无机材料学报, 2021, 36 (1): 9, 网络出版: 2021-01-21  

多孔碳纳米材料构建抗肿瘤药物靶向传递系统的研究进展 下载: 722次

Porous Carbon Nanomaterials Based Tumor Targeting Drug Delivery System: a Review
作者单位
1 河北科技大学 化学与制药工程学院,石家庄 050018
2 南非大学 非洲可持续性能源发展研究所, 约翰内斯堡 1710, 南非
3 河北医科大学第二附属医院 胆胰内镜外科, 石家庄 050000
摘要
抗肿瘤药物靶向传递系统是提高传统化疗药物疗效, 并降低其毒副作用的重要手段。以多孔碳纳米材料为药物载体, 根据肿瘤组织微环境特点, 构建抗肿瘤药物靶向传递系统是实现靶向治疗方案的有效方式。本文围绕基于多孔碳纳米材料的抗肿瘤药物靶向传递系统的构建及应用进行综述, 描述了多孔碳纳米材料适宜载药的设计、合成及功能化修饰; 通过理论与实例相结合的方式, 介绍了提高多孔碳纳米材料载药量和实现联合给药的有效策略; 从内源和外源性敏感刺激的角度, 重点分析了多孔碳纳米材料基于肿瘤微环境构建的靶向传递系统的机制和应用; 阐述了多孔碳纳米材料作为抗肿瘤药物载体面临的生物相容性和生物降解性的问题, 并分析了可能的解决途径; 展望了多孔碳纳米材料在构建肿瘤药物靶向传递系统应用中的前景及发展方向, 为研发靶向、可控的抗肿瘤药物传递系统提供了理论依据和例证支持。
Abstract
Chemotherapy is the main method used for cancer treatment. However, most chemotherapeutic drugs show low selectivity towards tumor cells. When killing tumor cells, chemotherapeutic drugs can also damage normal tissue cells and induce a series of side effects and toxic reactions, such as gastrointestinal reactions, calvities and so on. An effective way to reduce the adverse drug reactions is to construct targeted delivery systems based on the microenvironment properties of tumor tissue. Porous carbon nanomaterials (PCN), with excellent properties such as good structural stability, pores, and easily modified surface, are promising candidate to be used for such strategy. In this paper, the construction and application of the PCN-based targeted antitumor drugs delivery system were reviewed; the structural properties, the design philosophy of PCN suitable for drug loading were summarized; the effective strategies to improve drug loading on PCN for combined drug delivery were discussed both theoretically and experimentally. The mechanism and applications of PCN for tumor microenvironment based targeted delivery system were analyzed from the perspectives of endogenous sensitive stimulations (such as acidity, redox potential and specific enzyme), exogenous sensitive stimulations (such as light and magnetic) and multiple sensitive stimulations (such as double sensitive stimulations, including acidity/redox potential, acidity/magnetic and magnetic/light, and three sensitive stimulation, including acidity/redox potential/light). The biocompatibility and biodegradability of PCN used as anti-tumor drug delivery system was discussed, and the possible solutions were analyzed. The prospects of the application of PCN to be used in tumor drugs were discussed at the end of this review. This review provides theoretical basis and examples towards design and synthesis of porous carbon (PC) materials based anti-tumor drug delivery system, which may help the research and development of targeted and controllable tumor treatment.

根据世界卫生组织最新发布的全球癌症统计报告, 2018年全球因癌症而死亡的人数高达960万人, 预计到2030年这个数据将会上升至1300万人[1]。在我国, 迄今为止, 每年新增癌症患者约430万人, 因癌症死亡的约281万人[2], 无论是癌症的发病率, 还是死亡率, 均呈现逐年上升的趋势。由此可见, 恶性肿瘤已经是严重威胁人类健康的重大疾病之一, 防治形势日益严峻。现阶段, 癌症的治疗主要依靠化学疗法[3], 然而, 现有的化疗药物虽然可以有效杀灭恶性肿瘤[4], 却存在附带杀伤正常细胞、损害正常生理机能、促使肿瘤细胞对化疗药物产生抗药性以及引起严重毒副作用等缺点[5], 导致应用受限。将适量的化疗药物选择性地传递到肿瘤部位, 实现可控释放是克服上述缺点的重要手段, 但传统的药物制剂在体内分布具有非选择性, 难以将抗肿瘤药物有效地传送到肿瘤细胞内部, 且停留时间较短, 严重影响药物的有效性[6]。通过选择合适的药物载体, 并基于肿瘤组织独特的微环境进行设计, 构建不同敏感特性的抗肿瘤药物靶向传递系统, 是实现药物有效、可控发挥作用的解决方案之一[7,8]

近年来, 碳纳米材料在靶向药物传递领域中的应用受到了国内外科研工作者们的密切关注, 诸如富勒烯、碳纳米管、石墨烯及氧化石墨烯等均已在药物传递领域获得了一些积极进展[9,10,11,12,13], 但这些碳纳米材料均具有一定的生物毒性[14,15,16,17], 长期使用会对人体健康带来潜在危害。多孔碳纳米材料由于具有较好的生物相容性[18,19], 可有效地避免对正常细胞和非肿瘤组织产生额外的毒副作用, 在抗肿瘤药物靶向传递领域展现出了独特的发展潜力和应用 价值。

本文以多孔碳纳米材料的结构特征为切入点, 通过多种对肿瘤微环境特性敏感的物理化学因素敏感机制和研究实例的分析, 以理论和实例相结合的方式对适宜构建抗肿瘤药物传递系统的多孔碳纳米材料设计合成及其应用进展进行了综述, 并提出了目前仍存在的问题, 展望了其未来的发展方向。

1 适宜载药的多孔碳纳米材料设计合成与功能化修饰

多孔碳纳米材料不仅具有酸碱体系中结构稳定、比表面积大和生物相容性良好等结构特征, 还存在可与药物分子形成超分子π-π堆叠作用、制备方法丰富多样和易于功能化修饰等特性[20,21], 为其应用于构建抗肿瘤药物靶向传递系统提供了良好的基础。

