The Experts below are selected from a list of 171 Experts worldwide ranked by ideXlab platform
Youngro Byun - One of the best experts on this subject based on the ideXlab platform.
-
preliminary safety evaluation of a taurocholate conjugated low molecular weight Heparin Derivative lht7 a potent angiogenesis inhibitor
Journal of Applied Toxicology, 2015Co-Authors: Farzana Alam, Hyun Tae Moon, Seung Woo Chung, Seung Rim Hwang, Jiyoung Kim, Jooho Park, Youngro ByunAbstract:In our previous studies, taurocholic acid (TA)-conjugated low-molecular-weight Heparin Derivative (LHT7) has been proven to be a potent anti-angiogenic agent by demonstrated successful blockage capability of vascular endothelial growth factors (VEGF). Preliminary safety evaluations were conducted based on its mechanism of action and chemical behavior. For this purpose, acute toxicity study, and hematological and serological evaluations were carried out. Additionally, in order to evaluate mechanism-related side effects, both blood pressure and the occurrence of proteinuria were measured using a treatment regime of multiple high doses of LHT7 in a biodistribution study. LD50 values for LHT7 in female and male mice were 56.9 and 64.7 mg kg–1 doses, respectively. There were no vital fluctuations in the serological and hematological parameters, except for the elevated levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) at 100 and 200 mg kg–1 doses of LHT7, representing vital changes in the liver function. Moreover, the results of mechanism-related studies showed that blood pressure at 50 mg kg–1 did not change but showed elevated levels of protein in urine. In the biodistribution study, a slight accumulation of LHT7 in the kidney and the liver were observed at the 50 mg kg–1 repeated dose owing to the presence of bile acid. No fatal damage was observed in this study; most observations were related to the chemical composition or the mechanism of action of the material. Copyright © 2014 John Wiley & Sons, Ltd.
-
reduced graphene oxide nanosheets coated with an anti angiogenic anticancer low molecular weight Heparin Derivative for delivery of anticancer drugs
Journal of Controlled Release, 2014Co-Authors: Gayong Shim, Seung Woo Chung, Jiyoung Kim, Jeonghoon Han, Soondong Lee, Youngro ByunAbstract:Abstract Here, we report reduced graphene oxide (rGO) nanosheets coated with an anti-angiogenic anticancer taurocholate Derivative of low-molecular-weight Heparin (LHT7) as a tumor-targeting nanodelivery platform for anticancer drugs. Surface coating of LHT7 onto rGO was confirmed using fluorescein isothiocyanate-labeled LHT7, monitored as fluorescence quenching due to associated rGO. Unlike plain rGO, LHT7-coated rGO (LHT-rGO) nanosheets maintained a stable dispersion under physiological conditions for at least 24 h. Moreover, LHT-rGO provided greater loading capacity for doxorubicin (Dox) compared with uncoated rGO nanosheets. Following intravenous administration into KB tumor-bearing mice, in vivo tumor accumulation of LHT-rGO/Dox was 7-fold higher than that of rGO/Dox 24 h post dosing. In tumor tissues, LHT-rGO/Dox was shown to localize not to the tumor vasculature, but rather to tumor cells. Intravenously administered LHT-rGO/Dox showed the greatest anti-tumor effect in KB-bearing mice, reducing tumor volume by 92.5% ± 3.1% compared to the untreated group 25 days after tumor inoculation. TUNEL assays revealed that the population of apoptotic cells was highest in the group treated with LHT-rGO/Dox. Taken together, our results demonstrate that LHT-rGO nanosheets confer improved dispersion stability, tumor distribution and in vivo antitumor effects, and may be further developed as a potential active nanoplatform of various anticancer drugs.
