中草药

叶酸修饰的藤黄酸纳米晶-磷脂复合递药系统的制备及评价

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刘思卓 ¹, , 吕佳蔚 ¹, , 凌延文 ¹, , 王琳翔 ¹, , 曾熙雯 ¹, , 王瑞平 ¹, , 苏瑾 ¹,

中草药 | 药剂与工艺 2026,57(16): 6303-6319

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中草药 |药剂与工艺 2026 , 57 (16) : 6303 -6319

叶酸修饰的藤黄酸纳米晶-磷脂复合递药系统的制备及评价

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刘思卓¹,, 吕佳蔚¹,, 凌延文¹,, 王琳翔¹,, 曾熙雯¹,, 王瑞平¹,, 苏瑾¹,

作者信息

^1.佳木斯大学药学院黑龙江省新药创制与药效毒理评价重点实验室, 黑龙江佳木斯 154007

^2.佳木斯大学药学院黑龙江省新药创制与药效毒理评价重点实验室, 黑龙江佳木斯 154007

通讯作者:

苏瑾

作者简介:

刘思卓: 刘思卓,硕士研究生,研究方向为靶向递药系统。E-mail:258073019@stu.jmsu.edu.cn

Preparation and evaluation of folic acid-modified gambogic acid nanocrystals-phospholipid composite drug delivery system

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出版时间: 2026-08-28 doi: 10.7501/j.issn.0253-2670.2026.16.008

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目的为改善藤黄酸原料药释放的靶向性，设计制备一种由叶酸修饰的藤黄酸纳米晶-磷脂复合递药系统（folic acid-modified gambogic acid nanocrystals-phospholipid composite drug delivery system，GA-NCs@PL-FA），优化其处方工艺，并考察GA-NCs@PL-FA的理化性质、体外抗肝癌活性及体内组织分布特征。方法通过CO₂辅助沉淀法制备藤黄酸纳米晶（gambogic acid nanocrystals，GA-NCs），再经薄膜水化法构建GA-NCs@PL-FA。结合单因素考察和星点设计-效应面法（central composite design-response surface methodology，CCD-RSM）优化处方工艺。透射电子显微镜（transmission electron microscopy，TEM）观察微观形态，测定粒径、ζ电位、包封率、载药量及稳定性；以透析袋法考察其在pH 7.4、6.5磷酸盐缓冲液（PBS，含0.5%聚山梨酯80）中的体外释放行为。利用细胞计数试剂盒-8（cell counting kit-8，CCK-8）法和细胞划痕实验，评价不同给药组对HepG2细胞活力和迁移能力的影响。采用超高效液相色谱-串联质谱法（ultra-high performance liquid chromatography-tandem mass spectrometry，UPLC-MS/MS）测定荷瘤裸鼠各组织中藤黄酸含量，分析其体内组织分布及肿瘤组织富集能力。结果 GA-NCs@PL-FA呈类球形，粒径为（183.07±0.55）nm，ζ电位为（-17.70±0.17）mV，包封率和载药量分别为（84.64±0.57）%和（4.33±0.07）%，在4、25 ℃条件下放置7 d后性质稳定；在2种释放介质中，均表现出明显的缓释效果。体外实验结果显示，与藤黄酸、GA-NCs及无叶酸修饰的藤黄酸纳米晶-磷脂复合递药系统（folic acid-free gambogic acid nanocrystals-phospholipid composite drug delivery system，GA-NCs@PL）相比，GA-NCs@PL-FA对HepG2细胞增殖和迁移的抑制作用更强，半数抑制浓度（half inhibitory concentration，IC₅₀）降至0.50 μg/mL。组织分布实验证实，GA-NCs@PL-FA可延长藤黄酸体内滞留时间，并促进其在肿瘤组织中的富集，具有良好的靶向性。结论优化了GA-NCs@PL-FA的处方和制备工艺，体系粒径均一、载药性能较好，具有良好的缓释效果和体外抗肝癌活性，并表现出较强的肿瘤组织富集能力，可为藤黄酸的靶向制剂开发及临床应用提供参考。

