- Email: [email protected]
Infrared radiation triggered detachable bio-adhesive hybrid hydrogels
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Abstracts / Journal of Controlled Release 213 (2015) e8–e152
Therapeutic response to HMGB1-R3V6-conjugated Ym1/Ym2 siRNA complex in ovalbumin-induced murine asthma Jahyun Gua,b, Moonhwan Choia,b, Taehyun Bana,b, Sol Kima,b, Youngjin Kimc, Minhyung Leea,b, Taiyoun Rhima,b a Department of Bioengineering, College of Engineering, Hanyang University, Seoul 133-791, Republic of Korea b Institute of Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul 133-791, Republic of Korea c Gyeonggi Science highschool for gifted, Seoul 133-791, Republic of Korea E-mail address: [email protected] (T. Ban). Asthma is a chronic inflammatory disease characterized by airway inflammation, mucus hypersecretion and airway hyper-responsiveness. Previously, we reported that the expression of Ym1 and Ym2 proteins was increased in allergic asthma lung tissue [1]. Ym1 and Ym2 were known to be synthesized by activated macrophages and homologous to chitinase. HMGB1-R3V6 is a delivery carrier of siRNA for treating acute lung injury [2]. In this study, we investigated the role of Ym1 and Ym2 in allergic asthma using siRNA mediated knock down approach. To facilitate the transfection of siRNA into allergic asthma mice model, HMGB1-R3V6 was used as carrier molecule. The results showed that silencing of Ym1 and Ym2 by HMGB1-R3V6-Ym1/Ym2 siRNA treatment significantly reduced allergic asthma. Treatment with siRNAs reduced the ovalbumin sensitization/challenge-induced enhancement of airway inflammation, goblet cell hyperplasia, and levels of eotaxin, interleukin-4, -5, -13, and interferon-g.
⁎Corresponding author. E-mail addresses: [email protected] (T. Sun), [email protected] (J.-C. Leroux). The delivery of poorly water-soluble drugs represents a considerable challenge in pharmaceutical sciences. Several approaches, such as solubilizing adjuvants (i.e., co-solvents, surfactants, complexing agents) or molecular dispersion, have been developed to overcome the solubility issue. Most of the strategies are based on the physical interactions between drugs and excipients, which are not so stable neither controllable, especially when in vivo. Stimuli-responsive prodrug approach, linking the drug and solubilizing groups via covalent bonds, is regarded as a favorable choice in managing the in vivo drug delivery in a controllable way. Among drug-delivery routes, oral administration is the preferred modality because of convenience and better patient compliance. Surprisingly, only few prodrug approaches have been proposed for the oral delivery of poorly soluble drugs [1]. Here, we report an oral prodrug strategy based on a redox-sensitive self-immolating platform (Scheme 1). A solubilizing group is conjugated to the drug via a disulfide bond in order to obtain a soluble prodrug. The reconversion of the prodrug takes place in the gut lumen by the action of a co-administered reducing agent, N-acetylcysteine (NAC), a safe dietary supplement. The disulfide bond cleavage generates an intermediate, which goes through a self-immolated process to release the free hydrophobic drug, which can then be absorbed. By controlling the amount of co-administered NAC, we can modulate the reconversion drug-release kinetic and location of the prodrug in the gastro-intestinal tract. Three prodrugs were successfully prepared with phenytoin, SN38 and mitomycin C as the drug models. The reconversion kinetic was studied in pH 4.5/6.8 buffers, as well as in simulated gastric fluid (SGF)/ simulated intestinal fluid (SIF). The drug-release was relatively slow in SGF and fast in SIF, serving well with the fact that the main drugabsorbance location is in the small intestinal.
Fig. 1. Ym1 is present in aveolar sacs (Blue — DAPI, Green — Ym1 antibody, Red — cy5 labeled siRNA). In asthma, macrophage increased and Ym1 also was overexpressed in macrophage. The expressions of Ym1 protein were reduced in HMGB1-R3V6 conjugated siRNA-treated groups.
