- Email: [email protected]
Biocompatible poly(ethylene oxide phosphonamidate) hydrogel for pH-sensitive doxorubicin release
Abstracts / Journal of Controlled Release 172 (2013) e14–e97
in the drug delivery research field. Poly(p-dioxanone) (PPDO) and poly(3(S)-isobutyl-morpholine-2,5-dione) (PIBMD) have already shown great potential for biomedical applications such as tissue engineering. However, these homopolymers are not suitable for the application as drug delivery matrices because the biodegradation rate and other properties of PPDO and PIBMD cannot be controlled over a wide range. In order to overcome the drawbacks, a promising approach is the introduction of depsipeptide units (having L-amino acid) into PPDO chains to improve its biodegradability and hydrophobicity [1]. Poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) as hydrophilic block has been attached to hydrophobic block mentioned before and then drug-loaded micelles were formed via self-assembly. In this paper, amphiphilic multiblock copolymers PDMAEMA-bP(IBMD-co-PDO)-b- PEG6000-b-P(IBMD-co-PDO)-b-PDMAEMA were synthesized by atom transfer radical polymerization (ATRP) of DMAEMA in CHCl3 using the diblock copolymer Br-P(IBMD-co-PDO)-b-PEG6000-bP(IBMD-co-PDO)-Br as macroinitiator. Micelle formation by the selfassembly process is shown in Scheme 1. Ibuprofen (IBU) [2], as a model drug which contains a carboxylic group and a hydrophobic moiety, was loaded into these micelles by a combination of ionic and hydrophobic interactions. These copolymer micelles had a high loading capacity for IBU (LC, up to 31.0%), encapsulation efficiency of IBU (EE, up to 62.1%) and sustained drug release behavior in phosphate buffered solution (PBS). They self-associated in PBS and formed micellar structures with a diameter less than 100 nm. Therefore, they will hopefully be very promising biomaterials for applications in controlled drug release.
Scheme 1. Schematic illustration of the mechanism of micelle formation by selfassembly.
Keywords: Biodegradable, Depsipeptide, ATRP, PDMAEMA, Ibuprofen Acknowledgements This work was financially supported by International Cooperation from Ministry of Science and Technology of China (MOST grant no. 2008DFA51170) References [1] Y.K. Feng, J. Lu, M. Behl, A. Lendlein, Progress in depsipeptide-based biomaterials, Macromol. Biosci. 10 (2010) 1008–1021. [2] A. Gallardo, J.L. Eguiburu, M.J.F. Berridi, J.S. Roman, Preparation and in vitro release studies of ibuprofen-loaded films and microspheres made from graft copolymers of poly(L-lactic acid) on acrylic backbones, J. Control. Release 55 (1998) 171–179.
doi:10.1016/j.jconrel.2013.08.102
e49
Reduction-sensitive reversible crosslinking of nanoparticles has shown to elegantly resolve the extracellular stability versus intracellular drug release dilemma of nanoscale drug delivery systems [1]. In this study, novel reduction and pH dual-sensitive reversibly core-crosslinked polypeptide micelles were developed from lipoic acid (LA) and cis-1,2cyclohexanedicarboxylic acid (CCA) decorated poly(ethylene glycol)poly(L-lysine) copolypeptides (PEG-P(LL-LA/CCA)) for doxorubicin (DOX) delivery. LA is a natural compound produced in human body. CCA can be easily introduced into the PLL block via amide bond, which is stable at extracellular pH but is readily cleaved at endosomal pH. The core-crosslinked PEG-P(LL-LA/CCA) micelles were observed to be very stable against large volume of dilution, a high salt concentration, and even addition of organic solvent. The in vitro release results showed that DOX was released rapidly from these core-crosslinked micelles under intracellular-mimicking reductive environments (10 mM glutathione (GSH)) at 37 °C in 24 h, whereas only a minor amount (less than 20%) of drug was released under non-reductive physiological conditions. Moreover, slightly increased DOX release was observed when decreasing pH from 7.4 to 5.0 in the presence of 10 mM GSH. MTT assays demonstrated that these polypeptide micelles were nontoxic up to a tested concentration of 1.0 mg/mL, while DOX-loaded micelles had pronounced cytoxic effects to HeLa and HepG2 tumor cells following 48 h incubation.
Fig. 1. Reversibly core-crosslinked PEG-P(LL-LA/CCA) micelles with reduction and pH dual sensitivity for triggered release of DOX. (A) Structure of PEG-P(LL-LA/CCA) copolymers, (B) reduction- and pH-dependent release of DOX from PEG-P(LL-LA/CCA) micelles (CLM: crosslinked micelles, NCLM: non-crosslinked micelles).
