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Chih-kuang Yeh - One of the best experts on this subject based on the ideXlab platform.
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Spatially Uniform Tumor Treatment and Drug Penetration by Regulating Ultrasound with Microbubbles.
ACS applied materials & interfaces, 2018Co-Authors: Tzu Chia Wang, Ching Hsiang Fan, Chih-kuang YehAbstract:Tumor microenvironment has different morphologies of vessels in the core and rim regions, which influences the efficacy of tumor therapy. Our study proposed to improve the spatial uniformity of the antivascular effect and Drug Penetration within the tumor core and rim in combination therapies by regulating ultrasound-stimulated microbubble destruction (USMD). Focused ultrasound at 2 MHz and lipid-shell microbubbles (1.12 ± 0.08 μm, mean ± standard deviation) were used to perform USMD. The efficiency of the antivascular effect was evaluated by intravital imaging to determine the optimal USMD parameters. Tumor perfusion and histological alterations in the tumor core and rim were used to analyze the spatial uniformity of the antivascular effect and liposomal-doxorubicin (5 mg/kg) Penetration in the combination therapy. Tumor vessels of specific sizes were disrupted by regulating USMD: vessels with sizes of 11 ± 3, 14 ± 5, 19 ± 7, and 23 ± 10 μm were disrupted by stimulation at acoustic pressures of 3, 5, 7, and 9 MPa, respectively (each p < 0.05). The effective treatment time of USMD (at 2 × 107 microbubbles/mouse, 7 MPa, and three cycles) was 60-120 min, which resulted in the disruption of 21-44% of vessels smaller than 50 μm. The reductions in perfusion and vascular density after combination therapy did not differ significantly between the tumor core and rim. This study found that regulating USMD can result in homogeneous antivascular effects and Drug Penetration within tumors and thereby improve the efficacy of combination therapies.
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Spatially Uniform Tumor Treatment and Drug Penetration by Regulating Ultrasound with Microbubbles
2018Co-Authors: Tzu Chia Wang, Ching Hsiang Fan, Chih-kuang YehAbstract:Tumor microenvironment has different morphologies of vessels in the core and rim regions, which influences the efficacy of tumor therapy. Our study proposed to improve the spatial uniformity of the antivascular effect and Drug Penetration within the tumor core and rim in combination therapies by regulating ultrasound-stimulated microbubble destruction (USMD). Focused ultrasound at 2 MHz and lipid-shell microbubbles (1.12 ± 0.08 μm, mean ± standard deviation) were used to perform USMD. The efficiency of the antivascular effect was evaluated by intravital imaging to determine the optimal USMD parameters. Tumor perfusion and histological alterations in the tumor core and rim were used to analyze the spatial uniformity of the antivascular effect and liposomal-doxorubicin (5 mg/kg) Penetration in the combination therapy. Tumor vessels of specific sizes were disrupted by regulating USMD: vessels with sizes of 11 ± 3, 14 ± 5, 19 ± 7, and 23 ± 10 μm were disrupted by stimulation at acoustic pressures of 3, 5, 7, and 9 MPa, respectively (each p < 0.05). The effective treatment time of USMD (at 2 × 107 microbubbles/mouse, 7 MPa, and three cycles) was 60–120 min, which resulted in the disruption of 21–44% of vessels smaller than 50 μm. The reductions in perfusion and vascular density after combination therapy did not differ significantly between the tumor core and rim. This study found that regulating USMD can result in homogeneous antivascular effects and Drug Penetration within tumors and thereby improve the efficacy of combination therapies
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Improvement of Drug Penetration in solid tumors by vascular disruption with acoustic nanodroplet vaporization
2015 IEEE International Ultrasonics Symposium (IUS), 2015Co-Authors: Yi-ju Ho, Chih-kuang YehAbstract:Acoustic droplet vaporization (ADV) provides chemical and physical effects due to the mechanical force and Drug releasing. Although nanodroplets can passive penetrate and deliver Drugs into tumor tissue via the enhanced permeability and retention (EPR) effect, various aspects of the tumor microenvironment still restrict this process. Therefore, our study applied vascular disruption induced by ADV to overcome the limitations of the EPR effect to allow Drug Penetration into extensive regions. The dorsal skinfold window chamber model and acousto-optical integrated system were applied to evaluate the intravital Penetration of DiI-labeled liposomes. The cumulative Penetration areas and extravascular fluorescence ratios of the ADV group were 3.46 fold and 1.7 fold, respectively, higher than that of the EPR group at 180 min. Histology images demonstrated that ADV can improve the DiI-labeled liposomes Penetration at the locations of intratumoral tissue damage and vascular disruption. This proposed strategy might improve the Drug accumulation in some tumors with poorly vascular permeability and deliver Drugs into tumor hypoxia regions.