-
oral delivery of a potent anti angiogenic Heparin conjugate by chemical conjugation and physical complexation using deoxycholic acid
Biomaterials, 2014Co-Authors: Farzana Alam, Seung Woo Chung, Taslim A Alhilal, Foyez Mahmud, Youngro ByunAbstract:Angiogenesis, the formation of new blood vessels, plays a pivotal role in tumor progression and for this reason angiogenesis inhibitors are an important class of therapeutics for cancer treatment. Heparin-based angiogenesis inhibitors have been newly developed as one of such classes of therapeutics and possess a great promise in the clinical context. Taurocholate conjugated low molecular weight Heparin Derivative (LHT7) has been proven to be a potent, multi-targeting angiogenesis inhibitor against broad-spectrum angiogenic tumors. However, major limitations of LHT7 are its poor oral bioavailability, short half-life, and frequent parenteral dosing schedule. Addressing these issues, we have developed an oral formulation of LHT7 by chemically conjugating LHT7 with a tetrameric deoxycholic acid named LHTD4, and then physically complexing it with deoxycholylethylamine (DCK). The resulting LHTD4/DCK complex showed significantly enhanced oral bioavailability (34.3 ± 2.89%) and prolonged the mean residence time (7.5 ± 0.5 h). The LHTD4/DCK complex was mostly absorbed in the intestine by transcellular pathway via its interaction with apical sodium bile acid transporter. In vitro, the VEGF-induced sprouting of endothelial spheroids was significantly blocked by LHTD4. LHTD4/DCK complex significantly regressed the total vessel fractions of tumor (77.2 ± 3.9%), as analyzed by X-ray microCT angiography, thereby inhibiting tumor growth in vivo. Using the oral route of administration, we showed that LHTD4/DCK complex could be effective and chronically administered as angiogenesis inhibitor.
-
in vivo tumor targeting imaging of cyclic rgd modified Heparin Derivative to α v β 3 integrin expressing tumor
Journal of Pharmaceutical Investigation, 2012Co-Authors: Sungeun Kim, Youngro Byun, Jungwook Chin, Hanna Lee, Kyeongsoon ParkAbstract:Therapeutic target for over-expressed αvβ3 integrins in angiogenic endothelial cells and tumors is one of the promising approaches for cancer imaging and therapy. In the previous study, we demonstrated that Heparin–lithocholic acid functionalized with cyclic RGDyK (cRGD–HL) had potent angiogenesis inhibition and tumor regression effects. The aim of this study is to validate the targeting property and specificity of cRGD–HL to αvβ3 integrin-expressing endothelial cells and tumor tissues by Cy5.5-labeled cRGDyK (RGD-Cy5.5) as αvβ3 integrin imaging agent and near-infrared fluorescence (NIRF) imaging systems. In this study, we demonstrated that cRGD–HL markedly inhibited the binding of fluorescein-labeled αvβ3 antibody to αvβ3 integrin-expressing endothelial cells when compared to non-functionalized Heparin Derivatives. Furthermore, in vivo NIRF images showed that cRGD–HL could decrease the NIRF signal intensities in both αvβ3 integrin-positive tumor (U87 MG) and αvβ3 integrin-negative tumor (SCC7) more effectively than non-functionalized Heparin Derivatives could. Therefore, with the help of αvβ3 integrin imaging agent and NIRF imaging systems, we verified that the functionalized cRGD–HL has much stronger tumor targeting property and specificity against αvβ3 integrin-expressing endothelial cells and tumors than non-functionalized Heparin Derivatives. Also, we believe that cRGD–HL will be useful and give affirmative outcomes for the treatment of angiogenesis-related diseases.
-
enhancement of blood compatibility of poly urethane substrates by mussel inspired adhesive Heparin coating
Bioconjugate Chemistry, 2011Co-Authors: Sung Min Kang, Youngro ByunAbstract:Heparin immobilization on surfaces has drawn a great deal of attention because of its potential application in enhancing blood compatibility of various biomedical devices such as catheters, grafts, and stents. Existing methods for the Heparin immobilization are based on covalent linkage formation and electrostatic interaction between substrates and Heparin molecules. However, complicated multistep procedures and uncontrolled desorption of Heparin are limitations of these methods. In this work, we report a new Heparin Derivative that exhibits robust adhesion on surfaces. The Derivative, called hepamine, was prepared via conjugation of dopamine, a mussel-inspired adhesive moiety, onto a Heparin backbone. Immersion of poly(urethane) substrates into an aqueous solution of hepamine resulted in robust Heparin coating of the poly(urethane), the most widely used polymeric material for blood-contacting medical devices. The hepamine-coated poly(urethane) substrate showed significant inhibition of blood coagulation ...
Shaker A Mousa - One of the best experts on this subject based on the ideXlab platform.
