药学学报

Inorganic nanomaterial	Mechanism of antibacterial therapy	Disadvantage
AgNPs	Permeability of biofilms; influence of bacterial replication; release of Ag⁺; generation of ·OH and ROS; broad antibacterial spectrum	Cytotoxity; environmental pollution
AuNPs	ROS-dependent antibacterial action; bacterial membrane disruption; influence of bacterial replication; photocatalytic degradation of bacterial cell membrane	Irreversible aggregation in solution
ZnO NPs	ROS-dependent antibacterial action; bacterial membrane disruption; photocatalytic degradation of bacterial cell membrane	Cytotoxity
CNs	Permeability of biofilms; bacterial membrane disruption; generation of O₂·^- and ·OH; photocatalytic degradation of microbial cell membrane; synergistic effect of inorganic materials and drugs	Cytotoxity; aggregation in solution; complex production processes
SiNs	High drug loading efficiency; surface-functionalization	Hydrophobicity; promote bacterial adhesion and subsequent biofilm formation

Inorganic nanomaterial	Mechanism of antibacterial therapy	Disadvantage
AgNPs	Permeability of biofilms; influence of bacterial replication; release of Ag⁺; generation of ·OH and ROS; broad antibacterial spectrum	Cytotoxity; environmental pollution
AuNPs	ROS-dependent antibacterial action; bacterial membrane disruption; influence of bacterial replication; photocatalytic degradation of bacterial cell membrane	Irreversible aggregation in solution
ZnO NPs	ROS-dependent antibacterial action; bacterial membrane disruption; photocatalytic degradation of bacterial cell membrane	Cytotoxity
CNs	Permeability of biofilms; bacterial membrane disruption; generation of O₂·^- and ·OH; photocatalytic degradation of microbial cell membrane; synergistic effect of inorganic materials and drugs	Cytotoxity; aggregation in solution; complex production processes
SiNs	High drug loading efficiency; surface-functionalization	Hydrophobicity; promote bacterial adhesion and subsequent biofilm formation

Nano-drug delivery system	Mechanism of antibacterial therapy	Agent
Liposomes	Fusion with biofilm; surface modification for active targeting; intelligent response for drug release; induction of immune reaction	Penicillin; ciprofloxacin; vancomycin; amikacin
SLNs/NLCs	High drug loading efficiency; sustained release of drugs; high biocompatibility	Clarithromycin; penicillin; tobramycin; oleuropein
Polymeric nanoparticles	High drug loading efficiency; sustained-release of drugs; co-delivery of drugs; surface modification for active targeting; intelligent response for drug release; membrane disruption by electrostatic adsorption	Cefixime; clarithromycin; rifampicin; azithromycin; clindamycin; ciprofloxacin
Dendrimers	Membrane disruption by electrostatic adsorption biofilms‐binding mechanism; nanostructured multifunctional surface	Auto antimicrobial activity
Niosomes	Skin accumulation and topical antifungal therapy stability; photobiologic-mediated the antibacterial activity	Doxycycline; ciprofloxacin; zinc phthalocyanide
Microemulsion	Generation of sufficient interfacial area; skin accumulation and topical antifungal therapy	Cephalosporin; ciprofloxacin; levofloxacin; moxifloxacin
Biomimetic nanomedicine	High biocompatibility; transport of the biofilm; specific targeting by cell membrane coating; reduce the MPS clearance of nanocarrier; immune activation by specific antigen protein; synergistic effect of nanoparticles and cell	Vancomycin; TPCA-1; Se; OMV; α-hemolysin

Nano-drug delivery system	Mechanism of antibacterial therapy	Agent
Liposomes	Fusion with biofilm; surface modification for active targeting; intelligent response for drug release; induction of immune reaction	Penicillin; ciprofloxacin; vancomycin; amikacin
SLNs/NLCs	High drug loading efficiency; sustained release of drugs; high biocompatibility	Clarithromycin; penicillin; tobramycin; oleuropein
Polymeric nanoparticles	High drug loading efficiency; sustained-release of drugs; co-delivery of drugs; surface modification for active targeting; intelligent response for drug release; membrane disruption by electrostatic adsorption	Cefixime; clarithromycin; rifampicin; azithromycin; clindamycin; ciprofloxacin
Dendrimers	Membrane disruption by electrostatic adsorption biofilms‐binding mechanism; nanostructured multifunctional surface	Auto antimicrobial activity
Niosomes	Skin accumulation and topical antifungal therapy stability; photobiologic-mediated the antibacterial activity	Doxycycline; ciprofloxacin; zinc phthalocyanide
Microemulsion	Generation of sufficient interfacial area; skin accumulation and topical antifungal therapy	Cephalosporin; ciprofloxacin; levofloxacin; moxifloxacin
Biomimetic nanomedicine	High biocompatibility; transport of the biofilm; specific targeting by cell membrane coating; reduce the MPS clearance of nanocarrier; immune activation by specific antigen protein; synergistic effect of nanoparticles and cell	Vancomycin; TPCA-1; Se; OMV; α-hemolysin

纳米材料和纳米药物递释系统在抗细菌感染中的应用及机制

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何盈盈 ^# , 周文铂 ^# , 邰启炜 , 李荣洁 , 俞媛 ^*

药学学报 | 综述 2023,58(1): 106-117

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药学学报 |综述 2023 , 58 (1) : 106 -117

纳米材料和纳米药物递释系统在抗细菌感染中的应用及机制

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何盈盈^#, 周文铂^#, 邰启炜, 李荣洁, 俞媛^*

作者信息

海军军医大学药学系, 上海 200433

通讯作者:

*俞媛, Tel: 86-21-81871289, E-mail: pharmyuu@163.com

Application and mechanism of nanomedicine and nanomaterials in antibacterial infection therapy

Ying-ying HE, Wen-bo ZHOU, Qi-wei TAI, Rong-jie LI, Yuan YU^*

Affiliations

Faculty of Pharmacy, Naval Medical University, Shanghai 200433, China

出版时间: 2023-01-12 doi: 10.16438/j.0513-4870.2022-0615

文章导航

摘要

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细菌感染治疗是全球关注的医学问题, 抗菌药物的误用和过度使用, 病原体新耐药机制的出现, 导致抗菌药物的耐药性问题日益严峻, 持续威胁抗感染治疗效果, 并增加疾病传播、严重疾病的死亡风险。随着生物材料和纳米技术广泛应用于生物医药, 围绕抗细菌感染展开了广泛研究。纳米无机材料特殊的光电磁和高穿透性等物理化学性质可产生天然抗菌作用。纳米药物递送系统可实现药物缓控释, 靶向输送从而提高抗菌疗效。本综述对抗菌药物的耐药机制进行阐述, 并对围绕纳米材料、纳米药物系统包括脂质体、聚合物纳米粒、树枝状聚合物、仿生纳米载体等开展的抗细菌感染研究进行总结。纳米材料和纳米技术为提高抗细菌感染疗效, 并可能克服耐药性的新型制剂的研发提供了有希望的策略。

关键词

细菌感染 / 抗菌药 / 耐药性 / 无机纳米材料 / 纳米递药系统

Abstract

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Antibacterial therapy is a global health issue. The antibiotic resistance is becoming an increasingly serious threat, which caused by misuse and overuse of antibacterial agents combined with the emergence of new resistance mechanism. The resulting infection treatment risk and incidence of the spread of disease, severe cases and deaths are increased in different degrees. With the extensive application of biomaterials and nanotechnology to biomedicine, extensive research has been conducted on antibacterial infection. With the specific physicochemical properties like optical, electric and magnetic and high penetration, inorganic nanomaterials can produce natural antibacterial effect. Nanomedicine can be designed to allow controlled drug release and targeting effect, thus demonstrated better antibacterial efficiency. In this review, the mechanism of antibacterial resistance is described, and the antibacterial infection research on inorganic nanomaterials, as well as nano-drug delivery system including liposomes, nanoparticles, dendrimers and biomimetic nanocarriers are summarized. Nanomaterials and nanotechnology offer promising strategies for the development of new agents that can improve efficacy on antibacterial infections and overcome antibiotic resistance potentially.