Danny Van Noort - One of the best experts on this subject based on the ideXlab platform.
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engineering a scaffold free 3d tumor model for in vitro Drug Penetration studies
Biomaterials, 2010Co-Authors: Ziqing W Zhao, Deqiang Zhao, Tiehua Du, Danny Van Noort, Talha Arooz, Martin Wasser, Shufang ZhangAbstract:Three-dimensional (3D) in vitro cultures are recognized for recapitulating the physiological microenvironment and exhibiting high concordance with in vivo conditions. In cancer research, the multi-cellular tumor spheroid (MCTS) model is an established 3D cancer model that exhibits microenvironmental heterogeneity close to that of tumors in vivo. However, the established process of MCTS formation is time-consuming and often uncontrolled. Here, we report a method for engineering MCTS using a transient inter-cellular linker which facilitates cell-cell interaction. Using C3A cells (a hepatocellular carcinoma cell line) as a model, we formed linker-engineered spheroids which grew to a diameter of 250 μm in 7 days, as compared to 16 days using conventional non-adherent culture. Seven-day old linker-engineered spheroids exhibited characteristics of mature MCTS, including spheroid morphology, gene expression profile, cell-cell interaction, extracellular matrix secretion, proliferation and oxygen concentration gradients, and cellular functions. Linker-engineered spheroids also displayed a resistance to Drug Penetration similar to mature MCTS, with dose-dependent extracellular accumulation of the Drug. The linker-engineered spheroids thus provide a reliable accelerated 3D in vitro tumor model for Drug Penetration studies.
Eva Benfeldt - One of the best experts on this subject based on the ideXlab platform.
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impact of adult atopic dermatitis on topical Drug Penetration assessment by cutaneous microdialysis and tape stripping
Acta Dermato-venereologica, 2009Co-Authors: Patricia Garcia Ortiz, Steen Honoré Hansen, Vinod P. Shah, Torkil Menné, Eva BenfeldtAbstract:Appropriate methodologies for the determination of Drug Penetration in diseased skin have not yet been established. The aim of this study was to determine the cutaneous Penetration of a metronidazole cream formulation in atopic dermatitis, employing dermal microdialysis and tape strip sampling techniques. Non-invasive measuring methods were used for the quantification of the severity of the dermatitis. Skin thickness and the depth of the microdialysis probes in the skin were measured by 20 MHz ultrasound scanning. Metronidazole concentration, sampled by microdialysis, was 2.4-fold higher in the atopic dermatitis compared with uninvolved skin (p<0.001). Tape stripping methodology did not disclose this difference in Penetration. Thus, the skin layer of interest and the integrity of the skin barrier should be considered when selecting sampling methodology. Microdialysis sampling is the method of choice whenever the dermis is the target tissue for topical treatment and a skin disease affecting the barrier function is present.
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Impact of adult atopic dermatitis on topical Drug Penetration: assessment by cutaneous microdialysis and tape stripping.
