基于树状大分子材料构建的纳米载药体系用于肿瘤靶向治疗的研究进展

陈倩倩; 张金赫

doi:10.3760/cma.j.cn121381-202106013-00166

Volume 46 Issue 5

Aug. 2022

Article Contents

Article Navigation > Int J Radiat Med Nucl Med > 2022, 46 > 5: (304-308)

Citation:

Research progress of nano-drug delivery systems based on dendrimer materials for tumor targeted therapy

Qianqian Chen¹,
Jinhe Zhang^2, ,

1.
Graduate School of Guangzhou University of Chinese Medicine, Guangzhou 510006, China
2.
Department of Nuclear Medicine, General Hospital of Southern Theater Command, Guangzhou 510010, China

Corresponding author: Jinhe Zhang, 64331671@qq.com
Received Date: 2021-06-13

Abstract

Dendrimer materials emerging in recent years have become excellent materials for constructing nano-drug delivery systems due to their controllable structures and unique interactions with cell membranes and various active drug molecules, and have been widely studied in the field of tumor targeted therapy. As nanomolecules with good biocompatibility, dendrimers can be conjugated to tumor-targeting molecules to specifically deliver active drug molecules to tumor tissues, which can maximize drug targeting and reduce toxic effects on non-target tissues. In this paper, the recently research progress of nano-drug delivery systems based on dendrimer materials for tumor targeted therapy is reviewed.
- Dendrimers,
- Nanocomposites,
- Radioisotopes,
- Drug delivery systems,
- Targeted therapy

References

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沈阳化工大学材料科学与工程学院沈阳 110142

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靶向治疗的基本原理是阻断特定的生物信号传导通路或定向破坏参与肿瘤生长或促进肿瘤进展的癌蛋白^[1]。靶向治疗除了可以通过单克隆抗体（monoclonal antibody，MAb）或小分子抑制剂改变特定细胞信号的直接方法来实现外，亦可通过间接方法（如利用细胞毒性药物靶向在肿瘤细胞中过表达或仅表达于肿瘤细胞的分子靶标）来实现。细胞毒性药物可通过纳米载药体系递送，该递送方法更特异和高效，可使靶向治疗克服传统化疗和生物治疗缺乏特异性的缺点^[1]。

树状大分子呈大小均匀的球形结构，其内部核心成分稳定，可提供动态内腔，外表面具有可供修饰的基团，且具有易于穿过细胞膜的能力，这些特点均有利于其作为载药体系的核心结构^[2-3]。近年来，针对基于树状大分子材料构建的纳米载药体系的研究较多，主要研究方向为采用不同的靶向基团对载药体系进行修饰、装载不同的治疗剂进行治疗、装载不同的放射性核素进行特异性显像和靶向治疗，这些研究使基于树状大分子材料构建的纳米载药体系的功能受到广泛关注。

1. 树状大分子简介

1.1. 树状大分子的结构与分类

树状大分子是高度支化的大分子，其基本结构包括3个主要组件：核心原子、重复分支单元和可供修饰的末端基团^[4-5]。常见的树状大分子包括聚酰胺-胺（polyamide-amine，PAMAM）树状大分子、聚丙烯亚胺（polypropylene imine，PPI）树状大分子、聚酯树状大分子、氨基酸树状大分子、糖树状大分子和疏水型树状大分子等^[4]。

1.2. 树状大分子的载药机制

树状大分子的3种药物负载点分别对应其不同的载药机制：（1）药物负载点为空腔，即通过分子捕获的方法载药；（2）药物负载点为分支点，即通过氢键的键合作用载药；（3）药物负载点为外表面基团，即通过电荷的相互作用载药^[2]。

1.3. 树状大分子的细胞毒性

尽管树状大分子在药物和基因递送方面具有巨大的应用潜力，但其仍有一些安全性问题（如细胞毒性、可引起溶血等）有待解决^[6-8]。树状大分子的细胞毒性是由其结构特性决定的，主要与其表面的特殊基团有关^[8]。在大多数情况下，细胞毒性的产生与纳米颗粒的强阳离子特性有关^{[3, 8-9]}。与其他带正电的聚合物一样，纳米颗粒的强阳离子与带负电的细胞膜之间的相互作用可能会导致细胞不稳定，甚至导致细胞裂解和胞质蛋白流出^[10]。有研究者发现，通过对树状大分子表面的官能基团进行功能化修饰可降低其细胞毒性，如树状大分子与聚乙二醇（polyethylene glycol，PEG）的连接或偶联已被证明可以降低树状大分子的细胞毒性^[11]。另外，PEG还能通过增强通透性和滞留效应延长树状大分子在血浆中的循环时间，并增加其在肿瘤部位的积聚^[12-13]。此外，通过乙酰化或羟基化来屏蔽树状大分子的强阳离子电荷也可以降低其细胞毒性^[5]。