Key words

bacterial infection / antibacterial agent / antibiotic resistance / inorganic nanomaterial / nano-drug delivery system

引用本文

何盈盈, 周文铂, 邰启炜, 李荣洁, 俞媛. 纳米材料和纳米药物递释系统在抗细菌感染中的应用及机制. 药学学报, 2023 , 58 (1) : 106 -117 . DOI: 10.16438/j.0513-4870.2022-0615

Ying-ying HE, Wen-bo ZHOU, Qi-wei TAI, Rong-jie LI, Yuan YU. Application and mechanism of nanomedicine and nanomaterials in antibacterial infection therapy[J]. Acta Pharmaceutica Sinica, 2023 , 58 (1) : 106 -117 . DOI: 10.16438/j.0513-4870.2022-0615

正文

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细菌感染由致病菌或条件致病菌侵入循环生长繁殖, 可引发皮肤、呼吸道、腹腔、颅内组织感染乃至脓毒症、败血症^[1]。致病菌包括金葡菌、铜绿假单胞菌、梭状芽孢杆菌、链球菌等^[2]。在细菌感染治疗中, 抗生素的过度使用和误用增加了世界范围内耐药菌的蔓延, 导致多药耐药(multidrug-resistant, MDR)、极端耐药细菌的出现^[3]。每年约有70万人死于耐药细菌引起的感染^[4], 重症监护病房、移植手术和癌症治疗的患者中耐药菌感染尤为严重。细菌耐药机制主要包括基因机制和生化机制, 基因机制涉及基因转导、基因突变及基因转化移位, 生化机制与靶点变化、药物摄入量降低、渗透屏障、胞膜主动转运减少及主动外排等相关^[5], 染色体编码的外排泵位于细菌的细胞质膜上, 能导致其对特定的抗生素耐药。产生抗生素修饰酶和水解酶是细菌对抗生素耐药性形成的主要途径之一, 大多数编码抗生素修饰酶和水解酶的基因位于移动元件上, 使得细菌在高浓度的抗生素浓度下正常生长。此外, 细菌形成生物被膜产生耐药性, 生物被膜是由细菌自身分泌出的细胞外多聚物, 将细菌黏附形成一种复杂的聚合体为细菌提供保护^[6]。抗细菌感染治疗中, 新型抗生素研发周期长, 新靶点的发现困难, 因此, 设计和开发新的给药策略加强细菌乃至耐药菌感染的预防和治疗具有重要意义。

无机纳米材料的热、电、磁物理化学特性, 可产生与其自身性质相关的独特的抗菌机制。这些机制与自由基生成、粒子电离和酸形成相关, 导致细菌膜破坏或细胞器修饰或两者兼而有之, 如附着在带负电荷的细菌膜上导致细菌渗漏, 细胞器的修饰修饰可能包括蛋白质/脂质的氧化/失活、巯基的消耗、DNA螺旋结构破坏、基因表达中断和碱基结构细胞器的酸攻击^[7]。另一方面, 构建纳米粒(nanoparticles, NPs) 携载药物起到缓释、控释或靶向抗菌作用。NPs通过静电吸附、范德华力、受体-配体结合等方式作用于细菌细胞, 藉由网格蛋白或小窝蛋白/脂筏介导的内吞、巨胞饮等机制增加摄取, 穿过细菌细胞膜后沿代谢途径聚集, 与细胞的基本成分DNA、溶酶体、核糖体和酶相互作用, 产生氧化应激、异质性改变、细胞膜通透性改变、电解质平衡紊乱、酶抑制、蛋白质失活和基因表达的改变^[8], 导致细菌死亡。此外, NPs可通过与复杂生物膜矩阵之间相互作用, 提高抗生素的渗透率, 清除生物膜中细菌。此外, 纳米载体的缓控释、靶向药物递释, 可控制药物的释放, 提高血浆抗生素水平, 降低毒副作用^[9]。作为抗细菌感染治疗新的研究方向, 本综述对无机纳米材料和纳米药物递送系统的抗细菌感染进行汇总并讨论其作用机制和应用特点。

1 无机纳米材料的抗细菌感染机制及应用

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无机纳米材料具有尺寸的单一分布特征、热、电和磁特性、穿透性, 因此具有特殊的生物膜高渗透性^[10], 分为金属/金属氧化物纳米材料及非金属的无机碳材料、硅材料等。金属和金属氧化物纳米粒由于其光学、磁性和电学性质, 具有高选择性的细菌检测和治疗的巨大潜力。金属基纳米材料的抗菌作用主要与金属离子的释放、活性氧(reactive oxygen species, ROS) 产生、直接破坏细菌生物膜及光诱导的光动力效应有关^[11]。