Acta dermato-venereologica, 2009Co-Authors: Patricia Garcia Ortiz, Steen Honoré Hansen, Vinod P. Shah, Torkil Menné, Eva BenfeldtAbstract:Appropriate methodologies for the determination of Drug Penetration in diseased skin have not yet been established. The aim of this study was to determine the cutaneous Penetration of a metronidazole cream formulation in atopic dermatitis, employing dermal microdialysis and tape strip sampling techniques. Non-invasive measuring methods were used for the quantification of the severity of the dermatitis. Skin thickness and the depth of the microdialysis probes in the skin were measured by 20 MHz ultrasound scanning. Metronidazole concentration, sampled by microdialysis, was 2.4-fold higher in the atopic dermatitis compared with uninvolved skin (p
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In vivo microdialysis for the investigation of Drug levels in the dermis and the effect of barrier perturbation on cutaneous Drug Penetration. Studies in hairless rats and human subjects.
Acta dermato-venereologica. Supplementum, 1999Co-Authors: Eva BenfeldtAbstract:The thesis opens with review chapters concerning theoretical and practical aspects of the investigation of Drug contents in the skin. A discussion of the advantages and limitations of the established methods as well as the relatively new sampling method of microdialysis, which is employed in the experimental section, is given. Factors influencing the barrier function of the normal human skin are described as are the alterations in skin barrier function found in diseased and experimentally barrier perturbed skin. The microdialysis technique consists of introducing an ultra thin, semipermeable tube, a so-called probe, in the dermis. The tube is connected to a precision pump, which provides a steady flow of a tissue-compatible fluid through the probe at a very low flow. Smaller molecules in the tissue, among them the non-protein bound fraction of the Drug content in the extracellular fluid, will passively diffuse across the surface of the membrane and thus enter the flow of the perfusate, which is sampled at regular intervals and analysed. Microdialysis is used for the determination of Drug levels in the skin after topical as well as systemic Drug delivery in the experimental part of the thesis. The method is not applicable to the investigation of all Drugs or compounds, as we have shown that it is not feasible to sample highly protein-bound Drugs or very lipophilic Drugs by microdialysis without further development of the method. The investigation of topical Drug administration consists of 2 studies of cutaneous Penetration of a model Drug, salicylic acid, initially investigated in hairless rats and subsequently in human volunteers. In both studies, barrier perturbation of the skin was undertaken by physical (removal of the stratum corneum by repeated tape stripping) or chemical (treatment with acetone) methods or by provocation of irritative dermatitis (by application of sodium lauryl sulphate, a detergent). Prior to the Penetration experiment, the barrier damage inflicted was quantified by non-invasive measurements of transepidermal, water loss and erythema. The Penetration of salicylic acid, applied in an ethanol solution in chambers glued to the skin in the barrier perturbed areas, was measured by microdialysis sampling of the Drug level in the underlying dermis. At the end of the experiment, probe depth in the dermis and skin thickness were measured by ultrasound scanning. In humans and hairless rats alike, the cutaneous Drug Penetration was highly increased in tape stripped skin (157- and 170-fold increased, respectively, in comparison to the Penetration in unmodified skin) and in skin with irritative dermatitis (46- and 80-fold increased). Delipidization by acetone led to a doubling of the Penetration in humans but had no effect on Penetration in hairless rats. In both studies a close correlation between the measurements of barrier perturbation by non-invasive methods and the cutaneous Drug Penetration in the same area was found. In the human study, the barrier perturbation in the acetone treated area was not measurable by non-invasive methods, whereas Drug Penetration, measured by microdialysis sampling, was significantly increased, indicating that the microdialysis method possesses high sensitivity in the detection and quantification of perturbed skin barrier function. In the human study, a dose-response relationship between the concentration of detergent used for the induction of irritant dermatitis and the ensuing increase in Drug Penetration across the skin could be demonstrated. In the hairless rat study a correlation between probe depth in the dermis and Drug Penetration was found, demonstrating that the more superficially a probe was placed, the earlier it would be reached by the influx of Drug across the skin. Systemic Drug distribution was studied in healthy volunteers following oral administration of 2 g acetylsalicylic acid. (ABSTRACT TRUNCATED)
Yu Nagase - One of the best experts on this subject based on the ideXlab platform.