1.1 多孔碳纳米材料适宜载药的优势结构特征

构建优异的抗肿瘤药物载体的主要目的是将足量药物定向传输到肿瘤部位, 并实现可控释放[22]。多孔碳纳米材料具备如下结构优势[23,24,25]: (1)多孔碳纳米材料的碳质结构不易与酸碱发生反应, 表现出良好的结构稳定性, 可作为药物分子的优良载体。同时, 利用载体的屏蔽作用可保护负载的药物分子在传输过程中不受酸碱介质的影响, 控制药物分子不过早释放, 使其能够完整到达肿瘤组织。(2)多孔碳纳米材料具有丰富的孔道结构, 以及较大的比表面积, 为药物分子提供了充足的结合或吸附位点, 可在有限的存储体积中实现高效负载, 并为药物分子的运输、扩散提供了传递通道。(3)多孔碳纳米材料的碳质骨架可通过特殊的超分子π-π堆叠作用和共价键作用与药物分子相结合, 有效提高药物分子的负载量, 另外, 超分子π-π堆叠作用易对外部触发如酸度、温度等刺激敏感, 可构建具有不同功能和协同作用的药物传递系统。(4)多孔碳纳米材料较容易通过共价及非共价修饰的手段进行表面改性, 有助于与具有刺激响应性的纳米粒子结合, 利用环境敏感因素驱动药物在细胞内释放, 提高对肿瘤微环境或靶标的特异性识别, 可较好地控制药物扩散动力学。

多孔碳纳米材料适宜载药的主要决定因素是较大的比表面积和孔容、丰富的多孔、易于与靶向配体结合以及易于在细胞内发挥作用。根据报道, 跨膜传递载体的最佳尺寸应小于100 nm[26], 另外, 载体材料的良好分散性决定了药物在体内循环传输过程中的流动性。因此, 在设计适于载药的多孔碳纳米材料时, 在粒径上应小于100 nm; 在分散形态上应具有良好的单分散性; 在结构上应以类球型[27]、具有中大孔或者大体积空腔的结构。

1.2 多孔碳纳米材料设计合成

多孔碳纳米材料的设计合成是构建抗肿瘤药物载体的关键步骤。近年来, 多孔碳纳米材料不断被优化创新, 发展了多种合成方法(表1)。理论上, 可通过多孔碳纳米材料制备方法中的一种或多种组合, 借助模板法、直接热解或化学气相沉积等手段, 获得可控的多孔碳结构, 从而设计出具有理想形态、尺寸、孔隙率和化学组成的载体材料[28]

表 1.

多孔碳纳米材料的制备方法

Table 1.

多孔碳纳米材料的制备方法

PreparationBasic stepsRef.
Hard template methodImpregnate the preformed hard template with carbon source, then remove the template after pyrolysis at a high temperature[29-30]
Soft template methodThrough surfactant assembly, the template is removed after pyrolysis at high temperature[31-33]
Direct pyrolysis methodDirect pyrolysis of carbon precursors, such as MOF, biomass, ionic liquid or polymer[34-37]
Chemical vapor deposition methodIntroducing two or more gaseous carbon precursors into the tubular quartz reactor, carbon materials obtained through pyrolysis[38-40]

查看所有表

1.2.1 模板法

模板法是获得具有规则孔结构和孔径分布的多孔碳纳米材料最成熟的方法之一, 主要分成硬模板法和软模板法[41](图1)。

10.15541/jim20200240.F001模板法合成多孔碳纳米材料示意图<sup>[<xref ref-type="bibr" rid="b41">41</xref>]</sup>Schematic illustration of template method for synthesis of PCN<sup>[<xref ref-type="bibr" rid="b41">41</xref>] </sup>

(a) Soft template method; (b) Hard template method

Fig. 1

硬模板法通常采用刚性结构的材料, 如二氧化硅、氧化镁、氧化铝和沸石等作为硬模板, 用可交联的前体填充或涂覆[42], 经热解处理将前体转化为均匀规则的碳质结构, 最后将模板蚀刻去除, 获得多孔碳纳米材料。硬模板法是对各种多孔模板的反向复制, 避免了控制客体物质的水解和缩合以及它们与表面活性剂的组装, 并确保完全填充中间通道, 因此可以合成各种多孔结构[43]。但可供使用的硬模板较少, 制备成本相对较高, 耗时较长[44], 还需要使用有害化学物质去除模板, 从而限制了其广泛应用[45]

软模板法主要采用可热分解的表面活性剂, 如阴离子和阳离子表面活性剂或非离子型表面活性剂用作软模板, 与碳前体和溶剂分子(水或乙醇)共同组成圆柱或球形胶束, 通过水热处理、协同组装或蒸发诱导自组装等策略, 得到多孔碳纳米材料。离子型表面活性剂热分解产生微孔或小的介孔(2~4 nm), 非离子表面活性剂还可以产生超过10 nm的介孔[46]。相较于硬模板法而言, 软模板法不需要提前合成模板, 操作工艺更简单, 成本更低廉, 并且制备的多孔碳纳米材料孔径分布更加均匀有序[47]

1.2.2 直接热解法

直接热解法是通过高温处理破坏碳前驱体材料中的化学键, 实现制备多孔碳纳米材料的过程[48]。常见的碳前驱体包括金属有机骨架化合物、生物质、聚离子液体和各种有机共聚物等。

