Tandem-multimeric F3-gelonin fusion toxins for enhanced anti-cancer activity for prostate cancer treatment

Shin, Meong Cheol,Min, Kyoung Ah,Cheong, Heesun,Moon, Cheol,Huang, Yongzhuo,He, Huining,Yang, Victor C. Elsevier/North Holland 2017 International journal of pharmaceutics Vol.524 No.1

<P><B>Abstract</B></P> <P>Despite significant progress in prostate cancer treatment, yet, it remains the leading diagnosed cancer and is responsible for high incidence of cancer related deaths in the U.S. Because of the insufficient efficacy of small molecule anti-cancer drugs, significant interest has been drawn to more potent macromolecular agents such as gelonin, a plant-derived ribosome inactivating protein (RIP) that efficiently inhibits protein translation. However, in spite of the great potency to kill tumor cells, gelonin lacks ability to internalize tumor cells and furthermore, cannot distinguish between tumor and normal cells. To address this challenge, we genetically engineered gelonin fusion proteins with varied numbers of F3 peptide possessing homing ability to various cancer cells and angiogenic blood vessels. The <I>E. coli</I> produced F3-gelonin fusion proteins possessed equipotent activity to inhibit protein translation in cell-free protein translation systems to unmodified gelonin; however, they displayed higher cell uptake that led to significantly augmented cytotoxicity. Compared with gelonin fusion with one F3 peptide (F3-Gel), tandem-multimeric F3-gelonins showed even greater cell internalization and tumor cell killing ability. Moreover, when tested against LNCaP <I>s.c.</I> xenograft tumor bearing mice, more significant tumor growth inhibition was observed from the mice treated with tandem-multimeric F3-gelonins. Overall, this research demonstrated the potential of utilizing tandem multimeric F3-modified gelonin as highly effective anticancer agents to overcome the limitations of current chemotherapeutic drugs.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Bioequivalence Evaluation of Two Brands of Lisinopril Tablets by in vitro Comparative Dissolution Test and in vivo Bioequivalence Test

Shin, Meong Cheol,Kim, JinKi,Kim, ChongKook Georg Thieme Verlag Stuttgart, New York 2008 Arzneimittel Forschung Vol.58 No.1

<P>The bioequivalence of a test formulation (Nanopril®, “test”) and a reference formulation (“reference”) of lisinopril (CAS 83915-83-7) was demonstrated by in vivo and in vitro tests. The in vivo bioequivalence study in 26 healthy volunteers was designed as a single dose, randomized, double-blind trial with a 2-week washout period between the doses. Prior to the in vivo study, an in vitro comparative dissolution test was performed by the paddle method following the bioequivalence guidance of the Korea Food and Drug Administration (KFDA). By the results of the dissolution test it was demonstrated from the similar and rapidly dissolving patterns of the two lisinopril tablets that the two formulations were pharmaceutically equivalent. However, the in vivo bioequivalence study was required to fully evaluate the bioequivalence of the two drug products. In the in vivo bioequivalence study, the plasma samples drawn from the volunteers were analyzed utilizing a sensitive LC-MS-MS analysis method and the bioequivalence between the two drug products was assessed by statistical analysis of the log transformed mean ratios of Cmax, AUC0–tand AUC0–∞. The mean maximum concentration (Cmax) of the test and reference were found to be 60.41 ± 20.07 ng/mL–1 and 61.11 ± 19.36 ng/mL, respectively. The 90% confidence intervals (C.I.) of Cmax were in the range from 0.91 to 1.08. As for the AUC0–t and the AUC0–∞, test values were 792.73 ± 273.41 ng · mL–1 · h, 862.74 ± 303.81 ng · mL–1 · h and the reference values were 841.66 ± 286.07 ng · mL–1 · h, 906.97 ± 318.72 ng · mL–1 · h, respectively. The 90% C. I. of AUC0–twere 0.86 to 1.01 and of AUC0–∞0.87 to 1.02 and thus were within the 80–125% interval proposed by the FDA. In addition to the 90% C. I. of the pharmaceutical parameters, a two-way ANOVA showed no significant difference between the two formulations. Based upon these statistical analyses, it was concluded that the test formulation is bioequivalent to the reference.</P>

Cell-penetrating peptide-based non-invasive topical delivery systems

Van Nguyen, Tru,Shin, Meong Cheol,Min, Kyoung Ah,Huang, Yongzhuo,Oh, Euichaul,Moon, Cheol Springer-Verlag 2018 Journal of Pharmaceutical Investigation Vol.48 No.1

Functional and cytometric examination of different human lung epithelial cell types as drug transport barriers

