한빛사 논문
Abstract
Jae Og Jeon†¶ , Soyoun Kim †¶ , Eunsu Choi ‡, Kihyuk Shin ‡, Kiweon Cha §, In-Seop So †, Sun-Ji Kim †, Eunsung Jun †⊥, Dohee Kim †, Hyung Jun Ahn⊥ , Byung-Heon Lee †, Seung-Hyo Lee ‡*, and In-San Kim †⊥*
† Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea
‡ Graduate School of Medical Science and Engineering, Biomedical Research Center, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea
§ Division of High-Risk Pathogen Research, Korea National Institute of Health (KNIH), Korea Centers for Disease Control & Prevention (KCDC), Osong, Chungbuk 363-951, Republic of Korea
⊥Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea
*Address correspondence to : Seung-Hyo Lee, In-San Kim
¶ J. O. Jeon and S. Kim contributed equally to this work.
Abstract
Protein-cage nanoparticles are promising multifunctional platforms for targeted delivery of imaging and therapeutic agents owing to their biocompatibility, biodegradability, and low toxicity. The major advantage of protein-cage nanoparticles is the ability to decorate their surfaces with multiple functionalities through genetic and chemical modification to achieve desired properties for therapeutic and/or diagnostic purposes. Specific peptides identified by phage display can be genetically fused onto the surface of cage proteins to promote the association of nanoparticles with a particular cell type or tissue. Upon symmetrical assembly of the cage, peptides are clustered on the surface of the cage protein in bunches. The resulting PBNC (peptide bunches on nanocage) offers the potential of synergistically increasing the avidity of the peptide ligands, thereby enhancing their blocking ability for therapeutic purposes. Here, we demonstrated a proof-of-principle of PBNCs, fusing the interleukin-4 receptor (IL-4R)-targeting peptide, AP-1, identified previously by phage display, with ferritin-L-chain (FTL), which undergoes 24-subunit assembly to form highly stable AP-1-containing nanocage proteins (AP1-PBNCs). AP1-PBNCs bound specifically to the IL-4R-expressing cell line, A549, and their binding and internalization were specifically blocked by anti-IL-4R antibody. AP1-PBNCs exhibited dramatically enhanced binding avidity to IL-4R compared with AP-1 peptide, measured by surface plasmon resonance spectroscopy. Furthermore, treatment with AP1-PBNCs in a murine model of experimental asthma diminished airway hyper-responsiveness and eosinophilic airway inflammation along with decreased mucus hyperproduction. These findings hold great promise for the application of various PBNCs with ligand-specific peptides in therapeutics for different diseases, such as cancer.
Keywords: protein cage; nanoparticles; AP-1 peptide; IL-4 receptor; asthma
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