Keywords: Micelle, Polypeptide, Reversible crosslinking, Reductionresponsive, pH-responsive Acknowledgements This work was supported by the National Natural Science Foundation of China (NSFC 51003070, 51173126, 50973078, and 20974073) and a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions. Reference [1] Y.L. Li, L. Zhu, Z.Z. Liu, R. Cheng, F.H. Meng, J.H. Cui, S.J. Ji, Z.Y. Zhong, Reversibly stabilized multifunctional dextran nanoparticles efficiently deliver doxorubicin into the nuclei of cancer cells, Angew. Chem. Int. Ed. 48 (2009) 9914–9918.
doi:10.1016/j.jconrel.2013.08.103 Reduction and pH dual-sensitive core-crosslinked polypeptide micelles for triggered doxorubicin release Liangliang Wu, Yan Zou, Chao Deng⁎, Ru Cheng, Fenghua Meng, Zhiyuan Zhong⁎ Biomedical Polymers Laboratory, Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China E-mail addresses: [email protected] (L. Wu), [email protected] (C. Deng), [email protected] (Z. Zhong).
Biocompatible poly(ethylene oxide phosphonamidate) hydrogel for pH-sensitive doxorubicin release Lidong Zhang, Sungil Jang, Eun Su Yun, Il Kim⁎ The World Class University Centre for Synthetic Polymer Bioconjugate Hybrid Materials, Department of Polymer Science and Engineering, Pusan National University, Busan 609-735, Republic of Korea E-mail addresses: [email protected] (L. Zhang), [email protected] (I. Kim).
e50
Abstracts / Journal of Controlled Release 172 (2013) e14–e97
Synthetic hydrogels are alternatives for natural hydrogels thanks to the convenient control of scaffold architecture and chemical composition. Among the family of synthetic hydrogels, poly(ethylene glycol) (PEG)-based hydrogels have attracted considerable interest which are preferable for multipurpose biomedicine applications, since PEGs are biocompatible, and don’t induce adverse reactions with blood and cellular proteins [1,2]. Here, we disclose an intriguing protocol for synthesizing poly (ethylene oxide phosphonamidate) hydrogels as a smart material with high water absorptivity and pH sensitivity. The gel was cross-linked via a condensation reaction between PEO-phosphorous chloride and PEOalkyl amine (Scheme 1). This new hydrogel system exhibits promising advantages including a short reaction time, mass-production, easy separation, and high yield. The hydrogels are noncytotoxic and slightly induce skin inflammation determined by an in vitro viability assay using human embryonic kidney 293T cells and in vivo subdermal implantation in mice models. In view of the results collected, the new hydrogels have been used as scaffolds for controlling drug release by mounting an anticancer drug—doxorubicin in vitro. The release exhibited sustained and reposeful profiles within 5 days, depending upon pH, with specifically enhanced release at low pH 6.0.
combination with both drug and an imaging agents encapsulated in a nanocarrier matrix. Cyanine dyes usually contain two heterocyclic rings linked by a polymethine bridge. Extending the length of the polymethine bridge to each vinyl group is known to cause a ~100 nm red shift of the system [2], but at the cost of the stability. Efforts have been made both to increase its chemical stability as well as optical properties during recent years. Polypeptide materials represent a class of biocompatible polymers with great potential in biomedical applications. They can be easily obtained by step-wise ring opening polymerization of amino acid Ncarboxyanhydride (NCA). Both their physical and chemical properties can be tuned if NCAs with different side groups are incorporated. Block copolymers as well as branched polymers with polypeptide moieties have been widely used by different researchers for different purposes such as gene delivery and drug delivery. Here, we report the synthesis of a series of polypeptide based theranostic nanogels with NIR fluorescence (NIRF nanogel). Cellular uptake study of both the NIRF nanogel and NIRF prodrug shows that both of the two materials could enter the cell via endocytosis, and the enwrapped drug can be released from the nanogel and accumulates inside the nuclei while the polymeric nanogel was disassembled in cytoplasm, and the process can be directly imaged by means of the NIR imaging. In vivo distribution of the NIRF nanogel and NIRF prodrug on tumor bearing nude mice shows that both the NIRF nanogel and NIRF prodrug accumulate at the tumor place 24 h after the tail veil injection via the enhanced permeability and retention (EPR) effect. The NIRF prodrug prepared here has the potential application for the theranosis of cancer.