1.1 金属及金属氧化物

纳米银(Ag nanoparticles, AgNPs) 表面积大、反应活性中心多、吸附力强, 具有多种抗菌机制: 一种是接触杀灭, 纳米银附着于细菌细胞膜上, 与DNA、RNA、蛋白等生物分子相互作用, 影响遗传物质复制, 使细胞分裂受阻^[12]; 另一种机制是离子产生抑菌, 纳米银溶解后可释放出银离子杀菌^[13], 有两种推测: ①接触反应假说, 银离子穿过细胞膜后与细菌酶的硫醇基团结合, 使之变性凝固破坏酶活性^[14]。如与NADH脱氢酶结合可破坏细菌呼吸链产生ROS, 导致氧化应激和细菌细胞损伤^[15]; ②催化反应假说, 银离子在光作用下, 作为催化活性中心激活水和空气中的氧, 产生氧化能力强的羟基自由基和ROS, 抑制细菌增殖^[16]。但高浓度的银在治疗时会对正常细胞造成损伤, 游离AgNPs可能引起聚集, 从而降低抗菌效果。纳米载体包裹银可避免银的聚集, 同时实现药物的共递药, 同时降低AgNPs的有效使用浓度。光动力疗法利用光敏剂和光照射产生具有细胞毒性的ROS使细胞消融, 也是一种有效的抗菌方法。Ma等^[17]将Ag⁺负载于氧化后的介孔碳纳米球(OMCN) 上, 制备出具有光热疗效的复合材料OMCN-Ag⁺, 在OMCN-Ag⁺的抗菌浓度(40 μg·mL^-1) 下, 小鼠背部大肠杆菌感染创面的面积小, 并有恢复趋势。这种基于OMCN-Ag⁺的新型光热协同抗菌系统具有显著的抗菌活性和生物相容性。此外, ROS对治疗靶点缺乏特异性, 可能会对正常组织造成毒副作用。针对此问题, Bi等^[18]合成了能控制ROS释放的过氧化银纳米粒, 由超声波和近红外光等激发因素严格控制银离子和ROS的释放, 具有较强的抗菌和抗生物被膜能力, 10 min细菌杀灭率 > 99.99%, 显著促进耐药金葡菌感染皮肤创面愈合, 具有良好的细胞相容性和血液相容性。AgNPs已被用于泌尿外科、牙科、普通外科和整形外科中。然而若应用于体内, 对正常细胞的毒副作用不容忽视, 需对纳米材料的安全性进行评估。纳米材料毒理学是一个相对较新和不断发展的领域, 大多数纳米毒理学研究都集中在通过使用体外模型来了解机制, 早期研究表明, 高浓度AgNPs对真核细胞具有显著毒性^{[19, 20]}。ROS的产生和氧化应激是细胞毒性的主要评价方法^[21]。然而, 细胞毒性机制仍不清楚, 仍需标准毒理学测试来评估AgNPs的风险, 在分子水平上阐明毒性机制及机体内环境与AgNPs间的相互作用。同时亟需标准化应用, 关注细胞毒性和获得最佳治疗效果所需的最低剂量^[22]。

金是化学性质最稳定的元素之一, 当转变为氧化态时具有较强毒性。Li等^[23]研究发现, 修饰后的纳米金(Au nanoparticles, AuNPs) 可与细胞膜蛋白结合, 影响细胞膜结构的稳定性和完整性。进入细胞的AuNPs既能阻碍核糖体亚基与转运RNA的结合, 影响细菌复制, 也能产生ROS以强氧化作用灭菌^[24]。且AuNPs具有光热效应, Kornilova等^[25]发现平均粒径约为5 nm的AuNPs随机分布在埃洛石纳米管的外表面, 表现出很强的局域等离子体共振。体外实验显示, 在532 nm纳秒激光脉冲照射后, 极大促进尾草履虫死亡。由于激光照射过程中的平均升温不超过3~4 ℃, 表明是AuNPs附近的局域加热产生细胞破坏, 即AuNPs可通过光热效应杀灭细胞。Yougbaré等^[26]合成了可见光激活的金属二硫化钼纳米片和吸收波长为808 nm的等离子体金纳米棒, 并采用静电吸附法将金纳米棒修饰到金属二硫化钼纳米片上。基于光热效应, 808 nm近红外激光辐照10 min后, 金纳米棒修饰金属二硫化钼纳米片(MoS₂@AuNRs) 的溶液温度从25 ℃提高到66.7 ℃, 同时也可由光动力效应, 在可见光照射下产生ROS。采用琼脂平板计数法检测了MoS₂@1/3AuNRs、MoS₂@1/2AuNRs和MoS₂@AuNRs的光诱导杀菌活性以评价光热疗和光动力治疗效果, 近红外激光照射2 min后, 其抑菌率分别为84.4%、97.5%和99.0%; 在可见光1 min照射下, 其抑菌率分别为83.8%、93.3%和98.5%, 表明纳米金含量增加后, 复合材料抗菌能力也随之提高。为研究光热治疗和光动力治疗的协同效应, 依次用近红外激光和可见光照射后, MoS₂@1/3AuNR、MoS₂@1/2AuNR和MoS₂@AuNR的杀菌率分别为94.5%、100%和100%, 说明MoS₂@AuNRs通过近红外激光和可见光联合照射可显著提高杀菌效率, 具有优异的光热治疗和光动力治疗的协同效应。

纳米氧化锌(ZnO nanoparticles, ZnO NPs) 主要通过细胞间ROS的作用进行抗菌, 也可与细胞膜直接接触并破坏细胞结构^[27], 同时大的比表面积显示出更强的抗菌活性特征^[28]。吲哚菁绿(indocyanine green, ICG) 由于其较强的近红外吸收能力, 成为光疗领域的一种极具吸引力的选择, ICG在近红外辐射下产生单线态氧, 并表现出光热效应。但它在水介质中聚集的倾向, 使得近红外辐射下产生单线态氧的能力受到抑制。针对以上问题, Bera等^[29]制备了一种以ZnO为基础的ICG-ZnO纳米杂化材料。密度泛函理论和含时密度泛函理论研究表明, 在光激发下, 电子从ICG的高能轨道转移到ZnO的导带, 使ICG分子在其表面的H-聚集减小, 显著防止ICG在水中的聚集, 从而产生更多ROS。结果表明, 大肠杆菌与纳米复合物物孵育后, 在光照射下菌落总数显著减少(96%)。然而, ZnO NPs的合成中存在有害有毒副产物的产生、有毒试剂的使用等问题, 绿色纳米技术生产ZnO NPs基于活生物体、天然生物分子的使用^[30]。但绿色合成的ZnO材料可能会出现一些问题, 纳米材料的异质性是合成方案固有的, 在合成方案中, 原材料在组成和化学分布上缺乏均质性, 而来自微生物细胞的有毒成分可能附着到纳米粒上, 与生物体接触时引发机体免疫反应, 导致ZnO NPs应用受限^[31]。

1.2 碳纳米材料(carbon nanos, CNs)

CNs包括零维碳纳米材料, 如富勒烯及其衍生物, 以及碳纳米管和石墨烯、氧化石墨烯等, 具有天然抗菌性能。CNs主要通过损伤细菌细胞膜产生抑菌作用, 如碳纳米管破坏细菌细胞膜结构完整性, 胞内物质流失, 使细菌失去生理功能^[32]; 也可通过超氧化物阴离子、羟基自由基等ROS产生, 导致细菌脂蛋白及核酸损伤^[33]。其中, 2004年在电弧放电的烟尘中发现的碳量子点(carbon dots, CDot) 引起了极大关注。CDot不仅具有与传统量子点相似的强发光和小尺寸特性, 而且还具有传统量子点所不具备的良好水分散性、低毒和高电导率等独特优势^[34]。Su等^[35]采用水热法合成了具有抗菌和成像功能的姜黄素碳量子点(Cur-NRCQDs), 其在水溶液中的荧光吸收范围为555~850 nm。在氙灯照射下, 浓度为10和15 μmol·L^-1的Cur-NRCQDs对金葡菌和大肠杆菌的杀灭率均为100%。CDots是一种特殊的“核-壳”纳米结构, 具有小于10 nm的碳核和1个官能团壳层, 其表面官能团在表面提供了丰富的含氧部分, 有利于进一步的功能化应用^[36]。基于此结构特点, Sviridova等^[37]用不同烷基链(C2、C4、C9、C12) 的含四烷基铵(TAA) 的新型重氮盐对碳点(CDs) 进行功能化, 以优化其抗菌活性。CDs-C9的抗菌机制归因于烷基链的正电荷和疏水性间的平衡, TAA部分则促进了细菌细胞膜的黏附、穿透和生理代谢障碍。实验表明CDs-C9有效促进了金葡菌和大肠杆菌生物膜的抗生物被膜效能, 在处理时间和最低抑菌浓度方面均优于以往报道的CDs。在对CDs进行功能化的基础上, 可结合化学动力学和光热疗法(photothermal therapy, PTT) 协同抗菌, Yan等^[38]提出了一种基于新型氧化铁纳米片(FeOCl-NS_S) 催化过氧化氢(H₂O₂) 诱导的化学动力学疗法和以CDs和聚乙二醇(polyethylene glycol, PEG) 为载体的近红外包覆PTT的治疗方法。FeOCl-NS_S中离子的氧化还原循环使得H₂O₂活化产生羟基自由基(·OH) 诱导细菌死亡。将PEG和硫化镉包覆在FeOCl-NS_S表面, 制备了FeOCl@PEG@CdS纳米复合材料, 在808 nm的近红外激光作用下, 表现出很强的PTT响应效应, 极大增强了抗菌效果。目前, 抗菌CNs仍在研究和开发中, 尽管已有多种碳同素异形体产品上市, 但由于其细胞毒性, 生产工艺繁复, 碳纳米管不能替代或竞争目前使用的抗菌材料(如AgNPs), 因此未来的研究应主要集中于低生产成本、量产高及安全性的CNs^[39]。功能化的CNs是一种策略, 引入强亲水性官能团羧基提高CNs分散性, 通过与可降解材料复合使其随着其他材料降解产物代谢排出, 降低其毒性^[40]。