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Novel transdermal Drug Penetration enhancer: synthesis and enhancing effect of alkyldisiloxane compounds containing glucopyranosyl group
Journal of controlled release : official journal of the Controlled Release Society, 2003Co-Authors: Tomoko Akimoto, Yu NagaseAbstract:Abstract The syntheses of alkyldisiloxanes containing sugar moiety with various alkyl chain length were investigated, in order to develop a silicone-based transdermal Penetration enhancer which was expected to show a low irritation to the skin. 1-Alkyl-3-β- d -glucopyranosyl-1,1,3,3-tetramethyldisiloxanes (Glc–SiCs) were prepared by two-step hydrosilylations of 1-alkene and 1-allyl-β- d -glucose tetraacetate with 1,1,3,3-tetramethyldisiloxane in the presence of bis(benzonitrile)platinum dichloride as the catalyst, followed by hydrolysis of the acetyl groups with sodium methoxide. The enhancing effect of Glc–SiCs on the percutaneous Drug Penetration was evaluated by in vitro experiments using a two-chamber diffusion cell. Antipyrine (ANP) and indomethacin (IND) were used as hydrophilic and hydrophobic model Drugs, respectively, and the amount of Drug permeating through the rat abdominal skin with or without Glc–SiCs was estimated by HPLC. As a result, Glc–SiCs exhibited a enhancing effect on the permeation of both Drugs through the skin, which was influenced by the alkyl chain length of Glc–SiCs. In addition, it was suggested that a suitable balance of polarity would be necessary to appear the high enhancing effect, where Glc–SiCs with octyl and decyl groups exhibited the highest enhancing effect. From the determination of kinetic parameters in the Drug permeation, it was also found that this enhancing effect was due to the increase of both partition and diffusion coefficients of Drug permeation through the skin. By experiments to determine the amount of cholesterol extracted from the skin, the defatting effect would be one of the functions of Glc–SiCs which resulted in the high enhancing activity. Furthermore, according to the Draize test, it was confirmed that Glc–SiCs showed a low irritation to the skin.
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Polymeric transdermal Drug Penetration enhancer. The enhancing effect of oligodimethylsiloxane containing a glucopyranosyl end group.
Journal of controlled release : official journal of the Controlled Release Society, 2001Co-Authors: Tomoko Akimoto, Yu Nagase, K Kawahara, Takao AoyagiAbstract:Oligodimethylsiloxanes (ODMSs) containing a beta-D-glucopyranosyl group at one chain end (Glc-ODMSs) with various molecular weights were prepared to develop a silicone-based polymeric transdermal Penetration enhancer with a non-ionic polar end group. Glc-ODMSs were prepared by hydrosilylation of hydrosilyl-terminated ODMS with 1-allyl-beta-D-glucose tetraacetate in the presence of bis(benzonitrile)platinum dichloride as the catalyst, followed by hydrolysis of the acetyl groups with sodium methoxide. The enhancing effect in the Drug Penetration was evaluated by in vitro experiments using a two-chamber diffusion cell. Antipyrine was used as a model Drug, and the amount of Drug permeating through the rat abdominal skin with or without Glc-ODMS was determined by HPLC. These enhancers were effective for the Penetration of antipyrine. On the other hand, the enhancing effects were influenced by the concentration of Glc-ODMS coexisted regardless of its ODMS chain length. The enhancing effect was also observed by the pretreatment of the skin with Glc-ODMS before the Drug permeation, the results of which suggested that the induction periods to appear the enhancing effects were different between Glc-ODMSs with the short and the long ODMS chain lengths. Furthermore, according to the Draize test, Glc-ODMSs exhibited no irritation to the skin regardless of the ODMS chain length.
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Polymeric transdermal Drug Penetration enhancer. The enhancing effect of oligodimethylsiloxane containing a glucopyranosyl end group.
