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Theranostics 2022; 12(4):1800-1815. doi:10.7150/thno.68459 This issue Cite

Research Paper

Re-engineering the inner surface of ferritin nanocage enables dual drug payloads for synergistic tumor therapy

Zhuoran Wang^1#, Yue Zhao^1,2#, Shuai Zhang^1,2, Xuehui Chen¹, Guoming Sun⁴, Baoli Zhang^1,2, Bing Jiang³, Yili Yang⁵, Xiyun Yan^1,2,3✉, Kelong Fan^1,2,3✉

1. CAS Engineering Laboratory for Nanozyme, Key Laboratory of Protein and Peptide, Pharmaceutical Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, P. R. China.
2. University of Chinese Academy of Sciences, Beijing, 101408, P. R. China.
3. Nanozyme Medical Center, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, P. R. China.
4. Nanjing Nanozyme Tech Co., Ltd., Nanjing, 211500, P. R. China.
5. China Regional Research Center, International Center for Genetic Engineering and Biotechnology, Taizhou, 225312, P. R. China.
#These authors contributed equally to this article.

✉ Corresponding authors: Xiyun Yan and Kelong Fan; CAS Engineering Laboratory for Nanozyme, Key Laboratory of Protein and Peptide, Pharmaceutical Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, P. R. China. E-mail: yanxyac.cn, fankelongac.cn; Tel: +8601064888584 (Xiyun Yan), +8601064888280 (Kelong Fan). More

Abstract

Rationale: With the advantages of tumor-targeting, pH-responsive drug releasing, and biocompatibility, ferritin nanocage emerges as a promising drug carrier. However, its wide applications were significantly hindered by the low loading efficiency of hydrophobic drugs. Herein, we redesigned the inner surface of ferritin drug carrier (ins-FDC) by fusing the C- terminus of human H ferritin (HFn) subunit with optimized hydrophobic peptides.

Methods: Hydrophobic and hydrophilic drugs were encapsulated into the ins-FDC through the urea-dependent disassembly/reassembly strategy and the natural drug entry channel of the protein nanocage. The morphology and drug loading/releasing abilities of the drug-loaded nanocarrier were then examined. Its tumor targeting character, system toxicity, application in synergistic therapy, and anti-tumor action were further investigated.

Results: After optimization, 39 hydrophobic Camptothecin and 150 hydrophilic Epirubicin were encapsulated onto one ins-FDC nanocage. The ins-FDC nanocage exhibited programed drug release pattern and increased the stability and biocompatibility of the loaded drugs. Furthermore, the ins-FDC possesses tumor targeting property due to the intrinsic CD71-binding ability of HFn. The loaded drugs may penetrate the brain blood barrier and accumulate in tumors in vivo more efficiently. As a result, the drugs loaded on ins-FDC showed reduced side effects and significantly enhanced efficacy against glioma, metastatic liver cancer, and chemo-resistant breast tumors.

Conclusions: The ins-FDC nanocarrier offers a promising novel means for the delivery of hydrophobic compounds in cancer treatments, especially for the combination therapies that use both hydrophobic and hydrophilic chemotherapeutics.

Keywords: re-design of ferritin nanocage, inner surface engineering, hydrophobic drugs loading, dual drug payloads, synergistic tumor therapy

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