1.3 硅纳米材料(silicone nanos, SiNs)

SiNs可高效负载药物, 具有非常良好的可修饰性, 被广泛用作递送酶、抗生素和DNA的载体。此类材料中, 介孔二氧化硅疏松多孔且化学性质稳定, 具有一定硬度, 表面硅醇基能与硅烷基以强弱不等的氢键结合, 是一种优良的载体材料。如二氧化硅负载纳米银存在载银效率低、抗菌性能不持久等问题, 而介孔二氧化硅具有有序的孔道结构、高水热稳定性、较大的比表面积, 可改善以上问题。Cheng等^[41]制备了介孔二氧化硅载银的复合材料并对抗菌性能进行研究。结果表明, 11.25 mg·L^-1的复合材料可在12 h内完全抑制大肠杆菌生长, 其对铜绿假单胞菌和金葡菌的抑菌浓度分别为5.625和22.5 mg·L^-1, 说明该复合材料具有较强的抑菌效果。聚二甲基硅氧烷(polydimethylsiloxane, PDMS) 又称有机硅, 具有良好的生物相容性、热稳定性和低毒等特性。Lou等^[42]通过CuI催化的Huisgen 1, 3-偶极点击环加成, 将制备的含炔基的PDMS表面与叠氮化克拉胺衍生物共价接枝。以脱氧胆酸为原料合成了氮化克拉胺衍生物。通过硅烷化反应将炔基引入到PDMS表面。荧光显微镜显示, 修饰后的表面对革兰阴性杆菌(大肠杆菌) 和革兰阳性菌(表皮葡萄球菌) 都有抗菌活性。这种基于克拉胺衍生物的PDMS可用于制备抑制生物膜形成和解决抗菌抗性问题的生物材料。作为具有很高耐抗性的材料, 有机硅越来越多作为单一和多用途材料在医疗领域中使用, 然而固有的疏水性使其易受到内源性蛋白质吸附, 形成以生物被膜生长为特征的微生物感染。提供抗菌特性来预防、减少或抵抗细菌黏附, 如带有抗生素的涂层、细菌或多肽等活性分子的共价结合等方法防止生物被膜的形成是一种主要策略^[43]。无机纳米材料的抗细菌感染机制见表 1。

2 纳米药物递送系统用于抗细菌感染治疗

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纳米药物递送系统可通过以下机制增强药物的抑菌作用: ①提高药物稳定性, 提高其体内生物利用度; ②纳米载体被细菌生物膜内化以突破耐药细菌的生物膜保护; ③经过结构修饰, 携带药物靶向输送至感染部位, 在特定pH或酶环境下响应释放药物。与游离药物相比, 纳米系统可靶向输送, 在细菌感染部位释放药物实现有效抑菌浓度, 保持较低给药剂量, 减少非感染部位药物富集, 降低药物毒副作用^{[44, 45]}。相较于无机纳米材料, 脂质体(liposomes)、聚合物纳米粒(polymer nanoparticles, PNs)、树枝状聚合物(dendrimers)、类囊脂泡(niosomes) 等纳米载体等具有更好的生物相容性和可降解特性^[46]。在此基础上, 可调控的智能化递药、仿生化的内源性载体系统也具有重要研究意义^[47]。

2.1 脂质体

脂质体为磷脂双分子膜层的封闭型囊泡, 具有良好的药物包载、缓控释及特异性靶向递送功能, 可携带抗菌药物运送至靶部位释放, 在较低给药剂量下实现感染部位的高药物浓度^[48]。Yu等^[49]设计制备了PEG修饰的长循环脂质体包裹青霉素, 将1 h内青霉素累计释放量控制在37.36%, 表现出较好的缓释作用, 该脂质体制剂在高浓度时细胞毒性作用也低于游离青霉素。脂质体由于其类生物膜结构, 能与致病细菌发生膜融合, 破坏细菌的膜结构并在细菌胞质内高浓度释放药物, 实现对致病菌的有效杀伤。Patil等^[50]为考察脂质体与细菌细胞的膜融合性, 共聚焦显微镜与小角度X射线衍射法观察了环丙沙星脂质体与金葡菌和大肠杆菌的融合, 证实脂质体可与细菌膜融合释放药物并破坏细菌膜结构, 且因细菌表面zeta电位的不同, 环丙沙星脂质体与金葡菌的融合率显著高于大肠杆菌, 为加强脂质体与细菌的膜融合提供了思路。Vandera等^[51]采用脂质体包载分散于环糊精的吡咯苯并二氮杂卓类新型抗菌剂PPA148, 圆盘扩散法测得抗大肠杆菌效果相当于30倍浓度的利福平对照组, 同时以Langmuir槽和中子反射技术, 验证了脂质体与革兰阴性菌外膜融合, 并推测其高效的抗菌活性与膜融合机制相关。