Keywords: asthma, Ym1, Ym2, HMGB1-R3V6, siRNA References [1] H.M. Song, A.S. Jang, M.H. Ahn, H. Takizawa, S.H. Lee, J.H. Kwon, Y.M. Lee, T. Rhim, C.S. Park, Ym1 and Ym2 expression in a mouse model exposed to diesel exhaust particles, Environ. Toxicol. 23 (2008) 110–116. [2] B. Oh, M. Lee, Combined delivery of HMGB-1 box A peptide and S1PLyase siRNA in animal models of acute lung injury, J. Control. Release 175 (2014) 25–35.
Scheme 1. Illustration of the mechanism of the oral prodrug strategy.
Keywords: oral, prodrug, drug delivery, poorly soluble drug, SN-38 Acknowledgments This work was supported by a Novartis Fellowship to Dr. Tao Sun. Reference [1] J. Rautio, H. Kumpulainen, T. Heimbach, R. Oliyai, D. Oh, T. Järvinen, J. Savolainen, Prodrugs: design and clinical applications, Nat. Rev. Drug Discov. 7 (2008) 255–270.
doi:10.1016/j.jconrel.2015.05.170 doi:10.1016/j.jconrel.2015.05.171 Oral prodrug strategy for poorly soluble drugs Infrared radiation triggered detachable bio-adhesive hybrid hydrogels Tao Sun, Andrea Morger, Bastien Castagner, Jean-Christophe Leroux* Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich (ETH Zurich), 8093 Zurich, Switzerland
Tao Wang, Yiqing Yang, Weixiang Sun, Chaoyang Wang, Xinxing Liu, Zhen Tong*
Abstracts / Journal of Controlled Release 213 (2015) e8–e152
Research Institute of Materials Science, State Key Laboratory of Luminescent Materials and Devices, South China University of Technology, Guangzhou 510640, China ⁎Corresponding author. E-mail addresses: [email protected] (T. Wang), [email protected] (Z. Tong). Hydrogels have essential applications in tissue engineering and controlled drug release. In the present work, we present a bio-adhesive hybrid hydrogel with infrared radiation (IR) triggered detaching property based on thermo-sensitive poly(N-isopropylacrylamide) (PNIPAm) and graphene oxide (GO). This kind of hydrogel can stick to skin during use and can be easily detached by IR triggering when necessary. The bio-adhesive hybrid hydrogel was prepared by in-situ polymerization of NIPAm in a hectorite clay and GO aqueous suspension [1]. αCyclodextrin (α-CD) was introduced to improve the stickiness. Fresh pig skin and stainless steel were used as substrates to test the adhesiveness of the hydrogels. The IR triggered detachment of hydrogel was controlled by laser irradiation (λ = 808 nm). The hydrogels showed excellent mechanical strength and extensibility. The tensile strength and elongation ratio at break were about 40 kPa and over 800%, respectively (Fig. 1A). The adhesive strength of hydrogels on pig skin was measured through the peeling test [2]. The adhesive strength of pure PNIPAm-clay hydrogels (type I) was low (~20 N/m), while it increased for more than 200% with the addition of α-CD (over 60 N/m). This may be due to introduction of a large amount of hydroxyl groups provided by α-CD, which could enhance the interaction between hydrogel and substrate through hydrogen bonding. When exposed to laser, the hydrogel with GO quickly underwent a phase transition as GO adsorbed the laser irradiation and turned it to thermal energy which heated the thermo-sensitive PNIPAm gel (the phase transition temperature of PNIPAm is ~32 °C, and this temperature could be adjusted by introducing hydrophilic monomers such as acrylamide). The phase transition will lead to the detachment of the gel from the substrate (type IV in Fig. 1B). The NC gels without GO did not change under laser irradiation (type III in Fig. 1B). In summary, we report a bio-adhesive hybrid hydrogel with IR triggered detachable properties, which has potential application in adhesive drug delivery systems and wound dress materials on human skins.
