Zhang Wenhui, Wang Qiang, Zhai Fengguo, Fan Xingjun, Meng Fanqin, Shen Guangzhi, Zhu Ying, Cao Jingdan, Yu Fengbo
School of Pharmacy, Mudanjiang Medical University, Mudanjiang, 157011, People's Republic of China.
Hongqi People Hospital, Mudanjiang Medical University, Mudanjiang, 157011, People's Republic of China.
Int J Nanomedicine. 2025 Mar 20;20:3671-3695. doi: 10.2147/IJN.S507458. eCollection 2025.
This study pioneers a pH-responsive core-shell nanoplatform integrating magnetic FeO-hydroxyapatite (Fe/HAP) with polysuccinimide (PSI) polymer, engineered to enhance tumor-targeted delivery of fluorouracil (5-FU) for liver cancer therapy.
The individual components-hydroxyapatite (HAP), magnetite (FO), iron-doped hydroxyapatite (Fe/HAP), and polysuccinimide (PSI)-were synthesized and systematically characterized through Fourier-transform infrared (FTIR) spectroscopy and scanning electron microscopy (SEM). Through a combination of single-factor experiments and Box-Behnken design (BBD) response surface methodology, the formulation parameters were optimized for two nanoparticle systems: (1) non-magnetic 5-FU-loaded PSI-HAP (designated as 5-FU@DC, where DC denotes "drug carrier") and (2) magnetic-targeted formulations 5-FU@PSI-Fe/HAP with varying iron content (5-FU@FeDC20, 5-FU@FeDC30, 5-FU@FeDC40). The engineered nanoparticles were thoroughly characterized for their morphological characteristics, hydrodynamic properties (particle size distribution and zeta potential), magnetic responsiveness (vibrating sample magnetometry), and pH-dependent drug release profiles. Nile Red was used to label the drug-loaded nanoparticles, and small animal imaging technology was employed to track their distribution in mice in vivo. Furthermore, in vitro studies examined the effects of these formulations on the proliferation, apoptosis, and migration of Huh-7 liver cancer cells.
The formulations (5-FU@DC and 5-FU@FeDC) were found to form uniform spherical or near-spherical nanoparticles. Vibrating sample magnetometer (VSM) analysis confirmed that the 5-FU@FeDC formulations displayed paramagnetic properties. Zeta potential measurements showed that all prepared systems had negative charges, similar to human biological membranes. All nanoparticles gradually released the drug at pH levels above 5, with the release rate increasing as the pH increased. Compared to the non-magnetic 5-FU@DC formulation, the magnetic 5-FU@FeDC formulations showed significantly longer distribution and retention times in liver tissue and more effectively inhibited the proliferation of Huh-7 cells.
The current study developed a magnetic targeting nano-delivery system using PSI and Fe/HAP as formulation excipients. The system offers uniform particle size, a simple preparation process, and a cost-effective method for targeted drug delivery. It is not only suitable for liver-targeted drug delivery but also applicable for drug delivery to other tissues in the body for anti-tumor drugs.
本研究开创了一种pH响应性核壳纳米平台，该平台将磁性FeO-羟基磷灰石（Fe/HAP）与聚琥珀酰亚胺（PSI）聚合物相结合，旨在增强氟尿嘧啶（5-FU）对肝癌的靶向递送用于肝癌治疗。
合成了各个组分——羟基磷灰石（HAP）、磁铁矿（FO）、铁掺杂羟基磷灰石（Fe/HAP）和聚琥珀酰亚胺（PSI），并通过傅里叶变换红外光谱（FTIR）和扫描电子显微镜（SEM）进行了系统表征。通过单因素实验和Box-Behnken设计（BBD）响应面方法相结合，对两种纳米颗粒系统的配方参数进行了优化：（1）非磁性载5-FU的PSI-HAP（命名为5-FU@DC，其中DC表示“药物载体”）和（2）具有不同铁含量的磁性靶向制剂5-FU@PSI-Fe/HAP（5-FU@FeDC20、5-FU@FeDC30、5-FU@FeDC40）。对制备的纳米颗粒进行了全面表征，包括其形态特征、流体动力学性质（粒径分布和zeta电位）、磁响应性（振动样品磁强计）和pH依赖性药物释放曲线。尼罗红用于标记载药纳米颗粒，并采用小动物成像技术追踪其在小鼠体内的分布。此外，体外研究考察了这些制剂对Huh-7肝癌细胞增殖、凋亡和迁移的影响。
发现制剂（5-FU@DC和5-FU@FeDC）形成均匀的球形或近球形纳米颗粒。振动样品磁强计（VSM）分析证实5-FU@FeDC制剂表现出顺磁性。zeta电位测量表明，所有制备的系统都带负电荷，与人体生物膜相似。所有纳米颗粒在pH值高于5时逐渐释放药物，释放速率随pH值升高而增加。与非磁性5-FU@DC制剂相比，磁性5-FU@FeDC制剂在肝组织中的分布和保留时间明显更长，并且更有效地抑制了Huh-7细胞的增殖。
本研究开发了一种以PSI和Fe/HAP为配方辅料的磁性靶向纳米递送系统。该系统具有粒径均匀、制备工艺简单且靶向药物递送成本效益高的特点。它不仅适用于肝靶向药物递送，也适用于体内其他组织的抗肿瘤药物递送。