-
sulfated non anticoagulant Heparin Derivative modifies intracellular hemoglobin inhibits cell sickling in vitro and prolongs survival of sickle cell mice under hypoxia
Haematologica, 2021Co-Authors: Osheiza Abdulmalik, Noureldien H E Darwish, Vandhana Muralidharanchari, Maii Abu Taleb, Shaker A MousaAbstract:Sickle cell disease (SCD) is an autosomal recessive genetic disease caused by a single point mutation, resulting in abnormal sickle hemoglobin (HbS). During hypoxia or dehydration, HbS polymerizes to form insoluble aggregates and induces sickling of red blood cells (RBCs). RBC sickling increases adhesiveness of RBCs to alter the rheological properties of the blood and triggers inflammatory responses, leading to hemolysis and vaso-occlusive crisis sequelae. Unfractionated Heparin (UFH) and low-molecular weight Heparins (LMWH) have been suggested as treatments to relieve coagulation complications in SCD. However, they are associated with bleeding complications after repeated dosing. An alternative sulfated nonanticoagulant Heparin Derivative (S-NACH) was previously reported to have none to low systemic anticoagulant activity and no bleeding side effects, and it interfered with P-selectindependent binding of sickle cells to endothelial cells, with concomitant decrease in the levels of adhesion biomarkers in SCD mice. S-NACH has been further engineered and structurally enhanced to bind with and modify HbS to directly inhibit sickling, thus employing a multimodal approach. Here, we show that S-NACH can (i) directly engage in Schiff-base reactions with HbS to decrease RBC sickling under both normoxia and hypoxia in vitro, ii) prolong the survival of SCD mice under hypoxia, and (iii) regulate the altered steady state levels of pro- and antiinflammatory cytokines. Thus, our proof of concept in vitro and in vivo preclinical studies demonstrate that the multimodal S-NACH is a highly promising candidate for development into an improved and optimized alternative to LMWHs for the treatment of patients with SCD.
-
modulation of sickle red blood cell adhesion and its associated changes in biomarkers by sulfated nonanticoagulant Heparin Derivative
Clinical and Applied Thrombosis-Hemostasis, 2016Co-Authors: Abdulelah Alshaiban, Vandhana Muralidharanchari, Anne Nepo, Shaker A MousaAbstract:Abnormal cellular adhesion is one of the primary causes of vaso-occlusive crisis in sickle cell disease (SCD). Levels of intercellular adhesion molecule 1 (ICAM-1) and P-selectin are upregulated, resulting in increased adhesion of leukocytes and sickle red blood cells (RBCs) to endothelium. This study compares the inhibitory effect of a sulfated nonanticoagulant Heparin (S-NACH) Derivative with a low-molecular-weight Heparin, tinzaparin, on the adhesion of sickle RBCs to endothelium. The S-NACH exhibits minimum effects on hemostasis and bleeding and interferes with the binding of pancreatic cancer cells to endothelial cells via P-selectin. We show by static binding assay that pretreatment of both erythrocytes and endothelial cells with S-NACH significantly inhibits the increased adhesion of sickle RBCs to endothelial cells. The S-NACH treatment also decreases the higher plasma levels of (adhesion biomarkers) ICAM-1 and P-selectin in SCD mice. This investigation signals further research into the potential use of S-NACH in treating vaso-occlusions with minimal bleeding events in patients with SCD.
-
anti metastasis efficacy and safety of non anticoagulant Heparin Derivative versus low molecular weight Heparin in surgical pancreatic cancer models
International Journal of Oncology, 2015Co-Authors: Reem Alyahya, Thangirala Sudha, Michael J Racz, Steven C Stain, Shaker A MousaAbstract:Heparin and its Derivatives are known to attenuate cancer metastasis in preclinical models, but have not been used clinically due to adverse bleeding effects. This study compared the efficacy of S-NACH (a sulfated non-anticoagulant Heparin) versus tinzaparin (a low molecular weight Heparin) in inhibiting metastasis of a growing primary tumor and following surgical excision of primary tumor in a pancreatic cancer mouse model. The efficacy of S-NACH versus tinzaparin on metastasis of the primary tumor was evaluated in each experiment using IVIS imaging. Athymic female mice were treated with S-NACH or tinzaparin, and 30 min later luciferase-transfected pancreatic cancer cells (Mpanc96) were implanted into the spleen; treatment was continued daily until termination. Next we studied the effect of S-NACH versus tinzaparin on metastasis after surgical excision of the primary tumor after 3 weeks of daily treatment with S-NACH or tinzaparin. S-NACH reduced surgically induced metastasis (p<0.01) and tumor recurrence (p<0.05) relative to control. Histopathological studies demonstrated significant increase in tumor necrosis mediated by S-NACH and to lesser extent by tinzaparin as compared to control group. Furthermore, either S-NACH or tinzaparin upregulated the expression of the junctional adhesion molecule E-cadherin in pancreatic cancer cells where its low expression enhances cancer cell migration and invasion. In terms of bleeding time (BT), S-NACH did not affect BT as compared to tinzaparin, which doubled BT. These data suggest that S-NACH is an effective and safe anti-metastatic agent and warrants further clinical evaluation.