金属有机骨架是通过配位键将含金属(如Co、Fe、Zn等)的无机结构单元与有机配体组装在一起, 融合了配位聚合物以及晶体材料的结构特点[49], 具备组成和结构丰富多样[50]、较高的比表面积、均匀的孔径分布和可调的化学结构[51]等优势, 合成过程示意图见图2(a)[52]。直接热解炭化金属有机骨架及其衍生物时, 其有机配体在保持多孔骨架的同时转化为碳, 无机结构单元被还原为金属氧化物或金属, 可通过酸蚀去除[53], 获得具有可调粒径、高比表面积、较大孔体积和均匀孔结构的多孔碳纳米材 料[54,55]。这种制备方法简单, 不需要额外碳源, 但由于碳骨架的形成温度高于释放分解气体的温度, 金属有机骨架合成成本比较高昂, 难以大批量制备[56]

生物质不但具有独特的生物组织自然结构[47], 而且来源丰富、具有成本效益, 是可直接热解碳化的典型碳前驱体之一, 合成示意图见图2(b)[57]。在碳化过程中, 这些生物组织自然结构一般不会被破坏, 可以制备具有分级多孔结构的多孔碳纳米材料[58], 但通常直接热解生物质获得的多孔碳材料比表面积较低, 空隙不发达, 需要进一步活化[28]

10.15541/jim20200240.F002直接热解法制备(a)金属有机骨架热解成碳<sup>[<xref ref-type="bibr" rid="b52">52</xref>]</sup>, (b)植物组织制备分级多孔碳<sup>[<xref ref-type="bibr" rid="b57">57</xref>]</sup>, (c)苯胺-吡咯共聚物热解成碳<sup>[<xref ref-type="bibr" rid="b60">60</xref>]</sup>, (d)嵌段共聚物聚甲基丙烯酸甲酯-苯乙烯热解成碳<sup>[<xref ref-type="bibr" rid="b61">61</xref>]</sup>Schematic illustration of direct pyrolysis methods for synthesis of porous carbon nanomaterials (PCN) (a) Preparation of MOF and porous carbon (PC)<sup>[<xref ref-type="bibr" rid="b58">58</xref>]</sup>; (b) Preparation of PC from plant tissue<sup>[<xref ref-type="bibr" rid="b59">59</xref>]</sup>; (c) Preparation of PC from PAN-co-PPy<sup>[<xref ref-type="bibr" rid="b60">60</xref>]</sup>; (d) Preparation of PC from PMMA-co-PS<sup>[<xref ref-type="bibr" rid="b61">61</xref>]</sup>Fig. 2

聚离子液体由离子液体单体聚合生成, 在重复单元上具有阴、阳离子基团, 兼具离子液体和多聚物的特点[59], 由于阴、阳离子之间的静电作用, 致孔剂均匀地分布在聚合物基质中, 使多孔碳纳米材料的形貌和微观结构易于调控[32], 可通过不同种类、不同配比阴离子和阳离子的选择以及调节聚合方法获得不同性质的多孔碳纳米材料[53]

各种共价有机骨架和共轭共聚物, 如苯胺和吡咯共聚物、聚酰亚胺以及嵌段共聚物等, 也可用作碳前驱体, 通过控制热解参数, 如升温速率和热解时间, 可进行多孔碳纳米材料的结构和表面性质的精细设计, 如图2(c, d)[60,61]

1.2.3 化学气相沉积法

化学气相沉积法是一种可将不稳定的碳前驱体转化成稳定固态碳的合成方法, 具有经济有效、易于操作、可重复性高, 有利于大量制备等特点。通常可分为无催化剂的和有催化剂的化学气相沉积法[62]。无催化剂的化学气相沉积法可直接在保护气(如Ar、N2)的氛围中热解含碳的气相有机物, 获得多孔碳纳米材料。有催化剂的化学气相沉积法是在保护气的氛围下, 利用含碳前驱体的气体或蒸汽流经催化剂表面进行催化分解, 从而生成多孔碳纳米材料, 催化剂通常固定在载体上置于石英反应器内发挥作用[63]。化学气相沉积法制备多孔碳的过程中影响因素较多, 如温度、碳源的流速和沉积时间等均会对多孔碳纳米材料的尺寸、形貌和产率造成影响。另外, 使用含有杂原子的前驱体材料可以得到不同掺杂的多孔碳纳米材料。

1.3 多孔碳纳米材料功能化修饰

多孔碳纳米材料功能化的主要目的是在其表面进行亲水性修饰, 以避开巨噬细胞清除, 最大程度地延长药物循环时间和靶向能力[64]。多孔碳纳米材料的碳质结构具有高度的疏水性, 因此, 在构建药物传递载体之前须通过共价或非共价作用进行适当的功能化修饰[65]。经过修饰的多孔碳纳米材料不仅能够被环境敏感因素驱动, 增强药物的靶向性、溶解性和体外稳定性, 同时还具有高渗透、长滞留效应, 更容易实现被肿瘤细胞胞摄入等效果[66]

1.3.1 共价修饰

共价修饰通常是在多孔碳纳米材料表面引入羟基、羧基或氨基等亲水性官能团, 用来保护靶向配体或药物[67,68]。如采用硝酸、过硫酸铵/硫酸或双氧水等氧化剂在多孔碳纳米材料表面均匀地生成羧基官能团, 有利于多孔碳纳米材料与肿瘤细胞完成同质相互作用[69,70]。如图3所示, Kapri等[71]采用硝酸作为氧化剂, 获得了羧基官能化的多孔碳球, 将其通过4-苯肼甲酸/N-(3-二甲氨基丙基)-N-乙基酰胺、N-羟基琥珀酰胺/N-(3-二甲氨基丙基)-N-乙基酰胺、叶酸(FA)分别进行功能化修饰后, 进一步装载阿霉素(DOX), 结果表明, 修饰后的多孔碳球装载的药物量明显高于简单物理吸附, 并有效防止了药物分子过早释放, 叶酸/N-(3-二甲氨基丙基)-N-乙基酰胺修饰后的多孔碳球可进入细胞内部发挥作用。该课题组在后续的研究中, 采用聚乙烯亚胺和叶酸进行功能化修饰了将装载阿霉素的多孔碳球, 结果表明, 修饰后的多孔碳球对人宫颈癌细胞和乳腺癌细胞均表现出了良好的治疗效果[72]

