代谢物的分布情况有助于此类药物体内行为、有效性和安全性的评估。

3.1.3 代谢

聚合物纳米药物的代谢主要取决于其成分和性质, 如相对分子质量、粒子大小、聚合度等, 在被巨噬细胞吞噬之后, 可以由细胞溶酶体降解^[43]。细胞色素P450酶在大多数药物的代谢中具有重要作用, 而纳米药物本身可能会影响细胞色素P450酶的功能, 可能使得在联合用药时也许会产生药物之间的相互作用, 进而可能会带来潜在的安全性问题。顾景凯团队^[44]通过对小鼠静脉注射聚乳酸-羟基乙酸(PEG-PLGA) 研究其在体内的代谢过程。他们根据实验结果推测PEG-PLGA之间的酯键会在体内被酯酶作用断裂, 变成游离的PEG和PLGA, 之后再进一步被代谢成PEG、乳酸和乙醇酸。Shaffer等^[45]研究表明, 在人体内PEG不会被代谢为亚单位乙二醇, 其在体内主要代谢的途径是末端醇基团氧化成羧酸基团。Yin等^[46]进行了聚乙二醇化多柔比星(mPEG2K-DOX) 在大鼠体内的代谢实验, 结果表明: mPEG2K-DOX在体内可以代谢成DOX、游离PEG, 从而以DOX、游离PEG、mPEG2K-DOX的形式排出体外, 并且主要的排泄方式为肾排泄。Wang等^[47]通过对荷瘤鼠静脉注射7 mg·kg^-1 PEG化盐酸多柔比星脂质体注射液(doxorubicin hydrochloride PEGlyted liposome injection, DOX·HCl-PLI), 研究其在体内的代谢情况。研究结果表明DOX·HCl-PLI在进入体内后主要释放出DOX, 而DOX则会代谢为多种代谢产物, 主要为多柔比星醇、多柔比星酮、多柔比星醇酮、7-脱氧多柔比星苷元和7-脱氧多柔比星醇苷元等。相比于普通制剂, DOX·HCl-PLI显著改变了药物经肝脏和肾脏的排泄, 药物在尿液和胆汁中的总排泄量均明显发生下降。多柔比星在尿液中的总排泄量下降为原来的33%, 在胆汁中的总累计排泄量下降为原来的21%。综上, 聚合物纳米药物制剂在体内会释放出聚合物、游离药物, 并以此种形式参与后续体内的剩余的代谢过程。聚合物纳米药物制剂可以降低清除率, 延长体内停留时间。

3.1.4 排泄

粒径是影响纳米药物体内排泄的重要因素^{[43, 48, 49]}。粒径较小的纳米药物通常是由肾脏清除, 而粒径较大的纳米药物则可能会由不同的途径排泄, 如肝脏和MPS清除。经肝细胞处理的纳米粒子可通过胆汁排泄。其他器官如肺、乳腺和汗腺等也可以进行少量的排泄。纳米药物中的活性药物和载体材料可能通过肾小球滤过和肾小管分泌的方式进入尿液而排泄, 也可以通过肝脏, 以胆汁分泌的形式随粪便排泄; 而载药粒子一般自身不易经过上述途径, 大多是直接排泄, 通常解聚成载体材料或载体材料降解后主要经肾脏排泄。Ding等^[39]以去甲斑蝥素(NCTD) 为参比制剂, 考察小鼠静脉注射给予包衣去甲斑蝥素-壳聚糖纳米粒(PVP-NCTD-NPs) 后的排泄情况, 大鼠排泄研究表明, 注射PVP-NCTD-NPs 24 h后, 在尿液及粪便中NCTD累积排泄率分别为(17.80 ± 3.32)%和(4.51 ± 0.89)%, 大鼠尿样中共检测到8种代谢产物, 而粪便中只有两种: 壳聚糖及其高分子降解产物不易经外周组织吸收, 主要由尿液排出体外; 而低分子量壳聚糖及其部分降解产物则会主要经血管转移到外周组织, 并进一步降解为小分子。相对分子质量约460 kDa的FITC-羧甲基壳聚糖经腹腔注射给大鼠24 h后, 在大鼠肝脏中会被降解至相对分子质量10 kDa以下^[43]。经灌胃和腹腔注射给药的甘露葡聚糖主要通过粪便和尿液排出, 其中粪便中含22%原形糖, 而尿液中未检出原形糖^[50]。Liu等^[51]通过将聚乙二醇化干扰素α-1b (PEG-IFN α-1b) 皮下注射到猕猴体内研究其排泄情况。研究结果表明: ¹²⁵I-PEG-IFNα-1b主要从尿液中排泄, 少量从胆汁和粪中排泄。Yao等^[40]静脉注射大鼠给药聚乙二醇-干扰素α2b (0.002 mL·kg^-1), 研究其给药48 h之后的排泄量。结果表明: 干扰素α2b在胆汁中排泄总量占给药量的(4.18 ± 0.80)%, 在尿中排泄总量占给药量的(48.20 ± 3.24)%, 在粪中排泄总量占给药量的(4.72 ± 1.25)%。综上, 聚合物纳米制剂在体内代谢之后, 大部分会以代谢产物、游离药物、辅料、聚合物本身等形式排泄出体内, 肾排泄通常为主要排泄途径。