-
gold and silver nanoparticles conjugated with Heparin Derivative possess anti angiogenesis properties
Nanotechnology, 2009Co-Authors: Melissa M Kemp, Robert J. Linhardt, Ashavani Kumar, Shaymaa S Mousa, Evgeny Dyskin, Murat Yalcin, Pulickel M Ajayan, Shaker A MousaAbstract:Silver and gold nanoparticles display unique physical and biological properties that have been extensively studied for biological and medical applications. Typically, gold and silver nanoparticles are prepared by chemical reductants that utilize excess toxic reactants, which need to be removed for biological purposes. We utilized a clean method involving a single synthetic step to prepare metal nanoparticles for evaluating potential effects on angiogenesis modulation. These nanoparticles were prepared by reducing silver nitrate and gold chloride with diaminopyridinyl (DAP)-derivatized Heparin (HP) polysaccharides. Both gold and silver nanoparticles reduced with DAPHP exhibited effective inhibition of basic fibroblast growth factor (FGF-2)-induced angiogenesis, with an enhanced anti-angiogenesis efficacy with the conjugation to DAPHP (P<0.01) as compared to glucose conjugation. These results suggest that DAPHP-reduced silver nanoparticles and gold nanoparticles have potential in pathological angiogenesis accelerated disorders such as cancer and inflammatory diseases.
Farzana Alam - One of the best experts on this subject based on the ideXlab platform.
-
safety studies on intravenous infusion of a potent angiogenesis inhibitor taurocholate conjugated low molecular weight Heparin Derivative lht7 in preclinical models
Drug Development and Industrial Pharmacy, 2016Co-Authors: Farzana Alam, Seung Woo Chung, Seung Rim Hwang, Taslim A Alhilal, Haksoo Kim, Boohyun Kang, Husong Zhang, Seoho Shin, Jooyoung Lee, Minsoo KangAbstract:AbstractContext: As a class of angiogenesis inhibitors, Heparin conjugates have shown significant effectiveness in several studies.Objectives: The purpose of our current study is to evaluate the effectiveness and safety of infusing the conjugate of low molecular weight Heparin and taurocholate (LHT7), which has been developed as a potent angiogenesis inhibitor.Methods: To evaluate its safety, the method of intravenous infusion was compared with its i.v. bolus administration. Intravenous infusion was administered at a rate of 400 μl/min/kg of body weight for 30 min. Pharmacokinetic (PK) analysis, organ accumulation, and plasma concentration profiles of LHT7 were measured. The anticancer effect of LHT7 was evaluated in murine and human xenograft models, and preclinical studies were performed in SD rats and beagle dogs.Results: The results of the PK studies showed reduced organ accumulation in mice and the AUC(0–96 h) (area under the curve) was increased up to 1485 ± 125 h × μg/ml. The efficacy, at dose 1 mg...
-
preliminary safety evaluation of a taurocholate conjugated low molecular weight Heparin Derivative lht7 a potent angiogenesis inhibitor
Journal of Applied Toxicology, 2015Co-Authors: Farzana Alam, Hyun Tae Moon, Seung Woo Chung, Seung Rim Hwang, Jiyoung Kim, Jooho Park, Youngro ByunAbstract:In our previous studies, taurocholic acid (TA)-conjugated low-molecular-weight Heparin Derivative (LHT7) has been proven to be a potent anti-angiogenic agent by demonstrated successful blockage capability of vascular endothelial growth factors (VEGF). Preliminary safety evaluations were conducted based on its mechanism of action and chemical behavior. For this purpose, acute toxicity study, and hematological and serological evaluations were carried out. Additionally, in order to evaluate mechanism-related side effects, both blood pressure and the occurrence of proteinuria were measured using a treatment regime of multiple high doses of LHT7 in a biodistribution study. LD50 values for LHT7 in female and male mice were 56.9 and 64.7 mg kg–1 doses, respectively. There were no vital fluctuations in the serological and hematological parameters, except for the elevated levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) at 100 and 200 mg kg–1 doses of LHT7, representing vital changes in the liver function. Moreover, the results of mechanism-related studies showed that blood pressure at 50 mg kg–1 did not change but showed elevated levels of protein in urine. In the biodistribution study, a slight accumulation of LHT7 in the kidney and the liver were observed at the 50 mg kg–1 repeated dose owing to the presence of bile acid. No fatal damage was observed in this study; most observations were related to the chemical composition or the mechanism of action of the material. Copyright © 2014 John Wiley & Sons, Ltd.