10.15541/jim20200240.F003(a)羧基化的多孔碳球与阿霉素和叶酸偶联的制备, (b)阿霉素在孔道和表面的吸附形式<sup>[<xref ref-type="bibr" rid="b71">71</xref>]</sup>(a) Schematic illustration of the preparation of DOX and FA conjugate with f-PCN to form CB-DOX/FA, and (b) the loading of DOX inside the pores and at the surface of functionalized PCN (f-PCN)<sup>[<xref ref-type="bibr" rid="b71">71</xref>]</sup>Fig. 3

1.3.2 非共价修饰

在多孔碳纳米材料表面进行非共价修饰的反应条件相对温和, 主要通过静电力、π-π堆叠作用、氢键或范德华力等进行[73]。如利用π-π堆叠作用可将肿瘤标志物及其相应的适配体锚定在多孔碳纳米材料表面, 针对目标蛋白质有敏感的响应能力[45]。Li等[74]基于酞菁类荧光探针Cy3标记的单链DNA与多孔碳球之间的非共价π-π堆叠作用, 特异性结合在多种恶性肿瘤中过量表达的细胞表面粘蛋白1 (MUC1), 用于细胞、组织切片和体内肿瘤等的癌症成像, 可清晰地分辨肿瘤与正常组织之间的区别。同时, 通过该作用力还可以制备特异性酶识别的抗肿瘤药物传递系统[75], 如图4所示。

10.15541/jim20200240.F004多孔碳球装载阿霉素并基于π-π作用进行通道封装<sup>[<xref ref-type="bibr" rid="b75">75</xref>]</sup>Schematic preparation of DOX loaded on oxide mesoporous carbon nanospheres (OMCN) and its channel capped by the interaction of π-π<sup>[<xref ref-type="bibr" rid="b75">75</xref>]</sup>Fig. 4

2 基于多孔碳纳米材料的抗肿瘤药物靶向传递系统的构建

理想的药物传递载体应具有以下特征[76,77]: 具有可控的粒径、孔容和药物分子负载能力; 可避免对正常细胞和组织产生多余的毒副作用; 可设计特定的释放时间, 以响应内源性或外源性刺激; 具有对肿瘤微环境的高度选择性和对肿瘤靶细胞的特异性识别功能。多孔碳纳米材料不仅具有较高的药物负载量, 还可以实现对肿瘤微环境的多重刺激响应, 且具有良好的生物相容性, 是具有发展潜力的抗肿瘤药物载体之一[45]

2.1 多孔碳纳米材料对抗肿瘤药物的有效负载

载药量是成功构建抗肿瘤药物靶向传递系统重要的衡量指标。相对于其他的载体材料, 多孔碳纳米材料具有孔道结构丰富、比表面积大等特点, 有利于负载较多药物分子。

2.1.1 提高载药量的策略

提高载药量的关键是通过对多孔碳材料的可控调节, 增加碳质结构与药物分子之间的作用位点。一般认为具有较大的比表面积和孔容的多孔碳纳米材料具有更高的载药量。Kong等[78]采用简单的溶剂热法制备了粒径为100 nm, 孔径为2.7 nm的介孔碳纳米颗粒, 具有较大的比表面积和孔容, 以阿霉素为模型药物, 实现了76.1%的高负载率。

在多孔碳纳米材料上创造空腔结构也是获得较高载药量的有效方法。Li等[79]比较了多孔碳球和中空多孔碳球对阿霉素的载药能力, 发现具有空腔结构的多孔碳球的载药量提升了10.7%。这是由于中空多孔结构使材料具有较大的孔容和低密度, 提供了更多的反应位点, 从而可实现更有效的药物负载。Chen等[80]制备了红细胞形态的多孔中空碳球, 不仅阿霉素的负载量比传统的中空多孔硅纳米颗粒提升了31.4%, 研究还发现中空多孔碳球可以通过沉默转移促进蛋白的表达来抑制癌细胞的转移, 具有更好的生物相容性和传递载药性能, 因此, 中空多孔结构是实现高载药量的重要选择。

2.1.2 实现联合载药的策略

为了减少给药次数, 提高对肿瘤细胞的治疗效果, 还可以通过调节多孔碳纳米材料的孔道结构实现联合给药。

Fang等[81]以制备的双层介孔纳米碳/硅复合材料为载体, 分别以亲水性的介孔硅层负载亲水性药物顺铂, 疏水性的介孔碳内核负载疏水性药物紫杉醇, 实现了联合载药, 不仅对人类卵巢癌细胞具有明显的抑制作用, 甚至对多药耐药细胞也具有超过50%的杀灭作用(图5(a))。抗肿瘤药物40%是疏水性的, 60%是亲水性的, 传统的多孔硅纳米材料具有亲水性, 通过亲水/疏水两亲性多孔材料设计, 有利于改进抗肿瘤药物传递系统, 但是其制备方法、形貌和分级孔结构等因素对负载药物种类及抗肿瘤性能的影响还有待研究。

Du等[82]以具有分级孔道结构的多孔中空碳球为载体, 不仅有效提高了载药量, 也实现了抗癌药物阿霉素和小干扰RNA的共同装载, 在减少给药次数的同时, 还提升了对肿瘤细胞的治疗效果(图5(b)), 这是因为该结构具有独特的开放三维树状结构, 中心具有较大尺寸的中孔, 因此, 其较高的内比表面积为抗肿瘤药物提供了更短的扩散路径, 同时, 高度粗糙的内外表面可以大幅增加材料与药物分子的作用位点, 从而改善了装载性能。