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References [1] E. Zhang, T. Wang, C. Lian, W. Sun, X. Liu, Z. Tong, Robust and thermo-response graphene—PNIPAm hybrid hydrogels reinforced by hectorite clay, Carbon 62 (2013) 117–126. [2] T. Kurokawa, H. Furukawa, W. Wang, Y. Tanaka, J.P. Gong, Formation of a strong hydrogel-porous solid interface via the double-network principle, Acta Biomater. 6 (2010) 1353–1359.
doi:10.1016/j.jconrel.2015.05.172
Preparation of fluorescent microspheres via layer-by-layer self-assembly Tian Qiu, Jing Song, Li-Juan Fan* Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, Department of Polymer Science and Engineering, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China ⁎Corresponding author. E-mail address: [email protected] (L.-J. Fan). Fluorescent microspheres play a very important role in the modern high-throughput technology [1]. Layer-by-layer (LBL) selfassembly technology is an attractive approach for fabricating multilayer materials by depositing alternating layers through weak intermolecular interactions, such as electrostatic attraction, hydrogen bonding, and coordination bonding [2]. High structural integrity, stable performance and certain specific functions can be realized for this material if the whole process is well-controlled. Conjugated polymers have been demonstrated to have many merits as fluorophore. This study aims to employ LBL methods to prepare multilayer conjugated polymers coated microspheres. Poly-(p-phenylenevinylene) (PPV), one of the most extensively studied conjugated polymers, was used as the fluorophorein in this study. Polystyrene-divinylbenzene (SPSDVB) microspheres with negative sulfonic groups on the surface are used as substrate microspheres. PAAS/PSS was used as polyanion and PPV precursor was used as polycation. Thermal elimination following the LBL deposition gave a series of SPSDVB-(PPV/PAAS)n and SPSDVB(PPV/PSS)n multilayer fluorescent microspheres. These fluorescent microspheres were also found to have excellent morphology and strong fluorescence (Fig. 1).
Fig. 1. (A) Stress-strain curves of indicated types of hydrogels. (B) Laser induced detachment of type IV gel, type III gel was observed for comparison.
Keywords: infrared radiation, detachable, bio-adhesive, hydrogel, graphene oxide Acknowledgments The financial support from the NSFC (51173052, 51203052), the National Basic Research Program of China (973 Program, 2012CB821504) and the China Postdoctoral Science Foundation (2013T60801, 2012M511800) is gratefully acknowledged.
Fig. 1. SEM image (a) and fluorescence microscopy image (b) of SPSDVB-(PPV/PAAS)n microspheres obtained by layer-by-layer self-assembly.
Abstracts / Journal of Controlled Release 213 (2015) e8–e152
Therapeutic response to HMGB1-R3V6-conjugated Ym1/Ym2 siRNA complex in ovalbumin-induced murine asthma Jahyun Gua,b, Moonhwan Choia,b, Taehyun Bana,b, Sol Kima,b, Youngjin Kimc, Minhyung Leea,b, Taiyoun Rhima,b a Department of Bioengineering, College of Engineering, Hanyang University, Seoul 133-791, Republic of Korea b Institute of Bioengineering and Biopharmaceutical Research, Hanyang University, Seoul 133-791, Republic of Korea c Gyeonggi Science highschool for gifted, Seoul 133-791, Republic of Korea E-mail address: [email protected] (T. Ban). Asthma is a chronic inflammatory disease characterized by airway inflammation, mucus hypersecretion and airway hyper-responsiveness. Previously, we reported that the expression of Ym1 and Ym2 proteins was increased in allergic asthma lung tissue [1]. Ym1 and Ym2 were known to be synthesized by activated macrophages and homologous to chitinase. HMGB1-R3V6 is a delivery carrier of siRNA for treating acute lung injury [2]. In this study, we investigated the role of Ym1 and Ym2 in allergic asthma using siRNA mediated knock down approach. To facilitate the transfection of siRNA into allergic asthma mice model, HMGB1-R3V6 was used as carrier molecule. The results showed that silencing of Ym1 and Ym2 by HMGB1-R3V6-Ym1/Ym2 siRNA treatment significantly reduced allergic asthma. Treatment with siRNAs reduced the ovalbumin sensitization/challenge-induced enhancement of airway inflammation, goblet cell hyperplasia, and levels of eotaxin, interleukin-4, -5, -13, and interferon-g.
