In vitro Nasal Cell Culture Systems for Drug Transport Studies

조현종,Ubonvan Termsarasab,김정선,김대덕 한국약제학회 2010 Journal of Pharmaceutical Investigation Vol.40 No.6

Growing interest in the nasal route as a drug delivery system calls for a reliable in vitro model which is crucial for efficiently evaluating drug transport through the nasal cells. Various in vitro cell culture systems has thus been developed to displace the ex vivo excised nasal tissue and in vivo animal models. Due to species difference, results from animal studies are not sufficient for estimating the drug absorption kinetics in humans. However, the difficulty in obtaining reliable human tissue source limits the use of primary culture of human nasal epithelial cells. This shortage of human nasal tissue has therefore prompted studies on the “passage” culture of nasal epithelial cells. A serially passaged primary human nasal epithelial cell monolayer system developed by the air-liquid interface (ALI) culture is known to promote the differentiation of cilia and mucin gene and maintain high TEER values. Recent studies on the in vitro nasal cell culture systems for drug transport studies are reviewed in this article.

Preparation and characterization of self-assembled nanoparticles based on low-molecular-weight heparin and stearylamine conjugates for controlled delivery of docetaxel

Kim, Dong-Hwan,Termsarasab, Ubonvan,Cho, Hyun-Jong,Yoon, In-Soo,Lee, Jae-Young,Moon, Hyun Tae,Kim, Dae-Duk Dove Medical Press 2014 International journal of nanomedicine Vol.9 No.-

<P>Low-molecular-weight heparin (LMWH)–stearylamine (SA) conjugates (LHSA)-based self-assembled nanoparticles were prepared for intravenous delivery of docetaxel (DCT). 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide and <I>N</I>-hydroxysuccinimide were used as coupling agents for synthesis of LHSA conjugates. The physicochemical properties, in vitro antitumor efficacy, in vitro cellular uptake efficiency, in vivo antitumor efficacy, and in vivo pharmacokinetics of LHSA nanoparticles were investigated. The LHSA nanoparticles exhibited a spherical shape with a mean diameter of 140–180 nm and a negative surface charge. According to in vitro release and in vivo pharmacokinetic test results, the docetaxel-loaded LHSA5 (LMWH:SA =1:5) nanoparticles exhibited sustained drug release profiles. The blank LHSA nanoparticles demonstrated only an insignificant cytotoxicity in MCF-7 and MDAMB 231 human breast cancer cells; additionally, higher cellular uptake of coumarin 6 (C6) in MCF-7 and MDAMB 231 cells was observed in the LHSA5 nanoparticles group than that in the C6 solution group. The in vivo tumor growth inhibition efficacy of docetaxel-loaded LHSA5 nanoparticles was also significantly higher than the Taxotere<SUP>®</SUP>-treated group in the MDAMB 231 tumor-xenografted mouse model. These results indicated that the LHSA5-based nanoparticles could be a promising anticancer drug delivery system.</P>

Hyaluronic Acid in Drug Delivery Systems

Jin, Yu-Jin,Ubonvan, Termsarasab,Kim, Dae-Duk The Korean Society of Pharmaceutical Sciences and 2010 Journal of Pharmaceutical Investigation Vol.40 No.special

Hyaluronic acid (HA) is a biodegradable, biocompatible, non-toxic, non-immunogenic and non-inflammatory linear polysaccharide, which has been used for various medical applications including arthritis treatment, wound healing, ocular surgery, and tissue augmentation. Because of its mucoadhesive property and safety, HA has received much attention as a tool for drug delivery system development. It has been used as a drug delivery carrier in both nonparenteral and parenteral routes. The nonparenteral application includes the ocular and nasal delivery systems. On the other hand, its use in parenteral systems has been considered important as in the case of sustained release formulation of protein drugs through subcutaneous injection. Particles and hydrogels by various methods using HA and HA derivatives as well as by conjugation with other polymer have been the focus of many studies. Furthermore, the affinity of HA to the CD44 receptor which is overexpressed in various tumor cells makes HA an important means of cancer targeted drug delivery. Current trends and development of HA as a tool for drug delivery will be outlined in this review.

Chemosensitizing indomethacin-conjugated chitosan oligosaccharide nanoparticles for tumor-targeted drug delivery

Lee, Jae-Young,Termsarasab, Ubonvan,Lee, Mee Yeon,Kim, Dong-Hwan,Lee, Song Yi,Kim, Jung Sun,Cho, Hyun-Jong,Kim, Dae-Duk Elsevier Science B.V. Amsterdam 2017 ACTA BIOMATERIALIA Vol. No.

