Wenhui Zhang,1 Qiang Wang,2 Fengguo Zhai,1 Xingjun Fan,3 Fanqin Meng,1 Guangzhi Shen,1 Ying Zhu,1 Jingdan Cao,1 Fengbo Yu1 

1School of Pharmacy, Mudanjiang Medical University, Mudanjiang, 157011, People’s Republic of China; 2Hongqi People Hospital, Mudanjiang Medical University, Mudanjiang, 157011, People’s Republic of China; 3School of Public Health, Mudanjiang Medical University, Mudanjiang, 157011, People’s Republic of China

Correspondence: Fengbo Yu, School of Pharmacy, Mudanjiang Medical University, Mudanjiang, 157011, People’s Republic of China, Email yfb526@126.com

Objective: This study pioneers a pH-responsive core-shell nanoplatform integrating magnetic Fe3O4-hydroxyapatite (Fe/HAP) with polysuccinimide (PSI) polymer, engineered to enhance tumor-targeted delivery of fluorouracil (5-FU) for liver cancer therapy.
Methods: The individual components—hydroxyapatite (HAP), magnetite (F3O4), 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.
Results: 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.
Conclusion: 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.

Keywords: magnetic nanocarriers, Fe3O4-hydroxyapatite core, polysuccinimide coating, fluorouracil, liver cancer