⁎Corresponding author. E-mail addresses: [email protected] (T. Sun), [email protected] (J.-C. Leroux). The delivery of poorly water-soluble drugs represents a considerable challenge in pharmaceutical sciences. Several approaches, such as solubilizing adjuvants (i.e., co-solvents, surfactants, complexing agents) or molecular dispersion, have been developed to overcome the solubility issue. Most of the strategies are based on the physical interactions between drugs and excipients, which are not so stable neither controllable, especially when in vivo. Stimuli-responsive prodrug approach, linking the drug and solubilizing groups via covalent bonds, is regarded as a favorable choice in managing the in vivo drug delivery in a controllable way. Among drug-delivery routes, oral administration is the preferred modality because of convenience and better patient compliance. Surprisingly, only few prodrug approaches have been proposed for the oral delivery of poorly soluble drugs [1]. Here, we report an oral prodrug strategy based on a redox-sensitive self-immolating platform (Scheme 1). A solubilizing group is conjugated to the drug via a disulfide bond in order to obtain a soluble prodrug. The reconversion of the prodrug takes place in the gut lumen by the action of a co-administered reducing agent, N-acetylcysteine (NAC), a safe dietary supplement. The disulfide bond cleavage generates an intermediate, which goes through a self-immolated process to release the free hydrophobic drug, which can then be absorbed. By controlling the amount of co-administered NAC, we can modulate the reconversion drug-release kinetic and location of the prodrug in the gastro-intestinal tract. Three prodrugs were successfully prepared with phenytoin, SN38 and mitomycin C as the drug models. The reconversion kinetic was studied in pH 4.5/6.8 buffers, as well as in simulated gastric fluid (SGF)/ simulated intestinal fluid (SIF). The drug-release was relatively slow in SGF and fast in SIF, serving well with the fact that the main drugabsorbance location is in the small intestinal.
Fig. 1. Ym1 is present in aveolar sacs (Blue — DAPI, Green — Ym1 antibody, Red — cy5 labeled siRNA). In asthma, macrophage increased and Ym1 also was overexpressed in macrophage. The expressions of Ym1 protein were reduced in HMGB1-R3V6 conjugated siRNA-treated groups.
Keywords: asthma, Ym1, Ym2, HMGB1-R3V6, siRNA References [1] H.M. Song, A.S. Jang, M.H. Ahn, H. Takizawa, S.H. Lee, J.H. Kwon, Y.M. Lee, T. Rhim, C.S. Park, Ym1 and Ym2 expression in a mouse model exposed to diesel exhaust particles, Environ. Toxicol. 23 (2008) 110–116. [2] B. Oh, M. Lee, Combined delivery of HMGB-1 box A peptide and S1PLyase siRNA in animal models of acute lung injury, J. Control. Release 175 (2014) 25–35.
Scheme 1. Illustration of the mechanism of the oral prodrug strategy.
Keywords: oral, prodrug, drug delivery, poorly soluble drug, SN-38 Acknowledgments This work was supported by a Novartis Fellowship to Dr. Tao Sun. Reference [1] J. Rautio, H. Kumpulainen, T. Heimbach, R. Oliyai, D. Oh, T. Järvinen, J. Savolainen, Prodrugs: design and clinical applications, Nat. Rev. Drug Discov. 7 (2008) 255–270.