脂质体可诱导抗体和T淋巴细胞对细菌亚单位抗原产生免疫反应, 具有设计新型抗细菌疫苗的潜力。如Humbert等^[52]将脑膜炎奈瑟菌基因编码的巨噬细胞感染增强蛋白包载到脂质体中构建一种亚单位疫苗, 补体/血清杀菌实验测得该系统对脑膜炎球菌B型菌株的血清杀菌抗体滴度达128~256, 并对部分异源菌株具有显著的交叉灭菌活性。Hildebrand等^[53]制备了载siRNA的脂质体, 可作为细菌疫苗佐剂增强剂, 该策略通过抑制抗原递呈细胞激活的内源性抑制剂, 来增强TLR4诱导的抗原呈递细胞激活。Toll样受体TLR4激动剂单磷酸脂质A刺激的单核细胞活化, siRNA沉默细胞因子信号传导抑制蛋白1 (suppressor of cytokine signaling 1, SOCS1) 得到加强, 由此破伤风轻链毒素抗原更强烈地激活自体T细胞反应。此外, 脂质体通过设计修饰, 可实现对pH、氧化还原、酶活性等生理刺激及温度、光、磁场等外部条件的智能化响应, 达到定点靶向释放抗菌药物的目的^[54]。Omolo等^[55]将油酸和油酸衍生季脂作为pH响应分子, 构建具有pH响应开关的万古霉素-脂质体纳米系统, 与万古霉素相比, 对耐甲氧西林金葡菌(methicillin-resistant Staphylococcus aureus, MRSA) 的最小抑制浓度(minimum inhibitory concentration, MIC) 在pH 7.4时降低了75%, 在pH 6.0时降低了93%, 具有显著的耐药菌抗菌作用。

脂质体作为最为成功的纳米药物剂型, 拥有良好的应用前景, 目前Insmed、Transave等多家公司的阿米卡星等抗菌药物脂质体制剂已被美国食品药品监督管理局(FDA) 批准用于临床或临床试验^[56]。在非囊性纤维化支气管扩张患者中, 肺部感染铜绿假单胞菌与频繁的肺部恶化和死亡率增加有关。研究者对吸入型环丙沙星脂质体(ARD-3150) 治疗铜绿假单胞菌(ORBIT-3和ORBIT-4) 慢性肺部感染开展了临床Ⅲ期试验研究, 采用国际、随机、双盲、安慰剂对照同时进行^[57]。结果显示ARD-3150可减少慢性铜绿假单胞菌感染的肺部恶化, 其中对ORBIT-4的效果显著, 首次肺部恶化的中位天数较安慰剂组的158天延长为230天, 同时ARD-3150引起的不良反应与安慰剂相似。Griffith等^[58]在基于指南疗法(GBT) 的基础上加用阿米卡星脂质体吸入混悬剂(ALIS), 在治疗难治性鸟胞内分枝杆菌复合菌(MAC) 肺病的临床试验中, ALIS+GBT治疗3个月后, 16.1%的MAC肺病患者长期转阴, 继续治疗12个月后有55.4%长期转阴, 停药3个月内患者复发率为9.2%, 相较接受GBT治疗的患者(停药3个月内复发率30%) 优势显著。

2.2 脂质纳米粒

脂质纳米粒主要有两种亚型: 固体脂质纳米粒(solid lipid nanoparticles, SLNs) 和纳米脂质载体(nanostructured lipid carriers, NLCs)。SLN以卵磷脂、甘油三酯等天然或合成的固态脂质为基质, 将药物包裹其中形成纳米药物递送系统^[59]。Sharma等^[60]采用二元脂质基质与薄膜超声分散法制得克拉霉素-固体脂质纳米粒(CLR-SLNs), 体外抗菌膜活性表明, CLR-SLNs (40 μg·mL^-1) 相较于游离克拉霉素在较低药物浓度下具有更好的菌膜清除效果, 大鼠药代动力学研究表明, CLR-SLNs的相对口服利用度接近游离药物的5倍。Zhao等^[61]测试了青霉素SLNs对MRSA抗菌效果, 加入最小抑菌浓度(MIC) 的青霉素SLNs (13.8 mg·mL^-1) 后12 h的灭菌效果显著, MRSA菌落由10^4.98降至10^2.73 CFU·mL^-1, 且在此后36 h内均维持该水平, 而青霉素对照组在12 h对MRSA抑菌效果弱, 48 h可见MRSA菌落明显增多, 证明SLNs包裹显著增强了青霉素对耐药细菌MRSA的灭菌能力。Badawi等^[62]对优化后的甲硝唑固体脂质纳米粒(MTD-SLNs) 进行了治疗细菌性阴道病的临床试验, 与市售阴道凝胶对比, MTD-SLNs制剂具有高临床疗效(P < 0.05) 与低复发率(P < 0.01) 的显著优势。

NLCs是由固液两种物态的脂质混合形成的不完整非晶体内核, 相较SLN具有更好的载药能力, 并减少了药物的渗漏^[63]。Sans-Serramitjana等^[64]设计对照实验比较了SLNs与NLCs包载妥布霉素的抗菌能力, 结果显示NLC-妥布霉素对铜绿假单胞菌MIC低于0.5 μg·mL^-1, 较SLN-妥布霉素(MIC 1~4 μg·mL^-1) 表现出更高的抗菌活性。Palagati等^[65]针对细菌性脑膜炎的多药耐药性, 设计了一种NLCs纳米递药系统, 包载具有抗菌活性的橄榄苦苷(OLE-NLCs), 大鼠鼻部给药验证了OLE-NLCs的鼻-脑靶向释药效果, 将OLE释放时间由不足6 h延长至24 h, 释放率由50%提高到95%, 且可在给药后5~24 h内检测到脑内药物浓度(6~10 mg·mL^-1), 约为血浆内的2倍, 同时溶血实验及鼻黏膜毒性实验显示该递药系统具有较好安全性, 说明NLCs对治疗跨血脑屏障的细菌性脑膜炎的脑内递药具有研究价值。

2.3 PNs

PNs是基于高分子聚合物材料的纳米剂型, 载体材料可实现生物降解、缓释或控释药物及主动靶向的作用^[66]。常用的骨架材料有壳聚糖、葡聚糖、海藻酸、聚乳酸(PLA)、聚乳酸-羟基乙酸共聚物(PLGA) 和聚己内酯(PCL) 等^[67]。壳聚糖纳米粒抗菌机制为带正电氨基的壳聚糖与带负电的革兰阴性细菌膜表面结合, 破坏细胞膜并改变其通透性, 药物释放到细菌细胞中导致细菌死亡^[68]。Mahjoub等^[69]使用离子凝胶法制备了头孢克肟壳聚糖纳米粒, 大鼠肠屏障的转运率达20.2%, 是游离药物的2倍, 大肠杆菌的MIC (0.1 μg·mL^-1) 只有游离药物的1/10, 对革兰阴性细菌感染具有显著作用。此外, 以硫酸葡聚糖和硫酸软骨素多糖为基质的载抗生素PNs也被证实对沙门氏菌等致病细菌较游离抗生素有更好的抑制效果^[70]。以PLA、PLGA为代表的聚合物得到FDA的批准可用于人体, 具有良好的生物安全性和药物的缓控释性能。Lotfipour等^[71]采用乳液-溶剂扩散法将生物利用度相对较低(55%) 的克拉霉素(CLR) 包封在PLGA纳米粒中, 评价对幽门螺杆菌的抗菌活性。游离CLR对H. pylori菌株的MIC值为0.1 μg·mL^-1, 不同比例PLGA纳米粒的MIC值为0.003~0.05 μg·mL^-1, 显著提高了药物对幽门螺杆菌的抗菌效果。用作抗菌药物递送系统的PLGA纳米粒得到了广泛研究, 利福平、阿奇霉素、克林霉素、环丙沙星和克拉霉素PLGA纳米粒均可产生比游离药物更加有效的抑菌效率^[72]。Trousil等^[73]构建了利福平PCL纳米粒, 巨噬细胞对利福平吸收有显著提高, 提高了结核分歧杆菌感染治疗效果。