10.15541/jim20200240.F005(a) 双孔核壳介孔碳@二氧化硅<sup>[<xref ref-type="bibr" rid="b81">81</xref>]</sup>和(b)分级孔道多孔中空碳球装载阿霉素及小干扰RNA<sup>[<xref ref-type="bibr" rid="b82">82</xref>]</sup>联合给药载体制备方法Schematic illustration of preparing combined administration of (a) hierarchical hybrid dual-pore core-shell mesoporous carbon@silica<sup>[<xref ref-type="bibr" rid="b81">81</xref>]</sup> and (b) PHCNs-PEI-PEG for drug and gene co-loading<sup>[<xref ref-type="bibr" rid="b82">82</xref>] </sup>DOX: doxorubicin; PEI; polyethyleneimine; PEG: poly (ethylene glycol); RF: resorcinlo-formaldehydeFig. 5

2.2 构建抗肿瘤药物靶向传递系统

多孔碳纳米材料与药物的相互作用以及对肿瘤细胞所处的微环境的敏感程度是能否实现抗肿瘤药物靶向释放关键因素[83]。将药物加载到靶向受体功能化的多孔碳纳米材料上, 利用敏感刺激构建相应的药物传递系统, 是一种有效智能化的靶向策略。常见的构建思路包括(表2): (1)内源性敏感靶向, 主要基于肿瘤组织营造的独特生理环境, 如弱酸性、氧化还原势差、酶特异性等[84]。(2)外源性敏感靶向, 主要根据材料性质选择特定的外部措施, 如光热和磁等[85]。(3)利用两种或多种靶向刺激要素结合, 形成多功能增效的靶向机制。

表 2.

多孔碳纳米材料构建抗肿瘤药物靶向传递系统

Table 2.

多孔碳纳米材料构建抗肿瘤药物靶向传递系统

StructureResponse modesDrugs>啊.
Porous carbon spherepHMitoxantrone HCl[87]
Porous carbon spherepHDoxorubicin[26]
Porous carbon sphereSpecific enzymeDoxorubicin[91]
Porous carbon derived from ZIFSpecific enzymeMethylene blue[35]
Porous carbon sphereRedox potentialDoxorubicin[93]
Hollow porous carbon sphereNear infraredDoxorubicin[82]
Porous carbon sphereNear infraredDoxorubicin[98]
Porous carbon sphere coated with Fe3O4MagneticDoxorubicin[102]
Mesoporous carbon spherepH-redox potentialDoxorubicin[104][105]
Porous carbon spherepH-magneticDoxorubicin[106]
Ordered mesoporous carbon spherepH-magneticDoxorubicin[107]
Ordered mesoporous carbon spheres coated with Fe3O4Magnetic-near infraredDoxorubicin[108]
Porous carbon spheres coated with Au and Fe3O4Magnetic-near infraredDoxorubicin[109]
Hollow porous carbon spherepH-redox potential-near infraredDoxorubicin[110]

查看所有表

2.2.1 内源性敏感靶向

(1) pH敏感靶向

肿瘤细胞需要通过高速率的糖降解为其生长提供能量, 从而产生大量乳酸堆积于肿瘤部位, 导致肿瘤细胞周围处于弱酸环境, 其pH在6.2~6.8, 内涵体和溶酶体生理环境pH分别在5.8和4.8左右[86]

因此, 利用肿瘤细胞和正常组织细胞的微环境pH差异来设计制备pH依赖型药物载体, 在肿瘤部位弱酸环境中实现药物释放, 是常见的多孔碳纳米材料装载抗肿瘤药物实现靶向释放的重要途径之一。如图6所示, Huang等[87]以多孔碳球为载体, 负载了盐酸米托蒽醌, 使用N-(3-三甲氧基甲硅烷基丙基) 乙二胺三乙酸酯官能化的ZnO量子点, 通过双酰胺键与修饰过的介孔碳球以共价作用连接封装, 构建了pH敏感刺激响应药物传递系统, 成功实现了药物在酸性介质中的快速释放。Zhu等[26]制备了粒径为90 nm的多孔碳球, 通过装载酸敏感性药物阿霉素, 考察了不同pH环境下的负载和释放行为, 发现合适粒径的多孔碳球更易于携带阿霉素内化到宫颈癌细胞中, 并在酸性条件下发挥靶向治疗作用, 体现了良好的抗肿瘤特性。

10.15541/jim20200240.F006ZnO门控多孔碳球的pH响应性控制释放示意图<sup>[<xref ref-type="bibr" rid="b87">87</xref>]</sup>Schematic illustration of pH-responsive controlled release of ZnO-gated MCNs<sup>[<xref ref-type="bibr" rid="b87">87</xref>] </sup>

MCN: mesoporous carbon nanoparticles

Fig. 6

由文献[26]可知, 直径小于100 nm的多孔碳球具备发展为抗肿瘤药物跨膜载体的潜力, 但需经过表面亲水性修饰, 最大限度地提高循环次数。同时, 由于肿瘤细胞中内涵体和溶酶体生理环境的酸性更加明显, 对于碱性修饰过的多孔碳药物传递系统可能具有促进释放的作用, 从而提高靶向性能, 因此, 通过合理设计, 制备尺寸合适的多孔碳纳米材料, 有望实现抗肿瘤药物传递系统的pH敏感靶向释放。