关键词

藤黄酸 / 叶酸 / 纳米晶 / 制备工艺 / 体外释放 / 组织分布

Abstract

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Objective In order to improve the targeting release of gambogic acid, a folic acid-modified gambogic acid nanocrystals-phospholipid composite drug delivery system (GA-NCs@PL-FA) was designed and prepared, and its prescription process was optimized. The physicochemical properties, in vitro anti-hepatocarcinoma activity and in vivo tissue distribution characteristics of GA-NCs@PL-FA were investigated. Methods Gambogic acid nanocrystals (GA-NCs) were prepared by CO₂-assisted precipitation method, and then GA-NCs@PL-FA was constructed by thin film hydration method. The prescription process was optimized by single factor investigation and central composite design-response surface methodology (CCD-RSM). The microscopic morphology was observed by transmission electron microscopy (TEM), and the particle size, ζ potential, encapsulation efficiency, drug loading and stability were determined. The in vitro release behavior in pH 7.4, 6.5 phosphate buffer (PBS, containing 0.5% Tween 80) was investigated by dialysis bag method. The effects of different administration groups on the viability and migration ability of HepG2 cells were evaluated by cell counting kit-8 (CCK-8) method and cell scratch test. The content of gambogic acid in each tissue of tumor-bearing nude mice was determined by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), and its tissue distribution and tumor tissue enrichment ability were analyzed. Results The GA-NCs@PL-FA was spherical, the particle size was (183.07 ±0.55) nm, the ζ potential was (−17.70 ±0.17) mV, the encapsulation efficiency and drug loading were (84.64 ±0.57)% and (4.33 ±0.07)%, respectively. The properties were stable after 7 d at 4, 25 ℃. In both release media, it showed obvious sustained release effect. In vitro experiments showed that compared with gambogic acid, GA-NCs and folic acid-free gambogic acid nanocrystals-phospholipid composite drug delivery system (GA-NCs@PL), GA-NCs@PL-FA had a stronger inhibitory effect on the proliferation and migration of HepG2 cells, and the half inhibitory concentration (IC₅₀) was reduced to 0.50 μg/mL. The tissue distribution test confirmed that GA-NCs@PL-FA could prolong the retention time of gambogic acid in vivo and promote its enrichment in tumor tissues, with good targeting. Conclusion The formulation and preparation process of GA-NCs@PL-FA were optimized. The system had uniform particle size, good drug loading performance, good sustained release effect and in vitro anti-hepatoma activity, and showed strong tumor tissue enrichment ability. It can provide reference for the development and clinical application of gambogic acid targeted preparations.

Key words

gambogic acid / folic acid / nanocrystals / preparation technology / in vitro release / tissue distribution

引用本文

刘思卓, 吕佳蔚, 凌延文, 王琳翔, 曾熙雯, 王瑞平, 苏瑾. 叶酸修饰的藤黄酸纳米晶-磷脂复合递药系统的制备及评价. 中草药, 2026 , 57 (16) : 6303 -6319 . DOI: 10.7501/j.issn.0253-2670.2026.16.008

LIU Sizhuo, LYU Jiawei, LING Yanwen, WANG Linxiang, ZENG Xiwen, WANG Ruiping, SU Jin. Preparation and evaluation of folic acid-modified gambogic acid nanocrystals-phospholipid composite drug delivery system[J]. Chinese Traditional and Herbal Drugs, 2026 , 57 (16) : 6303 -6319 . DOI: 10.7501/j.issn.0253-2670.2026.16.008

基金

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黑龙江省北药与功能食品特色学科项目
黑龙江省自然科学基金项目
国家大学生创新训练计划
黑龙江省教育厅创新团队项目
佳木斯大学“东极”学术团队项目

