박주호 (건국대학교)

한빛사논문

조회283

건국대학교

CV File 139 kb

Biomaterials, Mar 24 2024, 308 S0142-9612(24)00073-5 | https://doi.org/10.1016/j.biomaterials.2024.122539 Design and development of novel self-assembled catechol-modified bile acid conjugates as pH-responsive apical sodium-dependent bile acid transporter targeting nanoparticles

Dong-Nyeong Lee ^a,1, Seong-Bin Yang ^a,1, Seho Kweon ^b,c,1, Jun-Hyuck Lee ^a, Kyeong-Ju Lee ^a, Yeonsu Ryu ^d, Dong Wook Shin ^e, Young Jun Kim ^d, Yong-Kyu Lee^f, Jooho Park ^a,d

^aBK21 Program, Department of Applied Life Science, Konkuk University, Chungju, 27478, Republic of Korea

^bDepartment of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, Republic of Korea

^cCollege of Pharmacy, Research Institute of Pharmaceutical Sciences, Chonnam National University, Gwangju, 61186, Republic of Korea

^dDepartment of Biomedical Chemistry, College of Biomedical and Health Science, Konkuk University, Chungju, 27478, Republic of Korea

^eCollege of Biomedical and Health Science, Konkuk University, Chungju, 27478, Republic of Korea

^fDepartment of Green Bio Engineering, Graduate School, Korea National University of Transportation, Chungju, 27469, Republic of Korea

¹These authors contributed equally to this work.

Corresponding authors: Yong-Kyu Lee, Jooho Park

Abstract

Catechol-based biomaterials demonstrate biocompatibility, making them suitable for a wide range of therapeutic applications when integrated into various molecular frameworks. However, the development of orally available catechol-based biomaterials has been hindered by significant pH variations and complex interactions in the gastrointestinal (GI) tract. In this study, we introduce a novel catechol-modified bile acid (CMBA), which is synthesized by anchoring the FDA-approved drug, ursodeoxycholic acid to the neurotransmitter dopamine. This modification could form a new apical sodium-dependent bile acid transporter (ASBT) inhibitor (ASBTi) due to the bile acid moiety. The computational analysis using the TRAnsient Pockets in Proteins (TRAPP) module, coupled with MD simulations, revealed that CMBA exhibits a strong binding affinity at residues 51-55 of ASBT with a low inhibitory constant (Ki) value. Notably, in slightly alkaline biological conditions, CMBA molecules self-assemble into carrier-free nanoparticles with an average size of 240.2 ± 44.2 nm, while maintaining their ability to bind with ASBT. When administered orally, CMBA accumulates in the ileum and liver over 24 h, exhibiting significant therapeutic effects on bile acid (BA) metabolism in a high-fat diet (HFD)-fed mouse model. This study underscores the therapeutic potential of the newly developed catechol-based, pH-responsive ASBT-inhibiting nanoparticles presenting a promising avenue for advancing therapy.

논문정보

형식Research article
게재일2024년 03월 (BRIC 등록일 2024-04-01)
연구진국내 연구진
분야 바이오·의료융합 > 바이오센싱 및 나노바이오물질

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