Chen Siwei, Ouyang Hu, He Dongxiu, Liu Daquan, Wang Xiao, Chen Hongyuan, Pan Wei, Li Qi, Xie Weiquan, Yu Cuiyun
Institute of Pharmacy & Pharmacology, University of South China, Hengyang, Hunan, China.
Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, University of South China, 28 Western Changshen Road, Hengyang, Hunan, China.
Curr Pharm Des. 2022;28(25):2113-2125. doi: 10.2174/1381612828666220506111918.
The efficacy of a traditional anticancer drug is challenged by adverse effects of the drug, including its nonspecific bio-distribution, short half-life, and side effects. Dendrimer-based targeted drug delivery system has been considered a promising strategy to increase targeting ability and reduce adverse effects of anti-cancer drugs.
This study analyzed the feasibility of whether the anticancer drug 5-fluorouracil (5-FU) could be delivered by functionalized fifth-poly(amidoamine) (PAMAM) with the peptide WP05 and the acetic anhydride to the liver cancer cells, reducing the toxicity of the PAMAM and improving the targeting property of 5-FU during delivery.
The functionalized PAMAM-based nanoformulation (WP05-G5.0NHAC-FUA) was fabricated through an amide condensation reaction to improve the therapeutic efficacy of 5-Fluorouracil (5-FU) in hepatocellular carcinoma (HCC). The physicochemical structure, particle size, zeta potential, stability, and in vitro release characteristics of WP05-G5.0NHAC-FUA were evaluated. In addition, the targeting, biocompatibility, anti-proliferation, and anti-migration of WP05-G5.0NHAC-FUA were investigated. The anti-tumor effect of WP05-G5.0NHAC-FUA in vivo was evaluated by constructing xenograft tumor models of human hepatoma cells (Bel-7402) implanted in nude mice.
The resultant WP05-G5.0NHAC-FUA displayed spherical-like nanoparticles with a size of 174.20 ± 3.59 nm. Zeta potential and the drug loading of WP05-G5.0NHAC-FUA were 5.62 ± 0.41mV and 28.67 ± 1.25%, respectively. Notably, the optimized 5-FU-loaded formulation showed greater cytotoxicity with an IC of 30.80 ± 4.04 μg/mL than free 5-FU (114.93 ± 1.43 μg/mL) in Bel-7402 cancer liver cells, but a significantly reduced side effect relative to free 5-FU in L02 normal liver cells. In vivo animal study further confirmed efficient tumor accumulation and enhanced therapeutic efficiency.
The developed nanoformulation is a promising platform for the targeting delivery of 5-FU and provides a promising solution for improving the efficacy of hepatocellular carcinoma chemotherapy.
传统抗癌药物的疗效受到药物不良反应的挑战，包括其非特异性生物分布、短半衰期和副作用。基于树枝状大分子的靶向给药系统被认为是一种有前途的策略，可提高抗癌药物的靶向能力并减少其不良反应。
本研究分析了抗癌药物5-氟尿嘧啶（5-FU）是否可通过用肽WP05和乙酸酐功能化的第五代聚酰胺-胺（PAMAM）递送至肝癌细胞，降低PAMAM的毒性并改善5-FU在递送过程中的靶向特性。
通过酰胺缩合反应制备功能化的基于PAMAM的纳米制剂（WP05-G5.0NHAC-FUA），以提高5-氟尿嘧啶（5-FU）在肝细胞癌（HCC）中的治疗效果。评估了WP05-G5.0NHAC-FUA的物理化学结构、粒径、zeta电位、稳定性和体外释放特性。此外，研究了WP05-G5.0NHAC-FUA的靶向性、生物相容性、抗增殖和抗迁移能力。通过构建人肝癌细胞（Bel-7402）植入裸鼠的异种移植肿瘤模型，评估了WP05-G5.0NHAC-FUA在体内的抗肿瘤作用。
所得的WP05-G5.0NHAC-FUA呈现出球形纳米颗粒，尺寸为174.20±3.59nm。WP05-G5.0NHAC-FUA的zeta电位和载药量分别为5.62±0.41mV和28.67±1.25%。值得注意的是，优化后的载5-FU制剂在Bel-7402肝癌细胞中显示出比游离5-FU（114.93±1.43μg/mL）更高的细胞毒性，IC为30.80±4.04μg/mL，但相对于L02正常肝细胞中的游离5-FU，其副作用显著降低。体内动物研究进一步证实了有效的肿瘤蓄积和增强的治疗效果。
所开发的纳米制剂是5-FU靶向递送的有前途的平台，为提高肝细胞癌化疗疗效提供了有前景的解决方案。