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孙强, 涂柯蓉, 姜先梅, 等. 藤黄酸抗肿瘤作用机制及联合用药研究进展[J]. 中草药, 2024, 55(7): 2423-2432.
Liu X, Hu Q, Wang W Y, et al. A protein-fragment complementation assay reveals that celastrol and gambogic acid suppress ERα mutants in breast cancer [J]. Biochem Pharmacol, 2021, 188: 114583.
Zhang Z, Qian H Q, Yang M, et al. Gambogic acid-loaded biomimetic nanoparticles in colorectal cancer treatment [J]. Int J Nanomed, 2017, 12: 1593-1605.
Du Q, Lv F N, Huang J, et al. A multiple environment-sensitive prodrug nanomicelle strategy based on chitosan graftomer for enhanced tumor therapy of gambogic acid [J]. Carbohydr Polym, 2021, 267: 118229.
赵广超, 庄婕. 藤黄酸的制剂研究进展[J]. 中国药师, 2020, 23(7): 1404-1408.
吕春艳, 信文婧, 崔闻宇, 等. 基于药物纳米晶的肿瘤靶向纳米递药系统研究进展[J]. 医药导报, 2026, 45(1): 100-108.
Dhibar M, Chakraborty S, Kundu A, et al. Chemistry characterization and application of nanocrystals-based drug delivery system:Present to future perspective [J]. Pharm Nanotechnol, 2023, 11(3):265-275.
Rana S, Tomar D, Kaushik P, et al. Targeted approach to enhance the solubility of weakly soluble drugs by nanocrystal technology [J]. Pharm Nanotechnol, 2023, 11(5): 425-432.
Wang Y, Tan X Y, Fan X Y, et al. Current strategies for oral delivery of BCS IV drug nanocrystals: Challenges, solutions and future trends [J]. Expert Opin Drug Deliv, 2021, 18(9): 1211-1228.
Liang H M, Zou F M, Liu Q W, et al. Nanocrystal-loaded liposome for targeted delivery of poorly water-soluble antitumor drugs with high drug loading and stability towards efficient cancer therapy [J]. Int J Pharm, 2021, 599: 120418.
Xiao Y X, Liu Q T, Clulow A J, et al. PEGylation and surface functionalization of liposomes containing drug nanocrystals for cell-targeted delivery [J]. Colloids Surf B Biointerfaces, 2019, 182: 110362.
Lu L W, Xu Q Z, Wang J, et al. Drug nanocrystals for active tumor-targeted drug delivery [J]. Pharmaceutics, 2022, 14(4): 797.
高娟, 李伟宏, 李秀芬, 等. pH敏感/叶酸修饰白藜芦醇脂质体的制备、表征及对子宫内膜癌荷瘤小鼠肿瘤的抑制作用[J]. 中草药, 2025, 56(20): 7368-7383.
顾永卫, 姜良弟, 杜月, 等. 叶酸介导的雷公藤甲素外泌体靶向给药系统抗恶性黑色素瘤体内外评价[J]. 药学学报, 2021, 56(12): 3224-3232.
杨坤, 张海珠, 张月辉, 等. 叶酸修饰的pH值响应型去甲斑蝥素脂质体的制备及促HepG2细胞凋亡研究[J]. 药物评价研究, 2025, 48(6): 1529-1545.
Yoo J, Park C, Yi G, et al. Active targeting strategies using biological ligands for nanoparticle drug delivery systems [J]. Cancers, 2019, 11(5): 640.
Ibrahim M A I, Othman R, Chee C F, et al. Evaluation of folate-functionalized nanoparticle drug delivery systems: Effectiveness and concerns [J]. Biomedicines, 2023, 11(7): 2080.
Han X F, Wang M L, Ma Z H, et al. A new approach to produce drug nanosuspensions CO₂-assisted effervescence to produce drug nanosuspensions [J]. Colloids Surf B Biointerfaces, 2016, 143: 107-110.
Zeng X W, Liu S Z, He Q H, et al. Preparation and antitumor activity evaluation of folic acid-modified phospholipid-gambogic acid nanocrystals [J]. Pharmaceutics, 2026, 18(2): 253.
杜建靓. 叶酸修饰紫杉醇纳米晶制备及抗乳腺癌作用研究[D]. 上海: 上海中医药大学, 2020.
田阳, 彭一凡, 张志伟, 等. 纳米晶体药物制备技术的研究进展[J]. 药学学报, 2021, 56(7): 1902-1910.
毕建云, 王嘉驿, 刘善新. 基于星点设计-响应面优化法的川芎挥发油二元醇质体制备及性能表征[J]. 中国医院药学杂志, 2025, 45(14): 1569-1577.
余红玲, 周丹, 葛均友, 等. 喜树碱衍生物T030长循环脂质体的制备及药效评价[J]. 华西药学杂志, 2025, 40(5): 502-506.
白皎皎. 藤黄酸纳米制剂的制备及体内药代动力学和急性毒性研究[D]. 成都: 电子科技大学, 2019.
Xu Y L, Wu H, Huang J, et al. Probing and enhancing ligand-mediated active targeting of tumors using sub-5 nm ultrafine iron oxide nanoparticles [J]. Theranostics, 2020, 10(6): 2479-2494.
欧阳振, 王利利, 张志浩, 等. 纳米晶药物技术创新、稳定机制与应用研究进展[J]. 聊城大学学报: 自然科学版, 2026, 39(5): 777-788.
闫宏丽. 叶酸靶向修饰载新藤黄酸纳米结构脂质载体的研究[D]. 天津: 天津中医药大学, 2020.

2026年第57卷第16期

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doi: 10.7501/j.issn.0253-2670.2026.16.008

接收时间：2026-02-03
首发时间：2026-10-22
出版时间：2026-08-28

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收稿日期：2026-02-03

基金

黑龙江省北药与功能食品特色学科项目

黑龙江省自然科学基金项目

国家大学生创新训练计划

黑龙江省教育厅创新团队项目

佳木斯大学“东极”学术团队项目

作者信息

^1.佳木斯大学药学院黑龙江省新药创制与药效毒理评价重点实验室, 黑龙江佳木斯 154007

^2.佳木斯大学药学院黑龙江省新药创制与药效毒理评价重点实验室, 黑龙江佳木斯 154007

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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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