(2)酶感靶向

许多肿瘤组织会过度分泌某些特定的酶[88], 这为构建酶特异性敏感的靶向药物传递系统提供了思路。核酸适配体是一小段经体外筛选得到的寡核苷酸序列或者短多肽, 采用核酸适配体对纳米颗粒进行表面修饰可与特定的酶或DNA序列形成高亲和力和强特异性的结合, 从而构建高敏感的靶向特异性识别系统[89]。细胞表面粘蛋白MUC1是一种Ⅰ型跨膜蛋白, 在多种肿瘤细胞中表达异常, 可达正常时的100倍以上, 是一种重要的肿瘤生物学靶标[90], 常被用于抗肿瘤靶向治疗。Li等[75]将单链DNA配对链涂覆在多孔碳球表面, 以阿霉素为模型药物, 利用MUC1粘蛋白标志物与单链DNA配对链特异性结合, 通过π-π作用封装多孔碳球的孔道, 实现了阿霉素的靶向传递。溶菌酶有一定的抗癌能力, 在生物医学领域有着很大的应用潜力[91]。Cao等[35]以ZIF-8衍生的多孔碳纳米材料为载体, 经羧化后, 进一步与胺修饰的单链DNA偶联, 通过溶菌酶核酸配体组成的DNA双链在载体表面上进行封装, 实现了对亚甲基蓝的负载, 通过对溶菌酶的响应, 实现了DNA双链解离, 靶向性地释放了亚甲基蓝, 其合成及释放过程见图7。使用特异性蛋白结合多孔碳纳米材料, 相当于在材料的通道入口安装了稳健的生物传感器“开关”, 以激活药物传递系统, 更加精准地实现靶向给药, 具有毒性小、治疗指数高等优点。

(3)氧化还原反应敏感靶向

肿瘤细胞内谷胱甘肽的浓度比正常细胞高出数倍[92], 形成了细胞内外显著的还原势差, 为构建还原敏感的靶向传递系统提供了条件。Zhou等[93]通过二硫键在多孔碳球表面修饰透明质酸, 并负载阿霉素, 构建了载药系统, 该载药系统可同时对细胞内的谷胱甘肽和透明质酸酶进行响应, 从而实现了阿霉素按需可控释放。由于代谢异常, 肿瘤细胞内还含有大量的活性氧, 从而使肿瘤细胞内具有显著的氧化能力[94,95]。利用对活性氧敏感的化学键构建氧化敏感抗肿瘤药物靶向传递系统也是一种可行的方式。王琳召等[96]分别用聚乙烯吡咯烷酮和培化磷脂酰乙醇胺对多孔碳球表面进行修饰, 考察了其对宫颈癌细胞氧化应激状态下细胞活力的影响, 发现经过聚乙烯吡咯烷酮修饰后的多孔碳球能明显减少活性氧的产生, 为构建氧化刺激响应的多孔碳纳米材料载药系统提供了重要依据。

10.15541/jim20200240.F007ZIF热解获得的多孔碳球酶敏感响应示意图<sup>[<xref ref-type="bibr" rid="b35">35</xref>]</sup>Schematic illustration of enzyme-responsive of porous carbon obtained from ZIF pyrolysis<sup> [<xref ref-type="bibr" rid="b35">35</xref>]</sup>Fig. 7

2.2.2 外源性敏感靶向

(1)光敏感靶向

由于肿瘤细胞的异常生理, 导致其对热的敏感性更强。多孔碳纳米材料可以吸收近红外区域(NIRⅠ: 700~1100 nm, NIR Ⅱ: 1~1.4 μm)中的光能, 并以热能的形式散发, 在短时间内局部温度升至40~45 ℃, 高于生理温度37 ℃, 从而诱导对癌细胞的热破坏[97]。Du等[82]采用带正电荷的聚乙烯亚胺修饰多孔中空碳球表面, 构建了大尺寸基因分子与阿霉素同时负载的药物传递系统, 结果表明, 该系统可以有效地将近红外光转化为热能, 在基因治疗的协同作用下, 几乎杀死了所有癌细胞。Xu等[98]采用聚乙烯亚胺和叶酸对多孔碳纳米材料进行修饰, 构建了化学光热靶向的药物传递载体, 发现将化学疗法与光热疗法相结合, 可以发挥更好的治疗功效(图8)。因此, 光敏感是构建抗肿瘤药物传递系统常用的体外敏感刺激方式。

10.15541/jim20200240.F008多孔中空碳球的修饰及光热响应示意图<sup>[<xref ref-type="bibr" rid="b98">98</xref>]</sup>Schematic illustration of modified porous hollow carbon spheres and the photothermal therapy<sup>[<xref ref-type="bibr" rid="b98">98</xref>]</sup>Fig. 8

(2)磁敏感靶向

在外部交变磁场中, 磁性纳米粒子可以通过Néel弛豫损耗产生热量[99], 将磁能转化为热能, 从而引起局部温度升至有效治疗温度, 使用磁靶向药物载体时, 将磁场置于目标位置能显著提高药物在病灶的积累[100,101]。Wu等[102]利用Fe3O4为造影剂和磁性靶向剂, 制备了多孔碳包覆Fe3O4纳米粒子, 依次通过乙二胺和透明质酸修饰, 以阿霉素药物模型, 构建了靶向药物传递系统, 研究表明该系统具有良好的生物相容性和光热转化能力, 对宫颈癌细胞具有良好的杀伤效果(图9)。

10.15541/jim20200240.F009多孔碳包覆Fe<sub>3</sub>O<sub>4</sub>纳米粒子并负载阿霉素的制备<sup>[<xref ref-type="bibr" rid="b102">102</xref>]</sup>Schematic illustration of MCNs coated Fe<sub>3</sub>O<sub>4</sub> nanoparticles and DOX loaded<sup>[<xref ref-type="bibr" rid="b102">102</xref>] </sup>

PCCMNs: porous carbon coated magnetic nanoparticles; DOX: doxorubicin; 1 Oe≈79.62 A/m

Fig. 9

2.2.3 多功能协同靶向

将两种或多种敏感靶向方法相结合, 可以产生协同诱导作用, 有利于提高多孔碳纳米材料药物传递系统载药能力、增强靶向释放性能、改良药物传递性能, 同时也可降低细胞毒性、减少药物的使用剂量并降低副作用[103]。因此, 构建双敏感刺激或多刺激响应的药物传递载体, 利用其多重控释和协同抗癌功能, 可以有效解决单敏感药物释放刺激不足, 实现更有效、更完全的药物释放, 在诊断和高效治疗肿瘤方面具有重要意义。