Journal of Controlled Release, 2001Co-Authors: Tomoko Akimoto, Yu Nagase, K Kawahara, Takao AoyagiAbstract:Abstract Oligodimethylsiloxanes (ODMSs) containing a β- d -glucopyranosyl group at one chain end (Glc–ODMSs) with various molecular weights were prepared to develop a silicone-based polymeric transdermal Penetration enhancer with a non-ionic polar end group. Glc–ODMSs were prepared by hydrosilylation of hydrosilyl-terminated ODMS with 1-allyl-β- d -glucose tetraacetate in the presence of bis(benzonitrile)platinum dichloride as the catalyst, followed by hydrolysis of the acetyl groups with sodium methoxide. The enhancing effect in the Drug Penetration was evaluated by in vitro experiments using a two-chamber diffusion cell. Antipyrine was used as a model Drug, and the amount of Drug permeating through the rat abdominal skin with or without Glc–ODMS was determined by HPLC. These enhancers were effective for the Penetration of antipyrine. On the other hand, the enhancing effects were influenced by the concentration of Glc–ODMS coexisted regardless of its ODMS chain length. The enhancing effect was also observed by the pretreatment of the skin with Glc–ODMS before the Drug permeation, the results of which suggested that the induction periods to appear the enhancing effects were different between Glc–ODMSs with the short and the long ODMS chain lengths. Furthermore, according to the Draize test, Glc–ODMSs exhibited no irritation to the skin regardless of the ODMS chain length.
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Polymeric percutaneous Drug Penetration enhancer: Synthesis and enhancing property of PEG/PDMS block copolymer with a cationic end group
Journal of Controlled Release, 1997Co-Authors: Tomoko Akimoto, Takao Aoyagi, Jun-ichi Minoshima, Yu NagaseAbstract:Poly(ethylene glycol)/polydimethylsiloxane (PEG/PDMS) block copolymers containing an ammonium moiety at one chain end with various molecular weights were prepared to develop a silicone-based polymeric transdermal Penetration enhancer. As the precursor of the desired block copolymer, 3-chloropropyl-terminated PEG/PDMS block copolymers were prepared via an initiator method, i.e. the anionic ring-opening polymerization of hexamethylcyclotrisiloxane was carried out by initiating with silanolate anion derived from PEG-silanol, α-3-(dimethylhydroxysilyl)propyl-ω-methyl-PEG oligomer. The initiator, PEG-silanol, was obtained from α-allyl-PEG by hydrosilylation with dimethylethoxysilane, followed by hydrolysis of the ethoxysilyl group. The enhancing activity in the Drug Penetration was evaluated by in vitro experiments using a two-chamber diffusion cell. Indomethacin and antipyrine were used as hydrophobic and hydrophilic model Drugs, respectively, and the amounts of Drugs permeating through the rabbit abdominal skin were measured with or without these polymeric enhancers. These enhancers were very effective for the Penetration of hydrophilic Drug, but not for that of hydrophobic one. On the other hand, the enhancing activities were influenced by the chain length of PDMS and PEG components. A suitable balance between the hydrophobic PDMS segment and the hydrophilic PEG segment would exist for a high enhancing activity of Drug Penetration. It was also found that the enhancing activity was due to an increase of the partition coefficient of a Drug into the stratum corneum, from the determination of kinetic parameters in the Drug permeation.
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Novel silicones for transdermal therapeutic system, 6. Preparation of oligodimethylsiloxane containing 2‐pyrrolidone moiety as a terminal group and its enhancing effect on transdermal Drug Penetration
Macromolecular Chemistry and Physics, 1996Co-Authors: Takao Aoyagi, Rie Tadenuma, Yu NagaseAbstract:Oligodimethylsiloxanes (ODMSs) containing a 2-pyrrolidone moiety at one chain end were prepared to develop a silicone-based transdermal Penetration enhancer. The 1-alkyl-2-pyrrolidon-3-yl group was introduced as a terminal group of ODMS via the initiator method, i.e., the anionic ring-opening polymerization of hexamethylcyclotrisiloxane was initiated with the silanolate anion derived from (1-alkyl-2-pyrrolidon-3-ylmethyl)dimethylsilanol. The disiloxanes were also prepared from the silanol derivatives by reaction with chlorotrimethylsilane. The enhancing activity of Drug Penetration was evaluated by in vitro experiments using a two-chamber diffusion cell. Indomethacin and antipyrine were used as model Drugs, and the amounts of Drugs permeating through the rabbit abdominal skin were measured with and without the ODMSs or disiloxanes. The enhancing activities are influenced by the chain length of the siloxane components and the chemical structure of their end groups. A suitable balance between the hydrophobic ODMS chain and the polar end group might be decisive for a high enhancing activity of Drug Penetration.
