基于环糊精的抗肿瘤药物主客体递送系统研究进展

doi:10.19894/j.issn.1000-0518.230055

摘要/Abstract

摘要：

恶性肿瘤是威胁人类健康的重大疾病。开发安全高效的抗肿瘤药物及其递送系统是改善抗肿瘤药物疗效的重要保证。近年来，基于环糊精的抗肿瘤药物主客体递送系统受到了广泛关注。环糊精是通过淀粉酶解获得的环状低聚糖，具有外部亲水内部疏水的特殊结构，在基因治疗、免疫细胞治疗、免疫靶向治疗和化疗中均得到了广泛的应用。本综述主要总结了环糊精作为抗癌药物递送载体近10年的相关进展，同时对主客体递送系统在癌症治疗方面的机遇和挑战进行了展望和讨论。

关键词: 恶性肿瘤, 主客体递药系统, 环糊精包合物, 环糊精偶联物, 环糊精聚合物。

Abstract:

Malignant tumors are major diseases that threaten human health. The development of safe and efficient antitumor drugs and their delivery systems is an important guarantee for improving the efficacy of antitumor drugs. In recent years， cyclodextrin-based antitumor drug host-guest delivery systems have received much attention. Cyclodextrins are cyclic oligosaccharides obtained by amylolytic enzymes with an external hydrophilic internal hydrophobic structure， and have been widely used in gene therapy， immune cell therapy， immune-targeted therapy， and chemotherapy. This review summarizes the advances related to cyclodextrins as antitumor drug delivery carriers， and also provides a perspective and discussion on the opportunities and challenges of host-guest delivery systems in oncology therapy.

Key words: Malignant tumor, Host-guest drug delivery systems, Cyclodextrin inclusion compounds, Cyclodextrin conjugates, Cyclodextrin polymers

中图分类号:

O641.3

刘小英, 陈方敏, 张惠娟, 于海军. 基于环糊精的抗肿瘤药物主客体递送系统研究进展[J]. 应用化学, 2023, 40(7): 964-975.

Xiao-Ying LIU, Fang-Min CHEN, Hui-Juan ZHANG, Hai-Jun YU. Advancement of Cyclodextrin-Based Host-Guest Drug Delivery System for Antitumor Therapy[J]. Chinese Journal of Applied Chemistry, 2023, 40(7): 964-975.

图/表 7

图1 环糊精的结构

Fig.1 Structure of cyclodextrin

表1 环糊精的衍生物及其性质

Table 1 Derivatives of CD and their properties

Type	Derivative	Characteristics	Example	Application	Ref.
Hydrophilic	Methylated	Good solubility in water as well as in organic solvents	RM-β-CD， per-O-methyl-β-CD	Nasal and ocular drug delivery systems	［34-38］
Hydrophilic	Hydroylated	Amorphous mixture and highly water soluble with very low toxicity	2-HP- β-CD， 3-HP- β-CD， 2，3-HP- β-CD	Parenteral， ocular and oral drug delivery systems	［39-41］
Hydrophilic	Alkylated	Poorly soluble in water， but soluble in organic solvents	2，6-Di-O-ethyl-β -CD， per-O-ethyl-β-CD	Parenteral and ocular drug delivery systems	［35， 42］
Ionizable	Anionic	Soluble at pH below 4 with low toxicity	SBE- β-CD	Parenteral drug delivery applications	［43-46］

图2 CD包合物的制备方法。A. 超声法，饱和水溶液法冷冻干燥法制备环糊精包合物； B. 共挥发法制备环糊精包合物； C. 研磨法制备环糊精包合物

Fig.2 Preparation of CD/drug inclusion complexes. A. Cyclodextrin inclusion complexes prepared by ultrasonic method， freeze-drying method in saturated aqueous solution； B. Cyclodextrin inclusion complexes prepared by co-volatilization method； C. Cyclodextrin inclusion complexes prepared by grinding method

图3 CD聚合物示意图

Fig.3 Schematic diagram of CD polymer types

图4 以环糊精为基础的瑞格拉非尼复合物治疗大肠癌癌症。A. RG@M-γ-CD的制备； B. RG@M-γ-CD抑制肿瘤细胞增殖的示意图［55］

Fig.4 CD-based regorafenib complex for the treatment of colorectal cancer cancers. A. Preparation of RG@M-γ-CD； B. Schematic of RG@M-γ-CD inhibiting tumor cell proliferation［55］

图5 可用于结直肠癌靶向化疗-免疫治疗的人参皂苷Rg3和槲皮素的环糊精主客体纳米制剂。A.叶酸修饰靶向制剂的制备流程；B.叶酸靶向共地送系统诱导肿瘤ICD，实现免疫联合治疗示意图； C. CRC在35天内生长曲线。数据以平均值表示，标准差（n=5）*P＜0.05和**P＜0.01； NS，无意义。D.肿瘤IVIS图像； E.去除CD4+或CD8+T细胞后，用靶向共制剂治疗的原位CRC小鼠（数据以平均值表示，标准差（n=4）*P＜0.05和**P＜0.01； NS，无统计意义）［71］

Fig.5 Cyclodextrin-based nanoformulation enabling the co-administration of ginsenoside Rg3 and quercetin in colorectal cancer chemoimmunotherapy. A. Preparation of FA-targeted co-formulation； B. Schematic diagram of FA-targeted co-formulation-induced tumor immunogenic cell death treatment passages； C. Treatment plan and CRC progression within 35 days. Data are expressed as mean， standard deviation （n=5） *P＜0.05 and **P＜0.01； NS， no significant difference； D. Tumor IVIS images； E. In situ CRC mice treated with targeted co-formulation after removal of CD4+ or CD8+ T cells. Data are expressed as mean， standard deviation （n=4） *P＜0.05 and **P＜0.01； NS， no significant difference［71］

图6 环糊精聚合物在治疗癌症方面的应用。A. HCJSP的合成； B. HCJSP诱导的激发T细胞活化和克服适应性免疫抵抗来增强胰腺癌症的光免疫治疗的示意图； C.环糊精交联聚合物CDNP的合成路线［77-79］

Fig.6 CD polymer-based drug delivery systems for cancer therapy. A. Synthesis of HCJSP； B. Cartoon schematic of HCJSP-induced stimulation of T cell activation and overcoming adaptive immune resistance to enhance photoimmunotherapy of pancreatic cancer； C. Synthetic route of cyclodextrin cross-linked polymer CDNP［77-79］

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