-
oral delivery of a potent anti angiogenic Heparin conjugate by chemical conjugation and physical complexation using deoxycholic acid
Biomaterials, 2014Co-Authors: Farzana Alam, Seung Woo Chung, Taslim A Alhilal, Foyez Mahmud, Youngro ByunAbstract:Angiogenesis, the formation of new blood vessels, plays a pivotal role in tumor progression and for this reason angiogenesis inhibitors are an important class of therapeutics for cancer treatment. Heparin-based angiogenesis inhibitors have been newly developed as one of such classes of therapeutics and possess a great promise in the clinical context. Taurocholate conjugated low molecular weight Heparin Derivative (LHT7) has been proven to be a potent, multi-targeting angiogenesis inhibitor against broad-spectrum angiogenic tumors. However, major limitations of LHT7 are its poor oral bioavailability, short half-life, and frequent parenteral dosing schedule. Addressing these issues, we have developed an oral formulation of LHT7 by chemically conjugating LHT7 with a tetrameric deoxycholic acid named LHTD4, and then physically complexing it with deoxycholylethylamine (DCK). The resulting LHTD4/DCK complex showed significantly enhanced oral bioavailability (34.3 ± 2.89%) and prolonged the mean residence time (7.5 ± 0.5 h). The LHTD4/DCK complex was mostly absorbed in the intestine by transcellular pathway via its interaction with apical sodium bile acid transporter. In vitro, the VEGF-induced sprouting of endothelial spheroids was significantly blocked by LHTD4. LHTD4/DCK complex significantly regressed the total vessel fractions of tumor (77.2 ± 3.9%), as analyzed by X-ray microCT angiography, thereby inhibiting tumor growth in vivo. Using the oral route of administration, we showed that LHTD4/DCK complex could be effective and chronically administered as angiogenesis inhibitor.
Seung Woo Chung - One of the best experts on this subject based on the ideXlab platform.
-
safety studies on intravenous infusion of a potent angiogenesis inhibitor taurocholate conjugated low molecular weight Heparin Derivative lht7 in preclinical models
Drug Development and Industrial Pharmacy, 2016Co-Authors: Farzana Alam, Seung Woo Chung, Seung Rim Hwang, Taslim A Alhilal, Haksoo Kim, Boohyun Kang, Husong Zhang, Seoho Shin, Jooyoung Lee, Minsoo KangAbstract:AbstractContext: As a class of angiogenesis inhibitors, Heparin conjugates have shown significant effectiveness in several studies.Objectives: The purpose of our current study is to evaluate the effectiveness and safety of infusing the conjugate of low molecular weight Heparin and taurocholate (LHT7), which has been developed as a potent angiogenesis inhibitor.Methods: To evaluate its safety, the method of intravenous infusion was compared with its i.v. bolus administration. Intravenous infusion was administered at a rate of 400 μl/min/kg of body weight for 30 min. Pharmacokinetic (PK) analysis, organ accumulation, and plasma concentration profiles of LHT7 were measured. The anticancer effect of LHT7 was evaluated in murine and human xenograft models, and preclinical studies were performed in SD rats and beagle dogs.Results: The results of the PK studies showed reduced organ accumulation in mice and the AUC(0–96 h) (area under the curve) was increased up to 1485 ± 125 h × μg/ml. The efficacy, at dose 1 mg...