2. 基于树状大分子材料构建的纳米载药体系的应用

2.1. 药物的靶向递送

当树状大分子连接到靶向基团时，其所负载的活性药物分子可被特异性地传递至肿瘤组织，从而实现药物的靶向递送，减少靶外效应^{[5, 14]}。目前，可与树状大分子偶联的配体有维生素、多肽、抗体和化合物等^{[3, 15]}。

2.1.1. 维生素与树状大分子偶联的应用

叶酸是一种重要的水溶性维生素，其可合成嘧啶和嘌呤，促进DNA的合成和修复。叶酸受体在正常细胞中的表达水平较低，而在肺癌、结直肠癌、卵巢癌、乳腺癌和子宫内膜癌等恶性肿瘤细胞中高表达^[3]。因此，将叶酸受体作为分子靶标构建基于树状大分子材料的纳米载药体系可实现药物的靶向递送。有研究结果表明，甲氨蝶呤与叶酸修饰的PPI树状大分子结合并负载维甲酸可以将活性药物特异性地递送到叶酸受体高表达的肿瘤细胞中^[16-17]。也有研究结果表明，用于治疗乳腺癌的处方药马法兰通过与叶酸修饰的PPI树状大分子结合成功实现了靶向递送，有效增强了其对肿瘤的抑制作用^[18]。

2.1.2. 多肽与树状大分子偶联的应用

精氨酸-甘氨酸-天冬氨酸（arginine-glycine-aspartic acid，RGD）是可与树状大分子官能基团偶联的著名多肽之一，其可与整合素αvβ3受体结合。整合素αvβ3受体在乳腺癌、前列腺癌、胶质母细胞瘤和卵巢癌等多种肿瘤细胞中高表达，且在肿瘤细胞的迁移和血管生成中发挥重要的调节作用^[19-20]。Anbazhagan等^[21]将PAMAM树状大分子与RGD偶联，并负载阿魏酸（ferulic acid，FA）和紫杉醇（paclitaxel，PTX）以克服P-糖蛋白介导的多药耐药难题，体外药物摄取结果显示，应用RGD-PAMAM-PTX的人宫颈癌长春新碱耐药细胞KB CH-R8-5的PTX摄取率高于PAMAM-FA-PTX；末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸核苷酸缺口末端标记实验和线粒体膜电位分析结果证实，RGD-PAMAM-FA-PTX聚合物在人宫颈癌长春新碱耐药细胞KB CH-R8-5中具有更强的抗肿瘤活性。

2.1.3. 抗体与树状大分子偶联的应用

MAbK1主要针对在某些类型肿瘤细胞中高表达的特异性蛋白，有研究结果表明，MAbK1-PPI-PTX聚合物对人卵巢癌细胞OVCAR-3的抗肿瘤作用强于游离的PTX或PPI-PTX聚合物^[22]。曲妥珠单抗是一种重要的重组人源化免疫球蛋白G1型MAbK1，Marcinkowska等^[23]合成了PAMAM树状大分子-曲妥珠单抗聚合物以负载多西紫杉醇（docetaxel，DOX）或PTX，并对其结构、纯度及抗肿瘤活性进行检测分析，发现曲妥珠单抗-PAMAM-DOX/PTX聚合物对人表皮生长因子受体2（human epidermal growth factor receptor 2，HER2）表达呈阳性的人乳腺癌细胞SKBR-3有极强的杀伤作用，而对HER2表达呈阴性的人乳腺癌细胞MCF-7的杀伤作用较弱；免疫荧光成像结果显示，曲妥珠单抗-PAMAM-DOX聚合物仅与HER2表达呈阳性的人乳腺癌细胞SKBR-3有较强的特异性结合。

2.1.4. 化合物与树状大分子偶联的应用

半乳糖胺（galactosamine，Gal）作为氨基糖类化合物，与肝癌细胞中过表达的去唾液酸糖蛋白受体有很高的亲和力，因此Gal是为数不多的靶向肝癌的选择性配体之一^[7]。Yousef等^[24]设计了锚定在Gal上的第4代PAMAM树状大分子，并负载有效的抗癌药物二氟化姜黄素（curcumin-difluorinated，CDF）以靶向人肝癌细胞HepG2，体内的生物学分布和治疗靶向性的深入研究结果表明，Gal-PAMAM-CDF聚合物可通过去唾液酸糖蛋白受体介导的内吞作用实现高特异性的细胞摄取以显著增强CDF的靶向递送效果。

2.2. 放射性核素治疗

放射性核素标记的树状大分子聚合物在体外具有很高的放射稳定性，且其在体内治疗方面也有很大的应用潜力^[25]。增强通透性和滞留效应可能会导致放射性核素在肿瘤组织中积聚，使放射性核素标记的树状大分子聚合物有望用于肿瘤治疗^[26]。