Kyoung Ah Min,Meong Cheol Shin,Gus R. Rosania,Chong Kook Kim 대한약학회 2016 Archives of Pharmacal Research Vol.39 No.3

To develop inhaled medications, various cell culture models have been used to examine the transcellular transport or cellular uptake properties of small molecules. For the reproducible high throughput screening of the inhaled drug candidates, a further verification of cell architectures as drug transport barriers can contribute to establishing appropriate in vitro cell models. In the present study, side-by-side experiments were performed to compare the structure and transport function of three lung epithelial cells (Calu-3, normal human bronchial primary cells (NHBE), and NL-20). The cells were cultured on the nucleopore membranes in the air–liquid interface (ALI) culture conditions, with cell culture medium in the basolateral side only, starting from day 1. In transport assays, paracellular transport across all three types of cells appeared to be markedly different with the NHBE or Calu- 3 cells, showing low paracellular permeability and high TEER values, while the NL-20 cells showed high paracellular permeability and low TEER. Quantitative image analysis of the confocal microscope sections further confirmed that the Calu-3 cells formed intact cell monolayers in contrast to the NHBE and NL-20 cells with multilayers. Among three lung epithelial cell types, the Calu-3 cell cultures under the ALI condition showed optimal cytometric features for mimicking the biophysical characteristics of in vivo airway epithelium. Therefore, the Calu-3 cell monolayers could be used as functional cell barriers for the lung-targeted drug transport studies.

Invited Mini Review : Transcutaneous antigen delivery system

( Mi Young Lee ),( Meong Cheol Shin ),( Victor C. Yang ) 생화학분자생물학회(구 한국생화학분자생물학회) 2013 BMB Reports Vol.46 No.1

Transcutaneous immunization refers to the topical application of antigens onto the epidermis. Transcutaneous immunization targeting the Langerhans cells of the skin has received much attention due to its safe, needle-free, and noninvasive antigen delivery. The skin has important immunological functions with unique roles for antigen-presenting cells such as epidermal Langerhans cells and dermal dendritic cells. In recent years, novel vaccine delivery strategies have continually been developed; however, transcutaneous immunization has not yet been fully exploited due to the penetration barrier represented by the stratum corneum, which inhibits the transport of antigens and adjuvants. Herein we review recent achievements in transcutaneous immunization, focusing on the various strategies for the enhancement of antigen delivery and vaccination efficacy. [BMB Reports 2013; 46(1): 17-24]

A self-assembly and stimuli-responsive fusion gelonin delivery system for tumor treatment

Quan Liu,Lu Zhang,Xiuru Ji,Meong Cheol Shin,Shuping Xie,Baoyan Pan,Fei Yu,Jingwen Zhao,Victor C. Yang 한국공업화학회 2020 Journal of Industrial and Engineering Chemistry Vol.89 No.-

Ribosome-inactivating proteins (RIPs) are potent protein toxins for cancer therapy, and they have strongability to inhibit protein synthesis and induce cell death via inactivation of ribosomes in eukaryotic cells. However, the delivery of RIPs has been a challenging task due to their large molecular weight and lack oftargeting property. Low molecular weight protamine (LMWP), a transmembrane peptide, has beenproved to effectively promote transmembrane transportation, whereas the enzyme-activatable systemcan enhance the specificity by enhancing the tumor drug concentration through enzymatic reaction. Weherein constructed a self-assembly and stimuli-responsive fusion gelonin delivery system. Gelonin, atypical RIP protein, was assembled with nickel ferrite nanoparticles by self-assembling between hexa-histidine tag (His-tagged) and nickel ions. Both in vitro and in vivo results indicated that the magneticnanoparticle carriers and the applied linkers did not damage the pharmaceutical effect of gelonin, andthe whole drug delivery system showed good biocompatibility, sensitive selectivity, and significantlyenhanced cytotoxic activity. This in turn presented theranostic nanoparticles as efficient delivery vehiclefor clinical use.

Evaluation of epithelial transport and oxidative stress protection of nanoengineered curcumin derivative-cyclodextrin formulation for ocular delivery

Pooja Maharjan,Minki Jin,Daseul Kim,JaeWook Yang,Anjila Maharjan,Meong Cheol Shin,Kwan Hyung Cho,김만수,Kyoung Ah Min 대한약학회 2019 Archives of Pharmacal Research Vol.42 No.10