此外, PNs经修饰可对特殊环境响应释药。Zhou等^[74]将三苯基膦引入含光热分子骨架与ROS敏感硫缩酮键的伪共轭聚合物中, 设计出了具有阳离子季鏻结构与光热效应的可降解伪共轭聚合物纳米粒, 在1 064 nm波长近红外激光下可产生光热抗菌效应, 从而持续杀灭细菌。针对抑制细菌耐药性, 可进行调控释药的PNs也得到了研究, Guo等^[75]开发出Hoechst 33258 (H33258) 修饰的PFDBT-Br共轭聚合物纳米粒(CPNs-H), H33258上的双苯并咪唑基团提高了CPNs-H的正电荷密度, 使其抗菌活性提高至未修饰CPNs的近3倍。同时, H33258可与细菌裂解后释放出的双链DNA结合而降低电正性, 使CPNs-H抗菌活性从70%降低至10%, 而在加入DNA酶I切割dsDNA后恢复至45%, 由此实现了对CPNs-H抗菌活性的智能化调控, 降低了因药物残留加剧的细菌耐药性的产生。

目前已有围绕PNs递药系统治疗细菌感染的临床试验研究, 如Farzanegan等^[76]研究评价了牙科正畸复合材料加入壳聚糖-TiO₂纳米粒后的抗变形链球菌能力, 实验组上颌侧切牙与第2前磨牙的变形链球菌计数在用药2~6月后可见显著减少(P < 0.01), 临床试验证实该纳米粒可显著增强牙科正畸复合材料的抗菌作用。然而, PNs也具有与其物理化学性质相关的缺陷, 由于通常带表面负电荷, 对于表面带正电的革兰阳性菌感染则存在一定限制, 如金葡菌会通过提高膜表面正电性对壳聚糖纳米粒产生耐药^[68]。

2.4 树枝状聚合物

树枝状聚合物是一类具有三维超支化结构的大分子聚合物, 由核心、树状分支单元和表面活性基团3个主要结构域构成^[77]。凭借其分支化的结构, 树枝状聚合物的粒径(1~10 nm) 小于线性聚合物(10~500 nm), 同时具有修饰灵活性高的特点^[78]。含有季铵盐等阳离子基团的树枝状聚合物可通过静电吸附与带负电荷的细菌膜表面相结合, 改变膜通透性, 引起钾离子外渗造成细菌膜的不可逆破坏, 因而具有很高的抗菌活性^[79]。Chen等^[80]以阳离子聚丙烯酸氨基乙酯为基质, 引入含季铵盐活性基团的超支化结构, 制得具有选择性毒性的树枝状聚合物, 低剂量(4 μg·mL^-1) 时, 对大肠杆菌和金葡菌的灭菌率分别为 > 99.99%和 > 98%。此外表现出较好的生物相容性, 1 024 μg·mL^-1的高浓度下仍保持35%的较低溶血率。Siriwardena等^[81]为考察脂化树枝状多肽TNS18的体内抗菌能力, 以MDR鲍曼不动杆菌(A. baumannii) 构建小鼠感染模型, TNS18使感染小鼠72 h后存活率由10%提升至100%, 而A. baumannii菌株耐药(MIC > 64 μg·mL^-1) 的头孢曲松在相同剂量下的小鼠存活率仅60%, 对菌株相对敏感(MIC < 1 μg·mL^-1) 的亚胺培南的染菌小鼠存活率为80%, 表明脂化树枝状多肽TNS18体内抗MDR细菌效果显著。Waldbaum等^[82]开展的含树枝状聚合物的astodrimer凝胶治疗细菌性阴道病的临床II期双盲试验中, 1% astodrimer凝胶治疗9~12天的治愈率高达74.1%, 显著优于安慰剂组(22.2%), 且可能相关的不良反应发生率与安慰剂组无明显差异。但研究表明, 树枝状聚合物以高世代或高剂量对多种细胞系具有显著毒性, 其机制与阳离子增加膜透化有关, 可通过胺基的PEG化修饰来降低细胞毒性和降低红细胞溶血^[83]。

2.5 类脂囊泡

类脂囊泡是一类由非离子表面活性剂组成、结构上类似于脂质体的双层球形囊泡, 相较于脂质体, 其具有表面活性强、化学稳定性高、配制储存成本低等优点, 在治疗局部感染、输送眼部药物、骨/牙科植入物涂层等方面抗菌效果良好^[84]。如Kashani-Asadi-Jafari等^[85]设计包载盐酸多西环素的类脂囊泡用于对痤疮的局部抗菌治疗, 大鼠皮肤渗透实验确定类脂囊泡中司盘60与胆固醇最优摩尔比为1∶1, 对痤疮丙酸杆菌与表皮葡萄球菌的体外抑菌活性实验显示类脂囊泡提高了盐酸多西环素的抑菌活性, 综合细胞毒性评价结果证明了类脂囊泡药物递送系统对痤疮类局部细菌感染症状的治疗潜力。Kashef等^[86]通过薄膜水合法制备了环丙沙星的类脂囊泡, 考察其对耐药金葡菌的抗菌能力, 结果表明类脂囊泡纳米载体可使环丙沙星对受试耐药菌株的MIC值降低87%, 同时使受试菌株的最小生物膜抑制浓度和最小生物膜清除浓度分别降低至42%和38%, 证实类脂囊泡作为纳米递药系统对治疗耐药细菌感染的显著效果。

此外, 类脂囊泡可与天然杀菌材料结合实现特定的抗菌特性, de Oliveira de Siqueira等^[87]将酞氰化锌(ZnPc) 作为光动力疗法中产生抗耐药菌作用ROS的光敏剂包埋于类脂囊泡中, 解决了酞氰化锌不溶于水、易聚集失活的问题, 在光生物学抗菌活性实验中, 带负电荷ZnPc-类脂囊泡对MRSA的MIC为0.25 mg·mL^-1, 仅为游离ZnPc的25%。而ZnPc-类脂囊泡表面经壳聚糖修饰后带正电荷, 通过与细菌的静电吸引进一步增强了光生物学灭菌活性, 对MRSA的MIC降低至0.10 mg·mL^-1。类脂囊泡作为类似脂质体的纳米药物递送系统, 在抗细菌感染领域具有发展潜力。

2.6 微乳(microemulsion)