-
preliminary safety evaluation of a taurocholate conjugated low molecular weight Heparin Derivative lht7 a potent angiogenesis inhibitor
Journal of Applied Toxicology, 2015Co-Authors: Farzana Alam, Hyun Tae Moon, Seung Woo Chung, Seung Rim Hwang, Jiyoung Kim, Jooho Park, Youngro ByunAbstract:In our previous studies, taurocholic acid (TA)-conjugated low-molecular-weight Heparin Derivative (LHT7) has been proven to be a potent anti-angiogenic agent by demonstrated successful blockage capability of vascular endothelial growth factors (VEGF). Preliminary safety evaluations were conducted based on its mechanism of action and chemical behavior. For this purpose, acute toxicity study, and hematological and serological evaluations were carried out. Additionally, in order to evaluate mechanism-related side effects, both blood pressure and the occurrence of proteinuria were measured using a treatment regime of multiple high doses of LHT7 in a biodistribution study. LD50 values for LHT7 in female and male mice were 56.9 and 64.7 mg kg–1 doses, respectively. There were no vital fluctuations in the serological and hematological parameters, except for the elevated levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) at 100 and 200 mg kg–1 doses of LHT7, representing vital changes in the liver function. Moreover, the results of mechanism-related studies showed that blood pressure at 50 mg kg–1 did not change but showed elevated levels of protein in urine. In the biodistribution study, a slight accumulation of LHT7 in the kidney and the liver were observed at the 50 mg kg–1 repeated dose owing to the presence of bile acid. No fatal damage was observed in this study; most observations were related to the chemical composition or the mechanism of action of the material. Copyright © 2014 John Wiley & Sons, Ltd.
-
reduced graphene oxide nanosheets coated with an anti angiogenic anticancer low molecular weight Heparin Derivative for delivery of anticancer drugs
Journal of Controlled Release, 2014Co-Authors: Gayong Shim, Seung Woo Chung, Jiyoung Kim, Jeonghoon Han, Soondong Lee, Youngro ByunAbstract:Abstract Here, we report reduced graphene oxide (rGO) nanosheets coated with an anti-angiogenic anticancer taurocholate Derivative of low-molecular-weight Heparin (LHT7) as a tumor-targeting nanodelivery platform for anticancer drugs. Surface coating of LHT7 onto rGO was confirmed using fluorescein isothiocyanate-labeled LHT7, monitored as fluorescence quenching due to associated rGO. Unlike plain rGO, LHT7-coated rGO (LHT-rGO) nanosheets maintained a stable dispersion under physiological conditions for at least 24 h. Moreover, LHT-rGO provided greater loading capacity for doxorubicin (Dox) compared with uncoated rGO nanosheets. Following intravenous administration into KB tumor-bearing mice, in vivo tumor accumulation of LHT-rGO/Dox was 7-fold higher than that of rGO/Dox 24 h post dosing. In tumor tissues, LHT-rGO/Dox was shown to localize not to the tumor vasculature, but rather to tumor cells. Intravenously administered LHT-rGO/Dox showed the greatest anti-tumor effect in KB-bearing mice, reducing tumor volume by 92.5% ± 3.1% compared to the untreated group 25 days after tumor inoculation. TUNEL assays revealed that the population of apoptotic cells was highest in the group treated with LHT-rGO/Dox. Taken together, our results demonstrate that LHT-rGO nanosheets confer improved dispersion stability, tumor distribution and in vivo antitumor effects, and may be further developed as a potential active nanoplatform of various anticancer drugs.
-
oral delivery of a potent anti angiogenic Heparin conjugate by chemical conjugation and physical complexation using deoxycholic acid
Biomaterials, 2014Co-Authors: Farzana Alam, Seung Woo Chung, Taslim A Alhilal, Foyez Mahmud, Youngro ByunAbstract:Angiogenesis, the formation of new blood vessels, plays a pivotal role in tumor progression and for this reason angiogenesis inhibitors are an important class of therapeutics for cancer treatment. Heparin-based angiogenesis inhibitors have been newly developed as one of such classes of therapeutics and possess a great promise in the clinical context. Taurocholate conjugated low molecular weight Heparin Derivative (LHT7) has been proven to be a potent, multi-targeting angiogenesis inhibitor against broad-spectrum angiogenic tumors. However, major limitations of LHT7 are its poor oral bioavailability, short half-life, and frequent parenteral dosing schedule. Addressing these issues, we have developed an oral formulation of LHT7 by chemically conjugating LHT7 with a tetrameric deoxycholic acid named LHTD4, and then physically complexing it with deoxycholylethylamine (DCK). The resulting LHTD4/DCK complex showed significantly enhanced oral bioavailability (34.3 ± 2.89%) and prolonged the mean residence time (7.5 ± 0.5 h). The LHTD4/DCK complex was mostly absorbed in the intestine by transcellular pathway via its interaction with apical sodium bile acid transporter. In vitro, the VEGF-induced sprouting of endothelial spheroids was significantly blocked by LHTD4. LHTD4/DCK complex significantly regressed the total vessel fractions of tumor (77.2 ± 3.9%), as analyzed by X-ray microCT angiography, thereby inhibiting tumor growth in vivo. Using the oral route of administration, we showed that LHTD4/DCK complex could be effective and chronically administered as angiogenesis inhibitor.
