Biotechnology and Bioprocess Engineering 2024; 29(2): 303-312  
Development of Tat‑fused drug binding protein to improve anti‑cancer effect of mammalian target of rapamycin inhibitors
Su Yeon Lim1 · Sugyeong Kim1 · Hongbin Kim1 · Hyun‑Ouk Kim1,2 · Suk‑Jin Ha1,2 · Kwang Suk Lim1,2
1 Department of Smart Health Science and Technology, Kangwon National University, Chuncheon 24341, Korea
2 Department of Biotechnology and Bioengineering, College of ACE, Kangwon National University, Chuncheon 24341, Korea
Correspondence to: Kwang Suk Lim
kslim@kangwon.ac.kr

Su Yeon Lim and Sugyeong Kim have contributed equally to this study as the first authors.
Received: August 24, 2023; Revised: November 15, 2023; Accepted: December 4, 2023; Published online: February 13, 2024.
© The Korean Society for Biotechnology and Bioengineering. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
The mammalian target of rapamycin (mTOR) is known to regulate cell growth, protein stability and cell-cycle progression, and many human tumors result from the dysregulation of mTOR signaling. Although various mTOR inhibitors have been developed, effective delivery systems are still needed to enhance the anti-cancer effects of mTOR inhibitors. In this study, we developed the Tat-fused mTOR inhibitor binding domain (Tat-MBD/TMBD) for the enhancement of the anti-cancer effect of mTOR inhibitors, due to the improvement of intracellular uptake. A TMBD/mTOR inhibitors complex spontaneously formed by biological affinity between MBD and mTOR inhibitors without chemical conjugation and modification. We constructed that a recombinant fusion protein expression vector composed of Tat (protein transduction domain) and mTOR inhibitor-binding domain (Tat-MBD) to deliver the mTOR inhibitors. The MBD spontaneously bound with mTOR inhibitors including sirolimus, everolimus, and temsirolimus, resulting in the formation of a TMBD/mTOR inhibitors complex. The enhancement of the delivery efficacy of mTOR inhibitors into various breast cancer cells was confirmed and improved anti-cancer efficacy was observed. We demonstrated the effective delivery systems of mTOR inhibitors without chemical conjugation of mTOR inhibitors.
Keywords: Mammalian target of rapamycin inhibitors · Recombinant fusion protein · Protein transduction domains · Self-assemble


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