(1) pH和谷胱甘肽双敏感靶向

Zhang等[104]采用聚丙烯酸对介孔碳球孔道进行封装, 制备了对pH和谷胱甘肽双敏感响应的药物载体, 一方面, 在细胞内酸性环境诱导下, 聚丙烯酸(PAA)门控部分释放; 另一方面, 通过还原型谷胱甘肽破坏药物载体的完整性, 实现了药物的可控释放。在后续的研究中[105], 通过将粘蛋白配体MUC1锚定在多孔碳球表面上, 提供特异性识别癌细胞的能力, 可实现阿霉素的靶向释放, 对人肺腺癌细胞和乳腺癌细胞可进行靶向识别和治疗(图10)。

10.15541/jim20200240.F0010制备pH和谷胱甘肽双敏感的多孔碳球示意图<sup>[<xref ref-type="bibr" rid="b105">105</xref>]</sup>Schematic preparation of MCN responsive controlled release by pH and glutathione<sup>[<xref ref-type="bibr" rid="b105">105</xref>] </sup>

PAA: polyacrylic acid; PEI: polyc (ethyllene glycol); DOX: doxorubicin

Fig. 10

(2) pH和磁双敏感靶向

Yang等[106]采用pH敏感的ZnO量子点对多孔碳球进行封装, 利用Fe3O4为磁性诱发剂, 构建了pH和磁性敏感双触发药物传递系统, 不仅实现了较高的药物负载率, 还实现了pH和磁性双敏感靶向释放(图11)。Chen等[107]以叶酸偶联磁性有序多孔碳球为载体, 阿霉素为模型药物, 构建了pH和磁性双敏感药物传递系统。在有效的靶向作用下, 药物可以很容易地被内化到癌细胞中, 提高了治疗作用, 同时载体的保护作用使阿霉素在体内循环过程中对正常组织细胞的毒性作用大幅减小。

10.15541/jim20200240.F0011利用花状多孔碳球构建pH和磁复合敏感材料<sup>[<xref ref-type="bibr" rid="b106">106</xref>]</sup>Schematic illustration of construction of pH and magnetic composite sensitive materials by flower-like porous carbon composite (FPCS)<sup>[<xref ref-type="bibr" rid="b106">106</xref>] </sup>

DOX: doxorubicin

Fig. 11

(3)磁和光热双敏感靶向

Chen等[108]制备了具有热敏性和磁性双功能的有序介孔碳球, 以阿霉素为模型药物, 实现了阿霉素可控释放, 为构建双敏感抗肿瘤药物传递系统提供了新思路(图12)。Wang等[109]制备了纳米金和Fe3O4共同修饰的多孔碳材料, 构建了磁性-近红外双功能敏感药物传递系统, 该系统可在交变磁场中产生局部化热, 从而引发阿霉素释放, 近红外光热效应在调节药物释放速率的同时, 还可以有效地杀伤肿瘤细胞, 发挥了磁热与光热的协同作用的效果。与单一的敏感刺激相比, 双敏感刺激可以更好地发挥协同效应, 对肿瘤细胞更具有杀伤力。

10.15541/jim20200240.F0012磁热、光热能双敏感释放药物传递载体构建示意图<sup>[<xref ref-type="bibr" rid="b108">108</xref>]</sup>Schematic illustration of construction drug delivery by pH and magnetic composite sensitive<sup>[<xref ref-type="bibr" rid="b108">108</xref>] </sup>

OMCNs: ordered mesoporous carbon nanospheres; MOMCNs: magnetically OMCNs; TMOMCNs: thermo-sensitiuely MOMCNs; SMOMCNs: silane modified MOMCNs; DOX: doxorubicin

Fig. 12

(4) pH、谷胱甘肽和光热多敏感靶向

Wu等[110]以磁性空心多孔碳球为载体, 以阿霉素为模型药物, 采用聚γ-谷氨酸作为通道封装剂, 构建了具有pH、谷胱甘肽和红外光三重响应特征的靶向药物传递系统, 对肿瘤细胞微环境具有多重敏感协同治疗效果, 不仅实现了优异的抗肿瘤靶向治疗能力, 还有效地阻止了药物在到达靶位点之前释放, 解决了对正常细胞的不良影响(图13)。与单敏感和双敏感刺激的药物传递系统相比, 三敏感刺激可以实现更有效和更完全的药物释放。

10.15541/jim20200240.F0013肿瘤化疗pH、谷胱甘肽和光热化疗协同刺激反应药物传递系统的合成示意图<sup>[<xref ref-type="bibr" rid="b110">110</xref>]</sup>Schematic preparation of stimuli-responsive MHPCNs based drug delivery system for synergistic pH, glutathione and photothermal of tumor chemotherapy<sup>[<xref ref-type="bibr" rid="b110">110</xref>] </sup>

MHPCNs: magnetic hollow porous carbon nanoparticles

Fig. 13

3 多孔碳纳米材料的安全性和降解性

3.1 多孔碳纳米材料的生物安全性

良好的生物安全性是多孔碳纳米材料应用于生物医学领域的基础, 是其在体内使用的先决条件。

目前, 关于多孔碳纳米材料的生物相容性研究大多集中于体外细胞毒性方面。研究表明, 当多孔碳纳米材料的浓度约200 μg·mL-1时, 对多种细胞均具有可忽略的细胞毒性, 该浓度已远大于最大的临床使用浓度(50 μg·mL-1)[72,74,106]。多孔碳纳米材料的表面化学特性是影响其细胞毒性的重要因素, 其表面的高活性化学基团(如不饱和键、羰基、羧基、羟基等)易反应生成氧自由基, 从而损伤细胞, 产生毒性, 因此, 高活性化学基团的增多可一定程度上增强碳纳米材料的细胞毒性[71]。Li等[74]以蔗糖为碳源, 以十六烷基三甲基溴化铵为表面活性剂获得的多孔碳纳米球, 与不添加表面活性剂相比, 由于具有较为丰富的表面活性基团, 易于形成活性氧自由基, 从而对细胞表现出了一定的毒性, 不过, 增强幅度有限。同时, 对多孔碳纳米材料进行表面修饰可以防止药物在传递过程中的非特异性释放, 从而可降低载药系统的细胞毒性, 提高系统的生物相容性。Xu等[98]通过测定细胞计数和乳酸脱氢酶活性, 证实了经聚乙烯亚胺和叶酸共同修饰的多孔碳纳米材料对HeLa细胞没有明显的细胞毒性, 生物相容性良好。Li等[79]通过流式细胞仪分析经羧基修饰的中空多孔碳球的细胞毒性, 结果表明细胞存活率保持在80%以上。由此可知, 在体外细胞毒性方面, 以多孔碳纳米材料构建药物传递系统具有良好的生物相容性。