doi:10.1016/j.jconrel.2015.05.170 doi:10.1016/j.jconrel.2015.05.171 Oral prodrug strategy for poorly soluble drugs Infrared radiation triggered detachable bio-adhesive hybrid hydrogels Tao Sun, Andrea Morger, Bastien Castagner, Jean-Christophe Leroux* Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zurich (ETH Zurich), 8093 Zurich, Switzerland
Tao Wang, Yiqing Yang, Weixiang Sun, Chaoyang Wang, Xinxing Liu, Zhen Tong*
Abstracts / Journal of Controlled Release 213 (2015) e8–e152
Research Institute of Materials Science, State Key Laboratory of Luminescent Materials and Devices, South China University of Technology, Guangzhou 510640, China ⁎Corresponding author. E-mail addresses: [email protected] (T. Wang), [email protected] (Z. Tong). Hydrogels have essential applications in tissue engineering and controlled drug release. In the present work, we present a bio-adhesive hybrid hydrogel with infrared radiation (IR) triggered detaching property based on thermo-sensitive poly(N-isopropylacrylamide) (PNIPAm) and graphene oxide (GO). This kind of hydrogel can stick to skin during use and can be easily detached by IR triggering when necessary. The bio-adhesive hybrid hydrogel was prepared by in-situ polymerization of NIPAm in a hectorite clay and GO aqueous suspension [1]. αCyclodextrin (α-CD) was introduced to improve the stickiness. Fresh pig skin and stainless steel were used as substrates to test the adhesiveness of the hydrogels. The IR triggered detachment of hydrogel was controlled by laser irradiation (λ = 808 nm). The hydrogels showed excellent mechanical strength and extensibility. The tensile strength and elongation ratio at break were about 40 kPa and over 800%, respectively (Fig. 1A). The adhesive strength of hydrogels on pig skin was measured through the peeling test [2]. The adhesive strength of pure PNIPAm-clay hydrogels (type I) was low (~20 N/m), while it increased for more than 200% with the addition of α-CD (over 60 N/m). This may be due to introduction of a large amount of hydroxyl groups provided by α-CD, which could enhance the interaction between hydrogel and substrate through hydrogen bonding. When exposed to laser, the hydrogel with GO quickly underwent a phase transition as GO adsorbed the laser irradiation and turned it to thermal energy which heated the thermo-sensitive PNIPAm gel (the phase transition temperature of PNIPAm is ~32 °C, and this temperature could be adjusted by introducing hydrophilic monomers such as acrylamide). The phase transition will lead to the detachment of the gel from the substrate (type IV in Fig. 1B). The NC gels without GO did not change under laser irradiation (type III in Fig. 1B). In summary, we report a bio-adhesive hybrid hydrogel with IR triggered detachable properties, which has potential application in adhesive drug delivery systems and wound dress materials on human skins.
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References [1] E. Zhang, T. Wang, C. Lian, W. Sun, X. Liu, Z. Tong, Robust and thermo-response graphene—PNIPAm hybrid hydrogels reinforced by hectorite clay, Carbon 62 (2013) 117–126. [2] T. Kurokawa, H. Furukawa, W. Wang, Y. Tanaka, J.P. Gong, Formation of a strong hydrogel-porous solid interface via the double-network principle, Acta Biomater. 6 (2010) 1353–1359.
doi:10.1016/j.jconrel.2015.05.172
Preparation of fluorescent microspheres via layer-by-layer self-assembly Tian Qiu, Jing Song, Li-Juan Fan* Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, Department of Polymer Science and Engineering, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China ⁎Corresponding author. E-mail address: [email protected] (L.-J. Fan). Fluorescent microspheres play a very important role in the modern high-throughput technology [1]. Layer-by-layer (LBL) selfassembly technology is an attractive approach for fabricating multilayer materials by depositing alternating layers through weak intermolecular interactions, such as electrostatic attraction, hydrogen bonding, and coordination bonding [2]. High structural integrity, stable performance and certain specific functions can be realized for this material if the whole process is well-controlled. Conjugated polymers have been demonstrated to have many merits as fluorophore. This study aims to employ LBL methods to prepare multilayer conjugated polymers coated microspheres. Poly-(p-phenylenevinylene) (PPV), one of the most extensively studied conjugated polymers, was used as the fluorophorein in this study. Polystyrene-divinylbenzene (SPSDVB) microspheres with negative sulfonic groups on the surface are used as substrate microspheres. PAAS/PSS was used as polyanion and PPV precursor was used as polycation. Thermal elimination following the LBL deposition gave a series of SPSDVB-(PPV/PAAS)n and SPSDVB(PPV/PSS)n multilayer fluorescent microspheres. These fluorescent microspheres were also found to have excellent morphology and strong fluorescence (Fig. 1).
Fig. 1. (A) Stress-strain curves of indicated types of hydrogels. (B) Laser induced detachment of type IV gel, type III gel was observed for comparison.
Keywords: infrared radiation, detachable, bio-adhesive, hydrogel, graphene oxide Acknowledgments The financial support from the NSFC (51173052, 51203052), the National Basic Research Program of China (973 Program, 2012CB821504) and the China Postdoctoral Science Foundation (2013T60801, 2012M511800) is gratefully acknowledged.
Fig. 1. SEM image (a) and fluorescence microscopy image (b) of SPSDVB-(PPV/PAAS)n microspheres obtained by layer-by-layer self-assembly.