2.2.1. ¹³¹I标记的树状大分子

¹³¹I的半衰期为8.02 d，是核医学中最常用的同时发射β和γ射线的放射性核素之一，发射γ射线的特点使其有SPECT显像的应用基础^[26]。钟建秋^[27]应用人造环状RGD肽衍生物RGDyC和PEG与PAMAM树状大分子偶联，并用氯胺T法进行¹³¹I标记（标记率达94.68%~98.87%），成功构建了¹³¹I-RGDyC-PEG-PAMAM聚合物，其具有良好的体外放射稳定性和较高的放射化学纯度；体外研究结果表明，该聚合物可与人肺腺癌细胞A549特异性结合，并对其增殖产生一定的抑制作用。Song等^[28]用肿瘤淋巴管靶向相关肽1（tumor lymphatic targeting related peptide-1，LyP-1）以及3-(4′-羟基苯基)丙酸-OSu（3-(4′-hydroxyphenyl)-propionic acid-OSu，HPAO）修饰第5代PAMAM树状大分子，并将剩余的树状大分子末端胺基乙酰化，随后进行¹³¹I标记，成功构建了SPECT显像、放射性核素治疗和肿瘤抗转移治疗的多功能平台；研究结果表明，LyP-1修饰的树状大分子被¹³¹I标记后具有良好的生物相容性以及较高的放射化学纯度（>99%）和稳定性（>90%）；体内外研究结果显示，G5-PAMAM-HPAO-¹³¹I-(PEG-LyP-1)聚合物能够作为SPECT显像的诊断探针，并可在皮下荷瘤小鼠模型中作为放射性核素治疗和抗肿瘤细胞转移的有效治疗剂^[28]。

2.2.2. ¹⁸⁸Re标记的树状大分子

¹⁸⁸Re的半衰期为16.9 h，是一种非常适合用于肿瘤治疗的放射性核素^[29]。Tassano等^[30]首先将树状大分子与琥珀酰亚胺基6-肼并吡啶-3-羧酸盐酸盐（Suc-HYNIC）偶联，再将其与¹⁸⁸ReO₄^-孵育，从而成功实现了¹⁸⁸Re的标记（标记率接近70%）；该聚合物在正常小鼠体内生物学分布的研究结果表明，其经肝脏和肾脏排泄；该聚合物在黑色素瘤荷瘤小鼠体内也具有相似的生物学分布，且肿瘤摄取达6%ID/g；给正常小鼠或黑色素瘤荷瘤小鼠注射该聚合物并进行染色体畸变试验以检测其对黑色素瘤的治疗能力，结果表明，该聚合物以0.555 MBq（15 µCi）的剂量作用24 h后产生的电离辐射可诱导黑色素瘤细胞的DNA双链断裂，且异常细胞的中位数从7.0%增加到29.5%，这表明其具有显著的抗肿瘤效果。

2.2.3. ¹⁷⁷Lu标记的树状大分子

¹⁷⁷Lu的半衰期为6.73 d，除了具有治疗肿瘤的作用外，其发射的低能γ光子也使肿瘤的SPECT显像成为可能^[31]。Mendoza-Nava等^[32]合成了¹⁷⁷Lu-PAMAM-G4-叶酸-蛙皮素聚合物，并在其树突内腔合成了金纳米粒子，叶酸和蛙皮素作为靶向分子可分别与乳腺癌细胞中高表达的叶酸受体和胃泌素释放肽受体结合；该聚合物的初步体外研究结果表明，人乳腺癌细胞T47D对其具有特异性摄取，且该聚合物具有明显的细胞杀伤作用，可使人乳腺癌细胞T47D的存活率下降90%，因此，¹⁷⁷Lu-PAMAM-G4-叶酸-蛙皮素聚合物有望用于叶酸受体和胃泌素释放肽受体高表达的乳腺癌的靶向放射性核素治疗。

3. 小结与展望

树状大分子是一种具有诸多优点的纳米材料，对其表面的官能基团进行修饰可以实现药物递送和放射性核素标记。基于树状大分子材料构建的纳米载药体系能够增强药物的递送效能、提高肿瘤治疗的靶向性，减少传统药物的治疗剂量及不良反应，提高放射性核素治疗的靶向性。在构建纳米载药体系的过程中，树状大分子的细胞毒性和过早从循环中清除的缺点是目前亟需解决的问题。有研究者提出2种解决方法：（1）合成生物相容性更高或可生物降解的树状大分子（外围带中性或阴离子基团），如聚醚、聚酯或聚醚亚胺、聚醚共聚酯、磷酸盐、柠檬酸、三聚氰胺、多肽或三嗪树状大分子等；（2）通过乙酰化或PEG化反应屏蔽树状大分子外围带正电荷的基团^{[9, 33]}。虽然以上方法可以解决一部分问题，但效果仍不佳，还需要进行更多研究不断完善优化。相信未来随着多个学科技术的融合发展，将有更多、更深入的研究围绕基于树状大分子材料构建的纳米载药体系展开，从而进一步提高肿瘤靶向治疗的效果。

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作者贡献声明　陈倩倩负责文献的查阅、综述的撰写；张金赫负责命题的提出、综述的审阅与修订

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Research progress of nano-drug delivery systems based on dendrimer materials for tumor targeted therapy