微乳是一种由表面活性剂、助表面活性剂、水相、油相自发组成的各向同性的热力学稳定分散体系。微乳具有极低的表面张力, 使药物扩散在表面活性剂上层或表面活性剂与皮肤表面之间, 增大药物接触面积, 增强药物在皮肤或生物膜的蓄积^[88]。Alkhatib等^[89]制备了头孢菌素微乳, 抑菌圈表明微乳对金葡菌的抗菌活性较空白微乳提高了117%, 较单独应用头孢菌素提高了20%。给药10~30 min内, 空微乳与单独头孢菌素组均从800降低至700 CFU·mL^-1, 微乳制剂起效更快。Siddique等^[90]制备了环丙沙星、左氧氟沙星、莫西沙星微乳制剂, 证明3种氟喹诺酮类药物的微乳在抗菌活性及抗菌效果上都要强于单独使用药物。Volpe等^[91]进一步证实了375 μg·mL^-1的环丙沙星微乳剂能破坏54%的菌膜, 且环丙沙星微乳治疗组小鼠的金葡菌含量可从4.7×10⁴降低至1.2×10³ CFU·mL^-1。Craig等^[92]采取随机双盲试验法, 评价MGO100麦卢卡蜂蜜微乳眼膏对于眼睑炎的临床疗效。试验随机选取53名患者, 每晚给药一次持续90天, 单眼给药, 另一眼作为对照。非参数邓恩检验表明, 给药90天后麦氏棒杆菌、痤疮丙酸杆菌、表皮葡萄球菌P值分别从0.52、0.69、0.27降低至小于0.001, 表现出显著的眼睑炎抗菌疗效。但微乳制剂对温度、盐浓度和酸碱度的变化敏感, 易出现相分离的情况, 故在临床应用中存在一定限制。

2.7 仿生纳米药物系统(biomimetic nanomedicine)

仿生纳米药物系统是一种设计仿生或利用生物内源性材料作为递送载体的药物递送体系, 包括细胞、细菌、细胞外囊泡及工程化的细胞膜与外源性载体材料制备的杂合体。这类载体具有良好的生物膜转运特性、高生物相容性和特异靶向机制, 通过模仿活体组织内生物结构单元的生理特点, 通过载体的结构修饰和转化, 可将诊断试剂、小分子药物、核酸和基因输送到靶部位, 达到良好的靶向效果^[93]。Hu等^[94]利用血小板表面蛋白介导炎症归巢效应, 制备了血小板包裹万古霉素的纳米药物(PNP-Vanc) 用于抗细菌感染, 与游离万古霉素及结合人Ⅳ型胶原蛋白的红细胞膜载体包载万古霉素(RECNP-Vanc) 相比, PNP-Vanc对MRSA的体外抗菌活性显著提升, 活菌计数相较前两者降低1~2个数量级, 肝脾活菌计数降低2~3个数量级。肺部是细菌感染的主要器官之一, Chu等^[95]开发了嗜中性粒细胞HL-60分泌的细胞外囊泡, 结合整合蛋白β2膜的纳米载体, 包载TPCA-1 (HV-TPCA-1) 用于急性肺损伤靶向治疗, 在内毒素脂多糖(LPS) 诱导模型中, HV-TPCA-1治疗组的肺部游离嗜中性粒细胞相较对照组明显减少, 显著提高了肺部靶向的抗菌治疗效果。利用仿生结构的靶向性, 减少巨噬系统对粒子的捕获, 将无机分子与仿生结构结合构建杂合纳米载体兼具二者优点。Lin等^[96]制备钌络合物修饰的硒纳米凝胶, 用红细胞膜包被制备响应型仿生纳米粒Ru-Se@G NPs-RBCM, 响应细菌感染微环境作为抗生素替代品来检测和抑制MRSA, 结合了天然红细胞膜低免疫清除的特点, 明胶纳米粒更多地转运至被感染区域, 被白明胶酶水解, Ru-SeNPs在感染部位高效释放, 中和细菌外毒素及杀灭细菌。溶血实验显示, 治疗组MRSA外毒素溶血率从71.8%降低至31.7%, 金葡菌从21.9%降低至8.1%, 对白明胶酶阳性和阴性的细菌外毒素都具有强中和效果。同时, 25 μg·mL^-1 Ru-Se@G NPs-RBCM对MRSA、金葡菌、铜绿假单胞菌的杀灭率分别达到90%、95.01%和70.3%, 展现出良好的体外灭菌活性。

细菌分泌的胞外囊泡(OMV) 表面具有特征性抗原蛋白, 作为抗原物质开发的纳米疫苗具有良好的淋巴结靶向能力及抗原递呈细胞(antigen-presenting cell, APC) 结合与抗原递呈效果, 可同时激活先天和后天免疫, 显著增强抗菌预防效果。Camacho等^[97]将甲乙烯和顺丁烯二酸酐聚合酸酐纳米分子包被弗氏志贺菌的OMV, 能有效引发Toll样受体-2 (TLR2) 和TLR4诱导的先天免疫。鼻腔接种OMV纳米疫苗, 小鼠达到了整体抗菌效果, 而对照组接种无OMV鼻疫苗小鼠抗菌率仅40%, 具有良好的抗菌预防效果。Gao等^[98]制备了AuNPs, 用大肠杆菌OMV包被制得BM-AuNPs纳米疫苗, 与单纯的大肠杆菌OMV相比, 具有更强的组织间转移能力、稳定性、淋巴结积聚及APC结合能力。BM-AuNPs在淋巴结中APC募集率超过15%, 而OMV仅有10%。0.2 μg的BM-AuNPs抗大肠杆菌IgG效价达到10⁶单位, 而OMV仅有10⁵单位, 展现出良好的抗菌效果。

细菌感染过程中, 释放的毒力因子(如外毒素) 对宿主机体有较大的毒性作用, 抗毒素疫苗是指将抗毒素策略与疫苗治疗进行结合, 尽可能减少细菌耐药现象的产生。成孔毒素是多种细菌感染的主要毒力因子, 游离成孔毒素会先与细胞膜表面的一些特异性受体(糖类、磷脂和蛋白) 结合, 组装插入细胞膜表面的特定区域。依此机制将细胞膜结合纳米粒制成的仿生类毒素疫苗具有强抗原性与免疫原性, 能结合成孔毒素, 具有广谱抗毒素中和作用。红细胞膜包被PLGA聚合物纳米粒制备杂合载体红细胞纳米粒(RBC-NPs), 能与金葡菌α-溶血素结合, 消除其体内毒性及溶血作用。接种RBC-NPs的小鼠对比灭活类毒素组表现出更强的免疫保护和更高的抗体效价。实验组89%的小鼠通过接种RBC-NPs能预防α-溶血素作用, 44%的小鼠在感染后能被RBC-NPs治疗痊愈^[99], 展现RBC-NPs纳米类毒素疫苗的抗菌治疗效果。

仿生载体兼顾内源性载体良好的生物相容性、特异靶向性及外源性载体的优良载药性能, 针对抗细菌感染有很新颖的研究价值。但由于制备工艺复杂、源细胞膜的数量受亲本细胞类型和纯化技术的限制使得应用仍具有困难。同时, 细胞膜蛋白具有多样性, 如何有效保存功能性蛋白质、去除杂蛋白质仍是需要解决的问题^[100]。纳米药物系统用于抗细菌感染见表 2。