Kyeongsoon Park - One of the best experts on this subject based on the ideXlab platform.
-
in vivo tumor targeting imaging of cyclic rgd modified Heparin Derivative to α v β 3 integrin expressing tumor
Journal of Pharmaceutical Investigation, 2012Co-Authors: Sungeun Kim, Youngro Byun, Jungwook Chin, Hanna Lee, Kyeongsoon ParkAbstract:Therapeutic target for over-expressed αvβ3 integrins in angiogenic endothelial cells and tumors is one of the promising approaches for cancer imaging and therapy. In the previous study, we demonstrated that Heparin–lithocholic acid functionalized with cyclic RGDyK (cRGD–HL) had potent angiogenesis inhibition and tumor regression effects. The aim of this study is to validate the targeting property and specificity of cRGD–HL to αvβ3 integrin-expressing endothelial cells and tumor tissues by Cy5.5-labeled cRGDyK (RGD-Cy5.5) as αvβ3 integrin imaging agent and near-infrared fluorescence (NIRF) imaging systems. In this study, we demonstrated that cRGD–HL markedly inhibited the binding of fluorescein-labeled αvβ3 antibody to αvβ3 integrin-expressing endothelial cells when compared to non-functionalized Heparin Derivatives. Furthermore, in vivo NIRF images showed that cRGD–HL could decrease the NIRF signal intensities in both αvβ3 integrin-positive tumor (U87 MG) and αvβ3 integrin-negative tumor (SCC7) more effectively than non-functionalized Heparin Derivatives could. Therefore, with the help of αvβ3 integrin imaging agent and NIRF imaging systems, we verified that the functionalized cRGD–HL has much stronger tumor targeting property and specificity against αvβ3 integrin-expressing endothelial cells and tumors than non-functionalized Heparin Derivatives. Also, we believe that cRGD–HL will be useful and give affirmative outcomes for the treatment of angiogenesis-related diseases.
-
tumor endothelial cell targeted cyclic rgd modified Heparin Derivative inhibition of angiogenesis and tumor growth
Pharmaceutical Research, 2008Co-Authors: Kyeongsoon Park, Rang-woon Park, In-san Kim, Yoo Shin Kim, Gee Young Lee, Sang Yoon Kim, Youngro ByunAbstract:Purpose We prepared tumor endothelium targeted cRGD-modified Heparin Derivative (cRGD-HL) by coupling Heparin-lithocholic acid (HL) with cRGDyK, and evaluated inhibition effects of cRGD-HL on angiogenesis and tumor growth.
-
antimetastatic effect of an orally active Heparin Derivative on experimentally induced metastasis
Clinical Cancer Research, 2008Co-Authors: Dong Yun Lee, Sang Kyoon Kim, Kyeongsoon Park, Rang-woon Park, Ick Chan Kwon, Sang Yoon Kim, Youngro ByunAbstract:Purpose: Orally active anticancer drugs have great advantages for the treatment of cancer. Compelling data suggest that Heparin exhibits critical antimetastatic effects via interference with P-selectin–mediated cell-cell binding. However, Heparin should be given parenterally because it is not orally absorbed. Here, we evaluated the inhibitory effect of orally absorbable Heparin Derivative (LHD) on experimentally induced metastasis. Experimental Design: We developed LHD, which is a chemical conjugate of low molecular weight Heparin and deoxycholic acid, and measured the plasma concentration of LHD after oral administration. To evaluate the antimetastatic effect of LHD, we carried out experimental lung metastasis assays in vivo using murine melanoma or human lung carcinoma cells and interruption assay between murine melanoma cells and activated platelets and human umbilical vascular endothelial cells in vitro . Results: In mice, the plasma concentration was ∼7 μg/mL at 20 minutes after oral administration of LHD (10 mg/kg), indicating that bleeding was not induced at this dose. Interestingly, we found that LHD dramatically attenuated metastasis experimentally induced by murine melanoma or human lung carcinoma cells and that its antimetastatic activity was attributed to the interruption of the interactions between melanoma cells and activated platelets and between melanoma cells and human umbilical vascular endothelial cells by blocking selectin-mediated interactions. Furthermore, it prevented tumor growth in secondary organs. Conclusions: On the basis of these findings, the present study shows the possibility of LHD as a suitable first-line anticancer drug that can be used for preventing metastasis and recurrence because it has therapeutic potential as an antimetastatic drug, has lower side effects, and can be orally absorbed.