体内生物安全是多孔碳纳米材料在生物医学领域应用发展的重要问题。Wu等[110]制备了磁性中空多孔碳球作为抗肿瘤药物阿霉素的载体, 并将阿霉素药物本身作为对照组, 考察对小鼠机体的生物毒性, 结果表明, 由于阿霉素的毒性和副作用, 药物组小鼠的重量明显下降, 而药物载体系统组的体重没有明显减少, 主要脏器(心、肝、脾、肺、肾)的组织学分析结果显示无明显脏器损害或脏器改变, 进一步确证了多孔碳纳米材料对机体的生物安全性, 因此, 多孔碳纳米材料有望成为高效抗肿瘤治疗的纳米平台。

3.2 多孔碳纳米材料的生物降解性

多功能修饰的多孔碳纳米材料由于具有低细胞毒性和高效抗肿瘤特性, 从而具有广阔的抗肿瘤前景, 但由于其碳骨架结构的稳固性, 导致生物降解性能较差, 并且在体内积聚过多可能会产生长期的生物毒性, 这极大地阻碍了其进一步的临床应用, 因此, 开发可降解或可清除的多孔碳纳米材料具有重要意义。

多孔硅纳米材料具有良好的生物降解性[111]。通过将其与具有良好生物相容性和结构稳定性的多孔碳纳米材料相结合可制备生物降解性能良好的复合型纳米材料。Zhang等[112]制备了包覆碳壳的中空多孔硅纳米球, 通过酸处理将羧基和羟基附着在碳壳上, 提高了材料的亲水性, 经阿霉素加载和聚乙二醇修饰后, 设计了兼具高载药量、pH和光热双敏感特性的药物载体, 将该纳米材料在模拟生理环境的缓冲溶液中震荡30 d, 通过SEM和TEM观察震荡前后的形貌, 可以清楚地观察到震荡后碳材料的坍塌、断裂等形态变化, 同时, 震荡后的缓冲溶液中硅的质量浓度从0.35%上升到了8.4%, 证实了包覆碳壳的中空多孔硅纳米球的降解。复合材料可降解性增加的原因可能在于复合元素的掺入, 这些元素与碳元素之间形成的结合键容易打开, 降低了碳骨架的坚固性。

另外, 大多数纳米粒子在组织器官中的可清除性可能受其粒径大小和组成的影响[113], 机体对于不规则形状或粒径较大的碳纳米粒清除较困难[72], 因此, 通过制备不同元素复合, 或控制多孔碳纳米材料的形状和尺寸, 可能实现其生物降解性或可清除性能的提高。

4 结语与展望

近年来, 癌症作为严重威胁我国居民健康的重大疾病, 对国家经济和社会的可持续发展造成了极大的负担。由于多孔碳纳米材料具有独特的物理特性、化学多功能性和出色的药物负载能力, 使其具备了作为有效的癌症治疗剂的先决条件[65]。采用多孔碳纳米材料为载体, 融合物理、化学作用协同增效, 构建兼具高负载能力和靶向识别肿瘤功能的抗肿瘤药物传递系统, 为肿瘤的诊治提供了重要方向。

目前, 采用多孔碳纳米材料构建靶向传递系统在基础研究方面取得了很多进展, 但仍然存在一些问题尚待解决, 比如, 现有方法合成大量的具有分散性良好、尺寸均一、高比表面积等适宜载药需求的多孔碳材料仍然面临挑战, 同时, 多孔碳纳米材料的结构特征和修饰与体内外生物相容性、生物降解性的关系尚不够明确。更重要的是, 多孔碳纳米材料与其生物降解性的相关研究较少, 不能为开展临床研究提供足够的数据支撑。

因此, 要实现多孔碳材料在生物医药领域有效临床转化, 还有很多问题需要继续探索: (1)设计结构更加可控的多孔碳纳米材料及其绿色制备方法, 实现载体对药物分子的高效负载。(2)探索更丰富的表面修饰方法, 实现多孔碳纳米材料在体内循环代谢过程中生物相容性良好。(3)考察多孔碳纳米材料结构特征对生物毒性和在不同组织器官中保留时间的影响因素, 形成不同结构形貌和器官降解清除的规律性认识。(4)深入研究肿瘤微环境敏感机制, 有针对性地设计载药多孔碳纳米材料更加有效的靶向策略。(5)建立规范化的适用于临床应用的检测标准, 保证临床转化成果可持续推广应用。我们相信, 随着科研工作的不断深入, 将会有越来越多基于多孔碳纳米材料的靶向抗肿瘤药物传递系统应用于临床治疗。

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程晓昆, 张越, 吕海军, 刘歆颖, 侯森林, 陈爱兵. 多孔碳纳米材料构建抗肿瘤药物靶向传递系统的研究进展[J]. 无机材料学报, 2021, 36(1): 9. Xiaokun CHENG, Yue ZHANG, Haijun Lü, Xinying LIU, Senlin HOU, Aibing CHEN. Porous Carbon Nanomaterials Based Tumor Targeting Drug Delivery System: a Review[J]. Journal of Inorganic Materials, 2021, 36(1): 9.

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