3 总结与展望

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细菌感染, 尤其多重耐药菌和超级耐药菌严重威胁人类健康, 由抗生素滥用、细菌耐药新机制而引起的耐药性感染日益严重的问题已成为全世界关注焦点, 对医疗保健系统构成了严重威胁, 需要新药物和新技术对抗耐药性问题, 降低药物脱靶毒性, 提高抗菌效果。而新靶点的发现较为困难, 新药研发成本高, 周期漫长。纳米生物材料和纳米技术用于疾病的诊断和药物治疗展现出强大活力和应用前景。结合纳米材料特殊的电、光、机械等性能, 对其抗菌机制和活性进行研究, 通过纳米技术为多功能的药物治疗系统提供满足不同生物学和治疗要求的可能性, 从生物相容性、精确靶点释放, 及通过相对可控的物理化学特性, 改善抗生素治疗中的剂量、毒副作用问题, 克服细菌耐药提供了非常有潜力的研究策略。但是, 抗细菌感染的纳米药物至今无上市产品, 纳米结构具有独特的物理化学性质、药代动力学和药效学特征, 纳米药物设计要考虑到这些因素。研究纳米载体在体内分布特点、如何实现药物的靶向递送来提高其疗效及安全性、纳米载体结构的物理稳定性、载药量的提高、药物释放如何调控、材料的热疗/光动力疗法, 以及药物的输送相结合的多功能体系的研究、纳米载体与细菌细胞、细胞外基质的作用机制, 都需深入研究从而提高细菌感染疗效。纳米材料及围绕纳米技术开展的递药系统在抗细菌感染, 特别是拮抗抗菌药物耐药性这一关键问题具有非常广阔的研究空间与应用潜力。

作者贡献: 何盈盈、周文铂、邰启炜、李荣洁负责文献的查阅和撰写; 俞媛负责文章选题和设计, 文章的关键理论指导及修改。

利益冲突: 文章内容不涉及相关利益冲突。

基金

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国家自然科学基金资助项目(82273487)
海军教育理论立项研究课题(2019128)
海军军医大学大学生创新能力培养计划(ZD2021026)

参考文献

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2023年第58卷第1期

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doi: 10.16438/j.0513-4870.2022-0615

接收时间：2022-05-20
首发时间：2025-11-21
出版时间：2023-01-12

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收稿日期：2022-05-20
修回日期：2022-08-05

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国家自然科学基金资助项目(82273487)

海军教育理论立项研究课题(2019128)

海军军医大学大学生创新能力培养计划(ZD2021026)

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海军军医大学药学系, 上海 200433

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*俞媛, Tel: 86-21-81871289, E-mail: pharmyuu@163.com

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2种不同金属材料的力学参数

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

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Inorganic nanomaterial	Mechanism of antibacterial therapy	Disadvantage
AgNPs	Permeability of biofilms; influence of bacterial replication; release of Ag⁺; generation of ·OH and ROS; broad antibacterial spectrum	Cytotoxity; environmental pollution
AuNPs	ROS-dependent antibacterial action; bacterial membrane disruption; influence of bacterial replication; photocatalytic degradation of bacterial cell membrane	Irreversible aggregation in solution
ZnO NPs	ROS-dependent antibacterial action; bacterial membrane disruption; photocatalytic degradation of bacterial cell membrane	Cytotoxity
CNs	Permeability of biofilms; bacterial membrane disruption; generation of O₂·^- and ·OH; photocatalytic degradation of microbial cell membrane; synergistic effect of inorganic materials and drugs	Cytotoxity; aggregation in solution; complex production processes
SiNs	High drug loading efficiency; surface-functionalization	Hydrophobicity; promote bacterial adhesion and subsequent biofilm formation

Inorganic nanomaterial

Mechanism of antibacterial therapy

Disadvantage

AgNPs

Permeability of biofilms; influence of bacterial replication; release of Ag⁺; generation of ·OH and ROS; broad antibacterial spectrum

Cytotoxity; environmental pollution

AuNPs

ROS-dependent antibacterial action; bacterial membrane disruption; influence of bacterial replication; photocatalytic degradation of bacterial cell membrane

Irreversible aggregation in solution

ZnO NPs

ROS-dependent antibacterial action; bacterial membrane disruption; photocatalytic degradation of bacterial cell membrane

Cytotoxity

CNs

Permeability of biofilms; bacterial membrane disruption; generation of O₂·^- and ·OH; photocatalytic degradation of microbial cell membrane; synergistic effect of inorganic materials and drugs

Cytotoxity; aggregation in solution; complex production processes

SiNs

High drug loading efficiency; surface-functionalization

Hydrophobicity; promote bacterial adhesion and subsequent biofilm formation

Nano-drug delivery system	Mechanism of antibacterial therapy	Agent
Liposomes	Fusion with biofilm; surface modification for active targeting; intelligent response for drug release; induction of immune reaction	Penicillin; ciprofloxacin; vancomycin; amikacin
SLNs/NLCs	High drug loading efficiency; sustained release of drugs; high biocompatibility	Clarithromycin; penicillin; tobramycin; oleuropein
Polymeric nanoparticles	High drug loading efficiency; sustained-release of drugs; co-delivery of drugs; surface modification for active targeting; intelligent response for drug release; membrane disruption by electrostatic adsorption	Cefixime; clarithromycin; rifampicin; azithromycin; clindamycin; ciprofloxacin
Dendrimers	Membrane disruption by electrostatic adsorption biofilms‐binding mechanism; nanostructured multifunctional surface	Auto antimicrobial activity
Niosomes	Skin accumulation and topical antifungal therapy stability; photobiologic-mediated the antibacterial activity	Doxycycline; ciprofloxacin; zinc phthalocyanide
Microemulsion	Generation of sufficient interfacial area; skin accumulation and topical antifungal therapy	Cephalosporin; ciprofloxacin; levofloxacin; moxifloxacin
Biomimetic nanomedicine	High biocompatibility; transport of the biofilm; specific targeting by cell membrane coating; reduce the MPS clearance of nanocarrier; immune activation by specific antigen protein; synergistic effect of nanoparticles and cell	Vancomycin; TPCA-1; Se; OMV; α-hemolysin

Nano-drug delivery system

Mechanism of antibacterial therapy

Agent

Liposomes

Fusion with biofilm; surface modification for active targeting; intelligent response for drug release; induction of immune reaction

Penicillin; ciprofloxacin; vancomycin; amikacin

SLNs/NLCs

High drug loading efficiency; sustained release of drugs; high biocompatibility

Clarithromycin; penicillin; tobramycin; oleuropein

Polymeric nanoparticles

High drug loading efficiency; sustained-release of drugs; co-delivery of drugs; surface modification for active targeting; intelligent response for drug release; membrane disruption by electrostatic adsorption

Cefixime; clarithromycin; rifampicin; azithromycin; clindamycin; ciprofloxacin

Dendrimers

Membrane disruption by electrostatic adsorption biofilms‐binding mechanism; nanostructured multifunctional surface

Auto antimicrobial activity

Niosomes

Skin accumulation and topical antifungal therapy stability; photobiologic-mediated the antibacterial activity

Doxycycline; ciprofloxacin; zinc phthalocyanide

Microemulsion

Generation of sufficient interfacial area; skin accumulation and topical antifungal therapy

Cephalosporin; ciprofloxacin; levofloxacin; moxifloxacin

Biomimetic nanomedicine

High biocompatibility; transport of the biofilm; specific targeting by cell membrane coating; reduce the MPS clearance of nanocarrier; immune activation by specific antigen protein; synergistic effect of nanoparticles and cell

Vancomycin; TPCA-1; Se; OMV; α-hemolysin