用于肝癌治疗的载有乐伐替尼的固体脂质纳米粒的制备、表征及体外评价，该纳米粒用二十聚甘油维生素E琥珀酸酯进行了功能化修饰。

Formulation, characterization, and In vitro evaluation of lenvatinib-loaded solid lipid nanoparticles functionalized with Twenty-Polyglycerol vitamin E succinate for liver cancer treatment.

作者信息

Zhou Yanyan, Luo Shengnan, Jiang Zhe, Luo Xiang, Yu Zhangsen, Wang Zhixin, Zhu Kewu

机构信息

Center for Drug Delivery System Research, School of Medicine, Shaoxing University, Shaoxing, Zhejiang, China.

Zhejiang Engineering Research Center of Fat-soluble Vitamin, College of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing, Zhejiang, China.

出版信息

Drug Dev Ind Pharm. 2025 Aug 6:1-14. doi: 10.1080/03639045.2025.2542473.

DOI:10.1080/03639045.2025.2542473

PMID:40751422

Abstract

OBJECTIVE

Lenvatinib (LEN), a first-line treatment for advanced hepatocellular carcinoma (HCC), faces limitations due to adverse effects and drug resistance. This study aimed to develop LEN-loaded solid lipid nanoparticles (SLNs) modified with Twenty-polyglycerol vitamin E succinate (PG20-VES@LEN-SLNs) to enhance therapeutic efficacy and compare them with Tween80-modified SLNs (Tween80@LEN-SLNs).

METHODS

The formulation of LEN-SLNs was optimized based on particle size and polydispersity index (PDI) by screening lipid matrices (GMS, GMP, SA, CP, GB, GMD), surfactant types (Tween80, PG20-VES, TPGS1000, F68), and GMS:SPC ratios. Physicochemical properties were characterized using dynamic light scattering (DLS), transmission electron microscopy (TEM), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy (FTIR). Encapsulation efficiency (EE), drug loading (DL), and drug release profiles were evaluated. Cytotoxicity against HepG2, Huh-7, and L02 cells was assessed MTT assay, while cellular uptake in HepG2 was visualized using Nile Red-labeled SLNs.

RESULTS

Optimized PG20-VES@LEN-SLNs exhibited a smaller particle size (294.6 ± 10.4 nm vs. 308.6 ± 29.5 nm for Tween80@LEN-SLNs) and higher EE (80.7 ± 5.1% vs. 72.7 ± 4.0%). Both formulations showed sustained drug release over 48 h, significantly slower than free LEN (97.4% released in 24 h). PG20-VES@LEN-SLNs demonstrated superior cytotoxicity against HepG2 cells (IC50 = 36.47 μM) compared to Tween80@LEN-SLNs (IC50 = 42.49 μM) and free LEN (IC50 = 116.8 μM), with enhanced cellular uptake observed confocal microscopy. In Huh-7 cells, PG20-VES@LEN-SLNs and Tween80@LEN-SLNs reduced the IC50 of lenvatinib from 189.21 μM (free LEN) to 18.04 μM and 18.41 μM, respectively.

CONCLUSION

PG20-VES@LEN-SLNs effectively improved LEN's therapeutic index through sustained release, enhanced tumor cell targeting, and synergistic cytotoxicity. This study highlights PG20-VES as a multifunctional surfactant for advanced HCC nanotherapy, offering a promising strategy to overcome clinical limitations of LEN.

摘要

目的

乐伐替尼（LEN）作为晚期肝细胞癌（HCC）的一线治疗药物，因不良反应和耐药性面临局限性。本研究旨在开发用二十聚甘油维生素E琥珀酸酯修饰的载乐伐替尼固体脂质纳米粒（PG20-VES@LEN-SLNs）以提高治疗效果，并将其与吐温80修饰的纳米粒（吐温80@LEN-SLNs）进行比较。

方法

通过筛选脂质基质（GMS、GMP、SA、CP、GB、GMD）、表面活性剂类型（吐温80、PG20-VES、TPGS1000、F68）以及GMS:SPC比例，基于粒径和多分散指数（PDI）优化LEN-SLNs的配方。使用动态光散射（DLS）、透射电子显微镜（TEM）、差示扫描量热法（DSC）和傅里叶变换红外光谱（FTIR）对物理化学性质进行表征。评估包封率（EE）、载药量（DL）和药物释放曲线。通过MTT法评估对HepG2、Huh-7和L02细胞的细胞毒性，同时使用尼罗红标记的纳米粒在共聚焦显微镜下观察HepG2细胞的摄取情况。

结果

优化后的PG20-VES@LEN-SLNs粒径更小（294.6±10.4nm，吐温80@LEN-SLNs为308.6±29.5nm）且EE更高（80.7±5.1%，吐温80@LEN-SLNs为72.7±4.0%）。两种配方均显示药物在48小时内持续释放，明显慢于游离乐伐替尼（24小时内释放97.4%）。与吐温80@LEN-SLNs（IC50 = 42.49μM）和游离乐伐替尼（IC50 = 116.8μM）相比，PG20-VES@LEN-SLNs对HepG2细胞表现出更强的细胞毒性（IC50 = 36.47μM），共聚焦显微镜观察到其细胞摄取增强。在Huh-细胞中，PG20-VES@LEN-SLNs和吐温80@LEN-SLNs分别将乐伐替尼的IC50从189.21μM（游离乐伐替尼）降低至了18.04μM和18.41μM。