BACKGROUND 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. OBJECTIVE 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. METHODS 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. RESULTS 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 IC50 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. CONCLUSION 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.

中文翻译：

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用于肝细胞癌靶向递送 5-氟尿嘧啶的功能化 PAMAM 纳米制剂。

背景技术传统抗癌药物的功效受到药物副作用的挑战，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，可以提高靶向能力并减少抗癌药物的副作用。目的分析抗癌药物5-氟尿嘧啶（5-FU）是否可以通过功能化第五聚（酰胺基胺）（PAMAM）与肽WP05和乙酸酐递送至肝癌细胞，降低毒性的可行性。 PAMAM 和提高 5-FU 在分娩过程中的靶向性。方法 功能化 PAMAM 基纳米制剂 (WP05-G5. 0NHAC-FUA) 通过酰胺缩合反应制备，以提高 5-氟尿嘧啶 (5-FU) 在肝细胞癌 (HCC) 中的治疗效果。评价了WP05-G5.0NHAC-FUA的理化结构、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、抗增殖和抗迁移性。通过构建植入裸鼠的人肝癌细胞（Bel-7402）的异种移植肿瘤模型来评估WP05-G5.0NHAC-FUA的体内抗肿瘤作用。结果 所得的 WP05-G5.0NHAC-FUA 显示出尺寸为 174.20 ± 3.59 nm 的球形纳米颗粒。WP05-G5.0NHAC-FUA的Zeta电位和载药量分别为5.62±0.41mV和28.67±1.25%。尤其，优化的 5-FU 负载制剂在 Bel-7402 癌肝细胞中显示出比游离 5-FU (114.93 ± 1.43 μg/mL) 更大的细胞毒性，IC50 为 30.80 ± 4.04 μg/mL，但相对于L02 正常肝细胞中游离 5-FU。体内动物研究进一步证实了有效的肿瘤积累和提高的治疗效率。结论 所开发的纳米制剂是靶向递送 5-FU 的有前景的平台，并为提高肝细胞癌化疗的疗效提供了有前景的解决方案。体内动物研究进一步证实了有效的肿瘤积累和提高的治疗效率。结论 所开发的纳米制剂是靶向递送 5-FU 的有前景的平台，并为提高肝细胞癌化疗的疗效提供了有前景的解决方案。体内动物研究进一步证实了有效的肿瘤积累和提高的治疗效率。结论 所开发的纳米制剂是靶向递送 5-FU 的有前景的平台，并为提高肝细胞癌化疗的疗效提供了有前景的解决方案。