N-Succinyl-chitosan nanoparticles coupled with low-density lipoprotein for targeted osthole-loaded delivery to low-density lipoprotein receptor-rich tumors

Chun-ge Zhang,*^,1 Qiao-ling Zhu,*^,1 Yi Zhou,*^,1,2 Yang Liu,¹ Wei-liang Chen,¹ Zhi-Qiang Yuan,¹ Shu-di Yang,¹ Xiao-feng Zhou,^3,4 Ai-jun Zhu,¹ Xue-nong Zhang,*^,1 Yong Jin*<sup>,5

1</sup>Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou, ²The Children's Hospital of Wuxi People's Hospital, Nanjing Medical University, Wuxi, ³College of Radiological Medicine and Protection, Soochow University, Suzhou, ⁴Changshu Hospital of Traditional Chinese Medicine, Changshu, ⁵Invasive Technology Department, The Second Affiliated Hospital of Soochow University, Suzhou, People's Republic of China
  
*These authors contributed equally to this work

Abstract: N-Succinyl-chitosan (NSC) was synthesized and NSC nanoparticles (NPs) with loaded osthole (Ost) (Ost/NSC-NPs) were prepared by emulsion solvent diffusion. Subsequently, low-density lipoprotein (LDL)-mediated NSC-NPs with loaded Ost (Ost/LDL-NSC-NPs) were obtained by coupling LDL with Ost/NSC-NPs through amide linkage. The average particle size of Ost/NSC-NPs was approximately 145 nm, the entrapment efficiency was 78.28%±2.06%, and the drug-loading amount was 18.09%±0.17%. The release of Ost from Ost/NSC-NPs in vitro showed a more evident sustained effect than the native material. The half maximal inhibitory concentration of Ost/LDL-NSC-NPs was only 16.23% that of the free Ost at 24 hours in HepG2 cells. Ost inhibited HepG2 cell proliferation by arresting cells in the synthesis phase of the cell cycle and by triggering apoptosis. Cellular uptake and subcellular localization in vitro and near-infrared fluorescence real-time imaging in vivo showed that Ost/LDL-NSC-NPs had high targeting efficacy. Therefore, LDL-NSC-NPs are a promising system for targeted Ost delivery to liver tumor.

Keywords: liver cancer, targeting efficacy, antitumor activity

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