Scheme 1. Low molecular weight PEG (Mn = 300–600 Da) based hydrogels that exhibit superior structural-integrity, low cytotoxicity (293T cells culture and hydrogel implantation assay on the back of mouse), and controlled drug release.
Keywords: Controlled drug release, Poly(ethylene glycol), Biocompatibility, Degradability, Hydrogel Acknowledgements This work was supported by grants-in-aid for the World Class University Program (No. R32-2008-000-10174-0). References [1] J.M. Zhu, Bioactive modification of poly(ethylene glycol) hydrogels for tissue engineering, Biomaterials 31 (2010) 4639–4656. [2] A.M. Kloxin, C.J. Kloxin, C.N. Bowman, K.S. Anseth, Mechanical properties of cellularly responsive hydrogels and their experimental determination, Adv. Mater. 22 (2010) 3484–3494.
doi:10.1016/j.jconrel.2013.08.104
Synthesis of NIR probe conjugated polypeptide for drug delivery and imaging
Fig. 1. Structure of one NIRF nanogel by a one-step ring opening copolymerization of L-Cystine-NCA and Lys-NCA, and the single cell image of NIRF prodrug cellular uptake at the early stage.
Keywords: Drug delivery, NIR imaging, Polypeptide Acknowledgements This work was supported by the National Natural Science Foundation of China (NSFC 50173147).
Tao Xing, Bin Lai, Chengqiong Mao, Lifeng Yan⁎ Hefei National Laboratory for Physical Sciences at the Microscale, Department of Chemical Physics, University of Science and Technology of China, Hefei 230026, China E-mail address: [email protected] (L. Yan).
References
Imaging of the drug delivery in the cell or body has attracted much attention recently [1]. Generally, the system is a three component
doi:10.1016/j.jconrel.2013.08.105
[1] H. Koo, M.S. Huh, I.C. Sun, S.H. Yuk, K. Choi, K. Kim, I.C. Kwon, In vivo targeted delivery of nanoparticles for theranosis, Acc. Chem. Res. 44 (2011) 1018–1028. [2] W. Pham, Z. Medarova, A. Moore, Synthesis and application of a water-soluble nearinfrared dye for cancer detection using optical imaging, Bioconjug. Chem. 16 (2005) 735–740.
in the drug delivery research field. Poly(p-dioxanone) (PPDO) and poly(3(S)-isobutyl-morpholine-2,5-dione) (PIBMD) have already shown great potential for biomedical applications such as tissue engineering. However, these homopolymers are not suitable for the application as drug delivery matrices because the biodegradation rate and other properties of PPDO and PIBMD cannot be controlled over a wide range. In order to overcome the drawbacks, a promising approach is the introduction of depsipeptide units (having L-amino acid) into PPDO chains to improve its biodegradability and hydrophobicity [1]. Poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) as hydrophilic block has been attached to hydrophobic block mentioned before and then drug-loaded micelles were formed via self-assembly. In this paper, amphiphilic multiblock copolymers PDMAEMA-bP(IBMD-co-PDO)-b- PEG6000-b-P(IBMD-co-PDO)-b-PDMAEMA were synthesized by atom transfer radical polymerization (ATRP) of DMAEMA in CHCl3 using the diblock copolymer Br-P(IBMD-co-PDO)-b-PEG6000-bP(IBMD-co-PDO)-Br as macroinitiator. Micelle formation by the selfassembly process is shown in Scheme 1. Ibuprofen (IBU) [2], as a model drug which contains a carboxylic group and a hydrophobic moiety, was loaded into these micelles by a combination of ionic and hydrophobic interactions. These copolymer micelles had a high loading capacity for IBU (LC, up to 31.0%), encapsulation efficiency of IBU (EE, up to 62.1%) and sustained drug release behavior in phosphate buffered solution (PBS). They self-associated in PBS and formed micellar structures with a diameter less than 100 nm. Therefore, they will hopefully be very promising biomaterials for applications in controlled drug release.
Scheme 1. Schematic illustration of the mechanism of micelle formation by selfassembly.