<P><B>Abstract</B></P> <P>A chitosan oligosaccharide (CSO)-indomethacin (IDM) conjugate (CI) was synthesized to fabricate chemosensitizing nanoparticles (NPs) for tumor-targeted drug delivery. IDM was conjugated to a CSO backbone <I>via</I> amide bond formation, of which successful synthesis was confirmed by proton-nuclear magnetic resonance analyses. Doxorubicin (DOX)-loaded CI (CI10/DOX; CI:DOX=10:1 [w/w]) NPs with <75nm of mean diameter, polydispersity index of ∼0.2, and positive zeta potential were prepared. The release of DOX from the NPs was enhanced at acidic pH (pH 5.5 and 6.8) compared to physiological pH (pH 7.4). The release of IDM increased in the presence of A549 cell lysates. In A549 cells (human lung carcinoma cells), more efficient cellular uptake of CI10/DOX NPs than that of free DOX was observed by using confocal laser scanning microscopy and flow cytometry. The <I>in vitro</I> cytotoxicity of CI10/DOX NPs in A549 cells was higher than those of free DOX and CI NPs with free DOX groups. <I>In vivo</I> pharmacokinetic studies after intravenous administration in rats showed significantly lower clearance of DOX from NPs compared with the free DOX group. Tumor targetability of the developed CI NPs was also verified by a real-time optical imaging study. In summary, the chemosensitizing CI/DOX NP with enhanced anticancer activity, prolonged blood circulation, and passive tumor targeting can be a promising anticancer drug delivery system for tumor-targeted therapy.</P> <P><B>Statement of Significance</B></P> <P>Chemosensitizing nanoparticles (NPs) based on amphiphilic chitosan oligosaccharide-indomethacin (CSO-IDM; CI) conjugate were developed for tumor-targeted delivery of doxorubicin (DOX). IDM was introduced to the CSO backbone as a hydrophobic residue to synthesize an amphiphilic conjugate and a chemosenstizer of DOX for improving antitumor efficacies. IDM, conjugated to CSO, may inhibit the efflux of cellular uptaken DOX via multidrug resistance-associated protein (MRP) and subsequently augment the anti-proliferation potentials of DOX in A549 cells (MRP-expressed human lung cancer cells). Chemosensitizing properties of developed CI NPs were assessed in cell culture models and the tumor targetability of CI/DOX NPs was demonstrated in A549 tumor-xenografted mouse model by a real-time optical imaging. Developed CI NPs can be used as a multifunctional nanosystem for the therapy of MRP-expressed cancers.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

In vitro Nasal Cell Culture Systems for Drug Transport Studies

Cho, Hyun-Jong,Termsarasab, Ubonvan,Kim, Jung-Sun,Kim, Dae-Duk The Korean Society of Pharmaceutical Sciences and 2010 Journal of Pharmaceutical Investigation Vol.40 No.6

Growing interest in the nasal route as a drug delivery system calls for a reliable in vitro model which is crucial for efficiently evaluating drug transport through the nasal cells. Various in vitro cell culture systems has thus been developed to displace the ex vivo excised nasal tissue and in vivo animal models. Due to species difference, results from animal studies are not sufficient for estimating the drug absorption kinetics in humans. However, the difficulty in obtaining reliable human tissue source limits the use of primary culture of human nasal epithelial cells. This shortage of human nasal tissue has therefore prompted studies on the "passage" culture of nasal epithelial cells. A serially passaged primary human nasal epithelial cell monolayer system developed by the air-liquid interface (ALI) culture is known to promote the differentiation of cilia and mucin gene and maintain high TEER values. Recent studies on the in vitro nasal cell culture systems for drug transport studies are reviewed in this article.

Hyaluronic acid derivative-based self-assembled nanoparticles for the treatment of melanoma.

Jin, Yu-Jin,Termsarasab, Ubonvan,Ko, Seung-Hak,Shim, Jae-Seong,Chong, Saeho,Chung, Suk-Jae,Shim, Chang-Koo,Cho, Hyun-Jong,Kim, Dae-Duk Kluwer Academic/Plenum Publishers 2012 Pharmaceutical research Vol.29 No.12

<P>Hyaluronic acid-ceramide (HACE)-based nanoparticles (NPs) were developed for the targeted delivery of doxorubicin (DOX), and their antitumor efficacy for melanoma was evaluated.</P>

Development of Polyethylene Glycol-Conjugated Chitosan Oligosaccharide Derivative-Stabilized Gold Nanoassemblies

Cho, Hyun-Jong,Termsarasab, Ubonvan,Lee, Song Yi,Maeng, Han-Joo,Kim, Dae-Duk,Yoon, In-Soo American Scientific Publishers 2017 Journal of Nanoscience and Nanotechnology Vol.17 No.4

<P>Gold nanoassemblies (AuNAs) stabilized by chitosan oligosaccharide (CSO), chitosan oligosaccharide-arachidic acid (CSOAA), and chitosan oligosaccharide-arachidic acid-polyethylene glycol (CSOAA-PEG) were fabricated and evaluated. CSOAA was synthesized by amide bond formation between CSO and arachidic acid (AA), and CSOAA-PEG was then prepared by amide bond formation between CSOAA and methoxypolyethylene glycol succinimidyl succinate (mPEGSS). All AuNAs, such as CSO-stabilized AuNA (C/AuNA), CSOAA-stabilized AuNA (CA/AuNA), and CSOAA-PEG-stabilized AuNA (CAPE/AuNA), exhibited < 150 nm hydrodynamic size in the aqueous environment. Unlike C/AuNA and CA/AuNA groups, CAPE/AuNA exhibited similar particle size in aqueous buffer and serum conditions as well as in water. The results of surface plasmon resonance (SPR) measurement provided corresponded particle size of all AuNA groups, which determined by an electrophoretic light scattering (ELS) method. Developed AuNAs also did not show serious cytotoxicity in A549 (human lung adenocarcinoma) and U87-MG (human glioblastoma) cells within tested Au concentration range. Conclusively, CAPE can be used for the fabrication of hybrid AuNAs which are stable in the blood stream.</P>