一些聚合物纳米药物药代动力学研究见表 1^{[34, 35, 39, 40, 44, 46, 47, 51]}。

4 总结与展望

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聚合物纳米药物制剂因其具有长循环、免疫原性低、不良反应小等优势, 成为了纳米药物制剂研究的热点。然而, 聚合物纳米制剂药代动力学研究仍有很多问题没有阐释清楚, 尤其是针对聚合物纳米制剂载药粒子、游离药物、游离辅料及其代谢物的体内动力学过程。聚合物纳米制剂体内的痕量多尺度成分的精准分析对分析技术和方法的灵敏度和选择性提出了更高的要求。随着分析技术和药动学研究的不断完善和创新, 聚合物纳米药物制剂的药动学研究必将向着更精确、更加透彻的方向发展, 而这也将会极大地提高聚合物纳米制剂研发和临床转化的成功率。

作者贡献: 崔雨琪、张霖茜、雷芳彬负责文献检索、分析及文稿撰写; 尹磊、史美云、尤建嵩负责文稿修改与检查。

利益冲突: 所有作者均声明不存在任何利益冲突。

基金

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国家自然科学基金资助项目(81603182)
国家自然科学基金资助项目(81703607)
大连市科技创新基金(2022JJ13SN075)
中央高校基本科研业务费资助引进人才科研专题(DUT21RC(3)057)

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2023年第58卷第4期

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doi: 10.16438/j.0513-4870.2022-1086

接收时间：2022-09-29
首发时间：2025-11-21
出版时间：2023-04-12

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收稿日期：2022-09-29
修回日期：2023-03-29

基金

国家自然科学基金资助项目(81603182)

国家自然科学基金资助项目(81703607)

大连市科技创新基金(2022JJ13SN075)

中央高校基本科研业务费资助引进人才科研专题(DUT21RC(3)057)

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1.大连理工大学生命科学与药学学院, 辽宁盘锦 124221

2.艾美诚信生物制药有限公司, 辽宁大连 116600

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*尹磊, E-mail: leiyin@dlut.edu.cn;

史美云, E-mail: shimy@dlut.edu.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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Pharmacokinetics	Administration route	Drug	Detail	Ref.
Absorption	Oral administration	CMLP-CS	After oral administration of CMLP-CS to mice with a dose of 45.0 mg·kg^-1, the AUC_{0-72 h} value of CM was 606.20 ± 93.58 μg·L^-1·h^-1, while pure CM was 67.76 ± 22.12 μg·L^-1·h^-1 in the same situation.	[34]
	Subcutaneous administration	PEG-G-CSF	After subcutaneous injection of hG-CSF and to cynomolgus monkeys with a dose of 100 μg·kg^-1, AUC_{0-240 h} of hG-CSF was 2 165 ± 552 ng·h·mL^-1, while PEG-G-CSF in the same situation, the AUC_{0-240 h} of hG-CSF was 3 794 ± 1 300 ng·h·mL^-1.	[35]
Distribution	Intravenous injection	PVP-NCTD-NPs	After intravenous injection of PVP-NCTD-NPs to mice with a dose of 5 mg·kg^-1, the concentrations of NCTD in mice tissues were as follows: cholecyst > kidney > liver > other organs, while the pure NCTD were lung > heart > kidney > other organs.	[39]
	Intravenous injection	Polyethylene glycol interferon α2b	After intravenous injection of polyethylene glycol interferon α2b to mice with a dose of 2 mL per 100 kg, the total distribution of unmodified interferon: stomach > kidney > lung > spleen > liver > heart > brain, while polyethylene glycol interferon α2b distribution: stomach > liver > kidney > spleen > lung > heart > brain.	[40]
Metabolism	Intravenous injection	PEG-PLGA	After intravenous injection of PEG-PLGA to mice, the bond between PEG and PLGA will break in vivo. PEG-PLGA is metabolized into PEG, lactic acid and glycolic acid under the action of esterase.	[44]
	Intravenous injection	mPEG2K-DOX	After intravenous injection of mPEG2K-DOX to mice with a dose of 2.5 mg·kg^-1, it can be metabolized into DOX and free PEG in the body, which can be discharged in the form of DOX, free PEG and mPEG2K-DOX.	[46]
	Intravenous injection	PEG modified DOX·HCl-PLI	After intravenous injection of PEG modified DOX·HCl-PLI to tumor bearing mice with a dose of 7 mg·kg^-1, DOX is mainly released, and DOX will be metabolized into a variety of metabolites, mainly doxorubicin alcohol, doxorubicin ketone, doxorubicin alkone, 7-deoxidodoxorubicin aglycone, 7-deoxidodoxorubicin aglycone, etc. Compared with ordinary preparations, DOX·HCl-PLI significantly changed the excretion of drugs through the liver and kidney, and the total excretion of drugs in urine and bile decreased significantly.	[47]
Excretion	Intravenous injection	PVP-NCTD-NPs	After intravenous injection of PVP-NCTD-NPs to mice with a dose of 5 mg·kg^-1, the cumulative excretion rates of NCTD in urine and feces were 17.80% ± 3.32% and 4.51% ± 0.89%, respectively. Eight metabolites were detected in rat urine, but only two in feces.	[39]
	Subcutaneous administration	Polyethylene glycol interferon α-1b (PEG-IFNα-1b)	After subcutaneous administration of PEG-IFN α-1b to macaque with a dose of 7.5 μg·kg^-1, radioactivity is mainly excreted from urine, and a small amount is excreted from bile and feces.	[51]
	Intravenous injection	Polyethylene glycol interferon α2b	After intravenous injection of polyethylene glycol interferon α2b to mice with a dose of 0.2 mL per 100 kg, the total amount of excretion in bile was (4.18 ± 0.80)% of the dose, in urine was (48.20 ± 3.24)%, and in feces was (4.72 ± 1.25)%.	[40]