Keywords: Biodegradable, Depsipeptide, ATRP, PDMAEMA, Ibuprofen Acknowledgements This work was financially supported by International Cooperation from Ministry of Science and Technology of China (MOST grant no. 2008DFA51170) References [1] Y.K. Feng, J. Lu, M. Behl, A. Lendlein, Progress in depsipeptide-based biomaterials, Macromol. Biosci. 10 (2010) 1008–1021. [2] A. Gallardo, J.L. Eguiburu, M.J.F. Berridi, J.S. Roman, Preparation and in vitro release studies of ibuprofen-loaded films and microspheres made from graft copolymers of poly(L-lactic acid) on acrylic backbones, J. Control. Release 55 (1998) 171–179.
doi:10.1016/j.jconrel.2013.08.102
e49
Reduction-sensitive reversible crosslinking of nanoparticles has shown to elegantly resolve the extracellular stability versus intracellular drug release dilemma of nanoscale drug delivery systems [1]. In this study, novel reduction and pH dual-sensitive reversibly core-crosslinked polypeptide micelles were developed from lipoic acid (LA) and cis-1,2cyclohexanedicarboxylic acid (CCA) decorated poly(ethylene glycol)poly(L-lysine) copolypeptides (PEG-P(LL-LA/CCA)) for doxorubicin (DOX) delivery. LA is a natural compound produced in human body. CCA can be easily introduced into the PLL block via amide bond, which is stable at extracellular pH but is readily cleaved at endosomal pH. The core-crosslinked PEG-P(LL-LA/CCA) micelles were observed to be very stable against large volume of dilution, a high salt concentration, and even addition of organic solvent. The in vitro release results showed that DOX was released rapidly from these core-crosslinked micelles under intracellular-mimicking reductive environments (10 mM glutathione (GSH)) at 37 °C in 24 h, whereas only a minor amount (less than 20%) of drug was released under non-reductive physiological conditions. Moreover, slightly increased DOX release was observed when decreasing pH from 7.4 to 5.0 in the presence of 10 mM GSH. MTT assays demonstrated that these polypeptide micelles were nontoxic up to a tested concentration of 1.0 mg/mL, while DOX-loaded micelles had pronounced cytoxic effects to HeLa and HepG2 tumor cells following 48 h incubation.
Fig. 1. Reversibly core-crosslinked PEG-P(LL-LA/CCA) micelles with reduction and pH dual sensitivity for triggered release of DOX. (A) Structure of PEG-P(LL-LA/CCA) copolymers, (B) reduction- and pH-dependent release of DOX from PEG-P(LL-LA/CCA) micelles (CLM: crosslinked micelles, NCLM: non-crosslinked micelles).
Keywords: Micelle, Polypeptide, Reversible crosslinking, Reductionresponsive, pH-responsive Acknowledgements This work was supported by the National Natural Science Foundation of China (NSFC 51003070, 51173126, 50973078, and 20974073) and a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions. Reference [1] Y.L. Li, L. Zhu, Z.Z. Liu, R. Cheng, F.H. Meng, J.H. Cui, S.J. Ji, Z.Y. Zhong, Reversibly stabilized multifunctional dextran nanoparticles efficiently deliver doxorubicin into the nuclei of cancer cells, Angew. Chem. Int. Ed. 48 (2009) 9914–9918.
doi:10.1016/j.jconrel.2013.08.103 Reduction and pH dual-sensitive core-crosslinked polypeptide micelles for triggered doxorubicin release Liangliang Wu, Yan Zou, Chao Deng⁎, Ru Cheng, Fenghua Meng, Zhiyuan Zhong⁎ Biomedical Polymers Laboratory, Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China E-mail addresses: [email protected] (L. Wu), [email protected] (C. Deng), [email protected] (Z. Zhong).
Biocompatible poly(ethylene oxide phosphonamidate) hydrogel for pH-sensitive doxorubicin release Lidong Zhang, Sungil Jang, Eun Su Yun, Il Kim⁎ The World Class University Centre for Synthetic Polymer Bioconjugate Hybrid Materials, Department of Polymer Science and Engineering, Pusan National University, Busan 609-735, Republic of Korea E-mail addresses: [email protected] (L. Zhang), [email protected] (I. Kim).