Ocular drug delivery has been a well-knownroute for the drug administration for the treatment of oculardiseases. However, numerous anatomical and physiologicalbarriers prevailing in the eye itself create considerablechallenges for achieving the necessitated therapeutic efficacyalong with ocular bioavailability. However, recentadvances in nanoengineered strategies hold definite promisesin terms of devising improved ophthalmic medicinesfor the effective drug delivery to target the sites withenhanced ocular bioavailability. Curcumin, a hydrophobicpolyphenol yellow colored compound, and its metabolicreduced product, tetrahydrocurcumin (THC), have beenknown for their beneficial pharmacological functions, suchas anti-inflammatory or anti-oxidant activities at varioustissue sites. However, the low aqueous solubility of thesecompounds results in their poor bioavailability, therebylimiting their widespread application. Therefore, in thepresent study, we investigated the changes in drug solubilityby forming inclusion complexes with differentderivatives of hydroxypropyl (HP)-cyclodextrins (CD). To this end, the spray drying technique was used for nanoengineeringcurcumin or THC-loaded formulations toimprove the stability of formulations during the storage. The formulations were characterized in terms of physicochemicalproperties and cellular permeability. The resultsdemonstrated that the encapsulation of curcumin (or THC)into the HP-CDs significantly increased the drug solubilityand enhanced the corneal and retinal epithelial permeability. Curcumin or THC complexes in HP-CDs withimproved bioavailability also induced anti-oxidant activity(SOD1, CAT1, and HMOX1) in higher levels in the ocularepithelial cells and showed oxidative protection effects inrabbit cornea tissues that will boost up their application inocular medicine.

Pharmaceutical challenges and perspectives in developing ophthalmic drug formulations

Kyoung Ah Min,Pooja Maharjan,조관형,Anjila Maharjan,Meong Cheol Shin,Cheol Moon 한국약제학회 2019 Journal of Pharmaceutical Investigation Vol.49 No.2

Ocular drug delivery has been widely recognized as an attractive route for drug administration for cures of ocular diseases. Overall, designing an effective therapy to cure ocular diseases has been considered as a formidable task. Even though some infectious or inflammatory eye diseases could be alleviated by eye drops or ointments, achieving the required therapeutic efficacy along with ocular bioavailability remains a challenge due to the numerous anatomical and physiological barriers prevailing in the eye. Drug delivery to the posterior segment of the eye is yet a more challenging task. In this context, a better understanding of physiologic natures of the eyes and ocular pharmacokinetics would facilitate the development of new drug delivery systems to treat various vision-threatening disorders. For the effective drug delivery to target sites and to enhance the ocular bioavailability, recent progress in formulation strategies using nanotechnologies holds promises in terms of devising improved ophthalmic medicines. Hence, this review presents an overview of various aspects of ocular drug delivery, with a specific emphasis on nanocarrier-based strategies, including physiological barriers in eyes and conventional drug formulations. Recent research on sustained, controlled, and targeted systems for ocular drug delivery was updated as well.

Construction and characterization of gelonin and saporin plasmids for toxic gene-based cancer therapy

Min, Kyoung Ah,He, Huining,Yang, Victor C.,Shin, Meong Cheol Springer-Verlag 2016 Archives of Pharmacal Research Vol.39 No.5

<P>Toxic gene therapy (or suicidal gene therapy) is gaining enormous interest, specifically for the treatment of cancer. The success of this therapy lies in several crucial factors, including the potency of gene products to kill the transfected tumor cells and the transfection ability of the transfection vehicles. To address the potency problem, in the present study, we engineered two separate mammalian transfection plasmids (pSAP and pGEL) containing genes encoding ribosome inactivating proteins (RIPs), gelonin and saporin. After the successful preparation and amplification of the plasmids, they were tested on various cancer cell lines (HeLa, U87, 9L, and MDA-MB-435) and a noncancerous cell line (293 HEK) using polyethyleneimine (PEI) as the transfection agent. Transfection studies performed under varying gene concentration, incubation time, and gene-to-PEI ratios revealed that, compared to the treatment of pGFP (GFP expression plasmid)/PEI, both pGEL/PEI and pSAP/PEI complexes could induce significantly augmented cytotoxic effects at only 2 mu g/mL gene concentration. Importantly, these cytotoxic effects were observed universally in all tested cancer cell lines. Overall, this study demonstrated the potential of pGEL and pSAP as effective gene candidates for the toxic gene-based cancer therapy.</P>

Expression of carbonic anhydrase 12 in cervical cancer is associated with differentiation status and superior radiotherapy outcome(초)

( Chong Woo Yoo ),( Byung Ho Nam ),( Sun Lee ),( Hye Jin Shin ),( Hyun Sun Lim ),( Su Kyoung Lee ),임명철 ( Meong Cheol Lim ),( Yong Jung Song ),( Joo Young Kim ) 대한산부인과학회 2009 대한산부인과학회 학술대회 Vol.95 No.-