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Bile acid transporter mediated endocytosis of oral bile acid conjugated nanocomplex
Park, Jooho,Choi, Jeong Uk,Kim, Kwangmeyung,Byun, Youngro Elsevier 2017 Biomaterials Vol.147 No.-
<P><B>Abstract</B></P> <P>The development of highly funtional and orally available nanoparticles is the ultimate goal in nanoparticle delivery. Various functional nanoparticles have been studied to that end but there has yet to be an oral nanoparticle that can be successfully applied. Here, we describe for the first time a novel bile acid conjugated nanoparticle that can be selectively absorbed by bile acid transporters in the small intestine. The bile acid conjugate nanoparticles that were first treated with enterocytes were successfully attached to the cell surface and then internalized inside the cells. We show that bile acid based interaction between a nanoparticle and its transporter induces its endocytosis and cellular uptake. This feature of cellular activity, described here for the first time, could be well utilized in the uptake of nanoparticles or macromolecules inside epithelial cells for oral delivery. In animal studies, bile acid conjugated self-assembling nanocomplexes successfully interacted with bile acid transporters in the ileum and were subsequently taken up into the epithelial cells. Considering the importance of orally deliverable nanoparticles, this nanotechnology using bile acid conjugation and transporter mediated endocytosis could be a crucial method for the successful application of various nanoparticles.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Senotherapeutics and Their Molecular Mechanism for Improving Aging
Park Jooho,Shin Dong Wook 한국응용약물학회 2022 Biomolecules & Therapeutics(구 응용약물학회지) Vol.30 No.6
Aging is defined as physiological dysfunction of the body and a key risk factor for human diseases. During the aging process, cellular senescence occurs in response to various extrinsic and intrinsic factors such as radiation-induced DNA damage, the activation of oncogenes, and oxidative stress. These senescent cells accumulate in many tissues and exhibit diverse phenotypes, such as resistance to apoptosis, production of senescence-associated secretory phenotype, cellular flattening, and cellular hypertrophy. They also induce abnormal dysfunction of the microenvironment and damage neighboring cells, eventually causing harmful effects in the development of various chronic diseases such as diabetes, cancer, and neurodegenerative diseases. Thus, pharmacological interventions targeting senescent cells, called senotherapeutics, have been extensively studied. These senotherapeutics provide a novel strategy for extending the health span and improving age-related diseases. In this review, we discuss the current progress in understanding the molecular mechanisms of senotherapeutics and provide insights for developing senotherapeutics.
Park, Jooho,Jeong, Jee-Heon,Al-Hilal, Taslim A.,Kim, Ji-young,Byun, Youngro American Chemical Society 2015 Bioconjugate chemistry Vol.26 No.5
<P>Heparin is a highly sulfated, long, and linear polysaccharide, which can inhibit tumor growth by interacting with growth factors such as bFGF and VEGF. Several researchers have shown the anti-angiogenic effect of heparin and its conjugates in relation to growth factor inhibition. For drug development and inhibition of growth factors using heparin conjugates, the molecular size of heparin may be crucial considering the size of the heparin binding site of growth factors. In this study, we synthesized heparin fragments and deoxycholic acid conjugated heparin fragments (HFD) to search for the optimal Size-controlled conjugate that will inhibit the angiogenic effect of VEGF(165). We have also shown that the HFDs could have an enhanced therapeutic effect in vitro and in vivo consequent to the molecular size control. HFDs have significant anti-angiogenic:effects by blocking the angiogenic activity of VEGF(165) depending on its molecular size. Among them, HFD2 was a promising Candidate for oral angiogenesis inhibitor. These results suggest that size-controlled synthesis is necessary for heparin-based drug development.</P>
Park, Jooho,Al-Hilal, Taslim A.,Jeong, Jee-Heon,Choi, Jeong uk,Byun, Youngro American Chemical Society 2015 Bioconjugate chemistry Vol.26 No.8
<P>Regulation of cholesterol and bile acid homeostasis has been attracting attention as a pharmaceutical target for the treatment of diseases, such as hypercholesterolaemia and type 2 diabetes. In recent years, small bile acid analogues have been developed for the purpose of apical sodium-dependent bile acid transporter (ASBT) inhibition. Here, we designed a novel hydrophilic ASBT inhibitor using oligomeric bile acid with a high affinity with ASBT. Polyacrylic acid-tetraDOCA conjugates (PATD) have the ability to bind to ASBT in order to induce hypocholesterolemic effects. Both the viability and the functionality of PATD were evaluated in vitro, showing that PATDs were effective in inhibiting the increases of cholesterol in the blood and oil in the liver induced by high fat diet (HFD). The results indicated that the newly developed biomaterials with oligomeric bile acids and a hydrophilic polymer are potent therapeutic agents for hyperlipidemia.</P>
Park, Jooho,Hwang, Seung Rim,Choi, Jeong Uk,Alam, Farzana,Byun, Youngro Elsevier/North Holland 2018 International journal of pharmaceutics Vol.535 No.1
<P><B>Abstract</B></P> <P>Heparin-like sulfated polysaccharides are potential drug candidates owing to their ability to interact with angiogenic factors and inhibit angiogenesis, tumor growth, and metastasis. This study aimed to improve the delivery of heparin-like anticancer polysaccharides for accumulation at the tumor site. We designed a nanocarrier system using protamine attached to polyethylene glycol (PEG) and evaluated the stability, tumor targeting, and tumor growth inhibition of the nanocarrier loaded with heparin derivatives. When mixed with various polyanionic heparin derivatives, the polycationic PEG–protamine formed stable self-assembled nanocomplexes via ionic interactions, with flexible PEG chains located on the outside. Among the complexes, a nanocomplex loaded with a low-molecular-weight heparin–suramin conjugate (LHsura) had the most suitable average size (101.9nm) for the enhanced permeability and retention effect and allowed accumulation of LHsura at the tumor site for up to 48h. In a tumor-bearing mouse model, the PEG–protamine and LHsura nanocomplex (10mg/kg/3days, intravenously), which could be extravasated through the tumor vasculature, significantly inhibited tumor growth, more than LHsura alone did. Overall, the self-assembled nanocomplexation of PEG–protamine and LHsura helped control the release and extravasation of LHsura, which resulted in an antitumor effect on the target tumor cells.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Recent advances in anticoagulant drug delivery
Park, Jooho,Byun, Youngro Informa UK (Ashley Publications) 2016 Expert opinion on drug delivery Vol.13 No.3
<P>Introduction: Anticoagulants have been prescribed to patients to prevent deep vein thrombosis or pulmonary embolism. However, because of several problems in anticoagulant therapy, much attention has been directed at developing an ideal anticoagulant, and numerous attempts have been made to develop new anticoagulant delivery systems in recent years. Areas covered: This review discusses the challenges associated with the recent development of anticoagulants and their delivery systems. Various delivery methods have been developed to improve the use of anticoagulants. Recent advances in anticoagulant delivery and antidote development are also discussed in the context of their current progression states. Expert opinion: There have been many different approaches to developing the delivery system of anticoagulants. One approach has been to expand the use of new oral agents and develop their antidotes. Reducing the size of heparins to use smaller heparins for delivery, and developing oral or topical heparins are also some of the approaches used. Various physical formulations or chemical modifications are other ways that have enhanced the therapeutic potential of anticoagulant agents. On the whole, recent advances have contributed to increasing the efficacy and safety of anticoagulant clinically and have benefited the field of anticoagulant delivery.</P>