-
The attenuation of experimental lung metastasis by a bile acid acylated-Heparin Derivative
Biomaterials, 2007Co-Authors: Kyeongsoon Park, Seok Ki Lee, Dai Hyun Son, Soo Ah Park, Kwangmeyung Kim, Hyo Won Chang, Eun Jeong Jeong, Rang-woon Park, In-san Kim, Ick Chan KwonAbstract:The inhibitory efficacies of new bile acid acylated-Heparin Derivative (Heparin-DOCA) were evaluated on experimental lung metastasis. We evaluated the effect of Heparin-DOCA on intercellular interactions including those between B16F10 and thrombin-activated platelets and TNF-α-activated HUVECs, and between B16F10 and immobilized mouse P-selectin. In addition, the inhibitory effects of Heparin-DOCA on adhesion and invasion of B16F10 to Matrigel were studied. In an animal mouse study, the blood clot formation and the retention of red fluorescence protein (RFP)-B16F10 in lungs were assessed after Heparin-DOCA and RFP-B16F10 intravenous administration. Furthermore, we investigated the anti-metastatic effect of Heparin-DOCA against lung metastasis induced by B16F10 and SCC7. Heparin-DOCA inhibited intercellular interactions between B16F10 and activated platelets or activated HUVECs by blocking P- and E-selectin-mediated interactions. Moreover, it reduced adhesion and invasion of B16F10 to ECM, thereby affecting the reduction of early retention of B16F10 in the lung. Heparin-DOCA attenuated lung colony formation on the surfaces and in interior of the lung, and attenuated metastasis by B16F10 and SCC7. These results suggest that Heparin-DOCA may have potentials as therapeutic agent that prevents tumor metastasis and progression.
-
antiangiogenic and apoptotic properties of a novel amphiphilic folate Heparin lithocholate Derivative having cellular internality for cancer therapy
Pharmaceutical Research, 2007Co-Authors: Dong Yun Lee, Jong Hee Nam, Kyeongsoon Park, Dai Hyun Son, Soo Ah Park, In-san Kim, Yoo Shin Kim, Gee Young Lee, Sang Yoon Kim, Rang-woon ParkAbstract:Purpose. Anitangiogenic and apoptotic properties of a novel chemically modified Heparin Derivative with low anticoagulant activity were evaluated on the experimental in vitro and in vivo model. Materials and Methods. Heparin-lithocholate conjugate (HL) was initially synthesized by covalently bonding lithocholate to Heparin. Folate-HL conjugate (FHL) was further synthesized by conjugating folate to HL. Antiangiogenic and apoptotic abilities of HL and FHL were characterized in vitro and in vivo experimentations. Results. Compared to unmodified Heparin, both HL and FHL represented a low anticoagulant activity (38 and 28%, respectively). HL and FHL maintained antiangiogenic activity even further modification from the results of Matrigel plugs assay. FHL specifically induced apoptosis on KB cells having highly expressed folate receptor after cellular internalization. Both administered HL and FHL had similar antiangiogenic activity and inhibitory effect on tumor growth in vivo although FHL induced higher apoptosis on tumor tissues. Conclusions. In vivo tumor growth inhibition was possibly due to the decrease of vessel density and apoptotic cell death, although antiangiogenic effect of FHL seemed more actively affected on growth inhibition than apoptotic potential in vivo system. Thus, Low anticoagulant FHL having antiangiogenic and apoptotic properties would provide benefits for the development of a new class of anticancer agent.