Tzu Chia Wang - One of the best experts on this subject based on the ideXlab platform.
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Spatially Uniform Tumor Treatment and Drug Penetration by Regulating Ultrasound with Microbubbles.
ACS applied materials & interfaces, 2018Co-Authors: Tzu Chia Wang, Ching Hsiang Fan, Chih-kuang YehAbstract:Tumor microenvironment has different morphologies of vessels in the core and rim regions, which influences the efficacy of tumor therapy. Our study proposed to improve the spatial uniformity of the antivascular effect and Drug Penetration within the tumor core and rim in combination therapies by regulating ultrasound-stimulated microbubble destruction (USMD). Focused ultrasound at 2 MHz and lipid-shell microbubbles (1.12 ± 0.08 μm, mean ± standard deviation) were used to perform USMD. The efficiency of the antivascular effect was evaluated by intravital imaging to determine the optimal USMD parameters. Tumor perfusion and histological alterations in the tumor core and rim were used to analyze the spatial uniformity of the antivascular effect and liposomal-doxorubicin (5 mg/kg) Penetration in the combination therapy. Tumor vessels of specific sizes were disrupted by regulating USMD: vessels with sizes of 11 ± 3, 14 ± 5, 19 ± 7, and 23 ± 10 μm were disrupted by stimulation at acoustic pressures of 3, 5, 7, and 9 MPa, respectively (each p < 0.05). The effective treatment time of USMD (at 2 × 107 microbubbles/mouse, 7 MPa, and three cycles) was 60-120 min, which resulted in the disruption of 21-44% of vessels smaller than 50 μm. The reductions in perfusion and vascular density after combination therapy did not differ significantly between the tumor core and rim. This study found that regulating USMD can result in homogeneous antivascular effects and Drug Penetration within tumors and thereby improve the efficacy of combination therapies.
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Spatially Uniform Tumor Treatment and Drug Penetration by Regulating Ultrasound with Microbubbles
2018Co-Authors: Tzu Chia Wang, Ching Hsiang Fan, Chih-kuang YehAbstract:Tumor microenvironment has different morphologies of vessels in the core and rim regions, which influences the efficacy of tumor therapy. Our study proposed to improve the spatial uniformity of the antivascular effect and Drug Penetration within the tumor core and rim in combination therapies by regulating ultrasound-stimulated microbubble destruction (USMD). Focused ultrasound at 2 MHz and lipid-shell microbubbles (1.12 ± 0.08 μm, mean ± standard deviation) were used to perform USMD. The efficiency of the antivascular effect was evaluated by intravital imaging to determine the optimal USMD parameters. Tumor perfusion and histological alterations in the tumor core and rim were used to analyze the spatial uniformity of the antivascular effect and liposomal-doxorubicin (5 mg/kg) Penetration in the combination therapy. Tumor vessels of specific sizes were disrupted by regulating USMD: vessels with sizes of 11 ± 3, 14 ± 5, 19 ± 7, and 23 ± 10 μm were disrupted by stimulation at acoustic pressures of 3, 5, 7, and 9 MPa, respectively (each p < 0.05). The effective treatment time of USMD (at 2 × 107 microbubbles/mouse, 7 MPa, and three cycles) was 60–120 min, which resulted in the disruption of 21–44% of vessels smaller than 50 μm. The reductions in perfusion and vascular density after combination therapy did not differ significantly between the tumor core and rim. This study found that regulating USMD can result in homogeneous antivascular effects and Drug Penetration within tumors and thereby improve the efficacy of combination therapies