Pharmacokinetics

Administration route

Drug

Detail

Ref.

Absorption

Oral administration

CMLP-CS

After oral administration of CMLP-CS to mice with a dose of 45.0 mg·kg^-1, the AUC_{0-72 h} value of CM was 606.20 ± 93.58 μg·L^-1·h^-1, while pure CM was 67.76 ± 22.12 μg·L^-1·h^-1 in the same situation.

[34]

Subcutaneous administration

PEG-G-CSF

After subcutaneous injection of hG-CSF and to cynomolgus monkeys with a dose of 100 μg·kg^-1, AUC_{0-240 h} of hG-CSF was 2 165 ± 552 ng·h·mL^-1, while PEG-G-CSF in the same situation, the AUC_{0-240 h} of hG-CSF was 3 794 ± 1 300 ng·h·mL^-1.

[35]

Distribution

Intravenous injection

PVP-NCTD-NPs

After intravenous injection of PVP-NCTD-NPs to mice with a dose of 5 mg·kg^-1, the concentrations of NCTD in mice tissues were as follows: cholecyst > kidney > liver > other organs, while the pure NCTD were lung > heart > kidney > other organs.

[39]

Intravenous injection

Polyethylene glycol interferon α2b

After intravenous injection of polyethylene glycol interferon α2b to mice with a dose of 2 mL per 100 kg, the total distribution of unmodified interferon: stomach > kidney > lung > spleen > liver > heart > brain, while polyethylene glycol interferon α2b distribution: stomach > liver > kidney > spleen > lung > heart > brain.

[40]

Metabolism

Intravenous injection

PEG-PLGA

After intravenous injection of PEG-PLGA to mice, the bond between PEG and PLGA will break in vivo. PEG-PLGA is metabolized into PEG, lactic acid and glycolic acid under the action of esterase.

[44]

Intravenous injection

mPEG2K-DOX

After intravenous injection of mPEG2K-DOX to mice with a dose of 2.5 mg·kg^-1, it can be metabolized into DOX and free PEG in the body, which can be discharged in the form of DOX, free PEG and mPEG2K-DOX.

[46]

Intravenous injection

PEG modified DOX·HCl-PLI

After intravenous injection of PEG modified DOX·HCl-PLI to tumor bearing mice with a dose of 7 mg·kg^-1, DOX is mainly released, and DOX will be metabolized into a variety of metabolites, mainly doxorubicin alcohol, doxorubicin ketone, doxorubicin alkone, 7-deoxidodoxorubicin aglycone, 7-deoxidodoxorubicin aglycone, etc. Compared with ordinary preparations, DOX·HCl-PLI significantly changed the excretion of drugs through the liver and kidney, and the total excretion of drugs in urine and bile decreased significantly.

[47]

Excretion

Intravenous injection

PVP-NCTD-NPs

After intravenous injection of PVP-NCTD-NPs to mice with a dose of 5 mg·kg^-1, the cumulative excretion rates of NCTD in urine and feces were 17.80% ± 3.32% and 4.51% ± 0.89%, respectively. Eight metabolites were detected in rat urine, but only two in feces.

[39]

Subcutaneous administration

Polyethylene glycol interferon α-1b (PEG-IFNα-1b)

After subcutaneous administration of PEG-IFN α-1b to macaque with a dose of 7.5 μg·kg^-1, radioactivity is mainly excreted from urine, and a small amount is excreted from bile and feces.

[51]

Intravenous injection

Polyethylene glycol interferon α2b

After intravenous injection of polyethylene glycol interferon α2b to mice with a dose of 0.2 mL per 100 kg, the total amount of excretion in bile was (4.18 ± 0.80)% of the dose, in urine was (48.20 ± 3.24)%, and in feces was (4.72 ± 1.25)%.

[40]