e50
Abstracts / Journal of Controlled Release 172 (2013) e14–e97
Synthetic hydrogels are alternatives for natural hydrogels thanks to the convenient control of scaffold architecture and chemical composition. Among the family of synthetic hydrogels, poly(ethylene glycol) (PEG)-based hydrogels have attracted considerable interest which are preferable for multipurpose biomedicine applications, since PEGs are biocompatible, and don’t induce adverse reactions with blood and cellular proteins [1,2]. Here, we disclose an intriguing protocol for synthesizing poly (ethylene oxide phosphonamidate) hydrogels as a smart material with high water absorptivity and pH sensitivity. The gel was cross-linked via a condensation reaction between PEO-phosphorous chloride and PEOalkyl amine (Scheme 1). This new hydrogel system exhibits promising advantages including a short reaction time, mass-production, easy separation, and high yield. The hydrogels are noncytotoxic and slightly induce skin inflammation determined by an in vitro viability assay using human embryonic kidney 293T cells and in vivo subdermal implantation in mice models. In view of the results collected, the new hydrogels have been used as scaffolds for controlling drug release by mounting an anticancer drug—doxorubicin in vitro. The release exhibited sustained and reposeful profiles within 5 days, depending upon pH, with specifically enhanced release at low pH 6.0.
combination with both drug and an imaging agents encapsulated in a nanocarrier matrix. Cyanine dyes usually contain two heterocyclic rings linked by a polymethine bridge. Extending the length of the polymethine bridge to each vinyl group is known to cause a ~100 nm red shift of the system [2], but at the cost of the stability. Efforts have been made both to increase its chemical stability as well as optical properties during recent years. Polypeptide materials represent a class of biocompatible polymers with great potential in biomedical applications. They can be easily obtained by step-wise ring opening polymerization of amino acid Ncarboxyanhydride (NCA). Both their physical and chemical properties can be tuned if NCAs with different side groups are incorporated. Block copolymers as well as branched polymers with polypeptide moieties have been widely used by different researchers for different purposes such as gene delivery and drug delivery. Here, we report the synthesis of a series of polypeptide based theranostic nanogels with NIR fluorescence (NIRF nanogel). Cellular uptake study of both the NIRF nanogel and NIRF prodrug shows that both of the two materials could enter the cell via endocytosis, and the enwrapped drug can be released from the nanogel and accumulates inside the nuclei while the polymeric nanogel was disassembled in cytoplasm, and the process can be directly imaged by means of the NIR imaging. In vivo distribution of the NIRF nanogel and NIRF prodrug on tumor bearing nude mice shows that both the NIRF nanogel and NIRF prodrug accumulate at the tumor place 24 h after the tail veil injection via the enhanced permeability and retention (EPR) effect. The NIRF prodrug prepared here has the potential application for the theranosis of cancer.
Scheme 1. Low molecular weight PEG (Mn = 300–600 Da) based hydrogels that exhibit superior structural-integrity, low cytotoxicity (293T cells culture and hydrogel implantation assay on the back of mouse), and controlled drug release.
Keywords: Controlled drug release, Poly(ethylene glycol), Biocompatibility, Degradability, Hydrogel Acknowledgements This work was supported by grants-in-aid for the World Class University Program (No. R32-2008-000-10174-0). References [1] J.M. Zhu, Bioactive modification of poly(ethylene glycol) hydrogels for tissue engineering, Biomaterials 31 (2010) 4639–4656. [2] A.M. Kloxin, C.J. Kloxin, C.N. Bowman, K.S. Anseth, Mechanical properties of cellularly responsive hydrogels and their experimental determination, Adv. Mater. 22 (2010) 3484–3494.
doi:10.1016/j.jconrel.2013.08.104
Synthesis of NIR probe conjugated polypeptide for drug delivery and imaging
Fig. 1. Structure of one NIRF nanogel by a one-step ring opening copolymerization of L-Cystine-NCA and Lys-NCA, and the single cell image of NIRF prodrug cellular uptake at the early stage.
Keywords: Drug delivery, NIR imaging, Polypeptide Acknowledgements This work was supported by the National Natural Science Foundation of China (NSFC 50173147).
Tao Xing, Bin Lai, Chengqiong Mao, Lifeng Yan⁎ Hefei National Laboratory for Physical Sciences at the Microscale, Department of Chemical Physics, University of Science and Technology of China, Hefei 230026, China E-mail address: [email protected] (L. Yan).
References
Imaging of the drug delivery in the cell or body has attracted much attention recently [1]. Generally, the system is a three component
doi:10.1016/j.jconrel.2013.08.105
[1] H. Koo, M.S. Huh, I.C. Sun, S.H. Yuk, K. Choi, K. Kim, I.C. Kwon, In vivo targeted delivery of nanoparticles for theranosis, Acc. Chem. Res. 44 (2011) 1018–1028. [2] W. Pham, Z. Medarova, A. Moore, Synthesis and application of a water-soluble nearinfrared dye for cancer detection using optical imaging, Bioconjug. Chem. 16 (2005) 735–740.