- Email: [email protected]
Preparation and salt-responsive drug controlled release of complex nanoparticles of poly[(2-dimethylamino) ethyl methacrylate] and Alginic acid
e34
Abstracts / Journal of Controlled Release 172 (2013) e14–e97
the acidic micro-environment in early endosome and late endosome/ lysosome, here, we report pH-responsive poly(ethylene glycol)block-poly(2-diisopropylamino ethyl methacrylate) (PEG-b-PDPA) wormlike micelles for the delivery of hydrophobic drugs. To exploit the pH-responsiveness of PEG-b-PDPA wormlike micelles, the PDPA segment was functionalized with hydroxyl pendant groups, and then labeled with a pH non-responsive fluorescence dye of tetramethyl rhodamine (TMR). Fluorescence images of a series of micellar solutions were taken at different pHs. At pHs above 6.3, the micellar solution produced negligible fluorophore signal owing to aggregation of TMR molecules inside the micelle core. At pHs below 6.3, the PDPA block was protonated and became water-soluble, thus leading to micelle disassembly and dramatic increase in fluorescence emission (Scheme 1) [1]. The TMR-conjugated wormlike micelles were further investigated for their intracellular uptake and activation in A-549 lung cancer cells. Punctuated fluorescence dots appeared inside the cells 30 min after micelle incubation, indicating the efficient uptake and activation of the TMR-labeled micelles inside the acidic endosomes. The number of red fluorescence dots increased gradually due to cellular accumulation of the wormlike micelles. All these data indicated that the pH-responsive wormlike micelles are potent candidates for intracellular delivery of hydrophobic drugs.
The prodrug strategy has been shown to be a powerful tool for drug delivery and has led to widespread clinical use. The main advantages of prodrugs include increased solubility, improved specificity and reduced toxicity [1]. Micelles characterized by a core shell nanostructure represent another promising tool for drug delivery. We are interested at developing prodrug based micelles [2].These novel nano-formulations are expected to provide benefits like enhanced drug loading efficiency, potential combinational drug delivery by loading other drugs and facilitating the enhanced permeability and retention (EPR) effect due to their size range within 10–100 nm. Herein we designed two prodrugs of mPEG-Methotrexate (mPEG(CH2)12-SS-MTX) and mPEG-SS-MTX. A dodecyl chain difference in the structures can be used for varying the hydrophilic/hydrophobic balance for optimized micelle stability. TEM observations showed both micelles with regular and spherical shape (Fig. 1). However, a remarkable difference was observed with respect to their critical micelle concentrations (CMC). mPEG-(CH2)12-SS-MTX micelles showed an obviously lower CMC (23 mg/L) than mPEG-SS-MTX micelles (102 mg/L). A micelle stability assay against large volume dilution to 100 times demonstrated that mPEG-(CH2)12-SS-MTX micelles show no significant changes while mPEG-SS-MTX micelles were hardly detected indicating the excellent stability of the former micelles. Interestingly, in vitro MTX release studies revealed a redox responsive release while dodecyl chain incorporation showed no negative impact (Fig. 1). Thus, we concluded that the mPEG-(CH2)12-SS-MTX prodrugs represent a promising class of new drug carriers.
Fig. 1. (a) TEM images and CMC of mPEG-(CH2)12-SS-MTX prodrug micelles; (b) Redox sensitive release of MTX using glutathione (GSH) with different concentrations in PBS (7.4) at 37 °C.
Scheme 1. Representation of intracellular acidic pH-mediated activation of PEG-bPDPA wormlike micelles.
Keywords: Drug delivery, Wormlike micelles, pH-responsive, Intracellular-activation Acknowledgements This project was supported by the World Premier International Research Center Initiative (WPI), MEXT, Japan, and the National Basic Research Program of China (2013CB932704, 2009CB930304). References [1] H.J. Yu, Y.L. Zou, Y.G. Wang, X.N. Huang, G. Huang, B.D. Sumer, D.A. Boothman, J.M. Gao, Overcoming endosomal barrier by amphotericin B-loaded dual pH-responsive PDMA-b-PDPA micelleplexes for siRNA delivery, ACS Nano 5 (2011) 9246–9255.
Keywords: Drug delivery, Prodrug, Hydrophilic/hydrophobic balance, Micellar stability Acknowledgements This work was financially supported by the National Natural Science Foundation of China (21104059 and 21004045) and the Fundamental Research Funds for the Central Universities. References [1] V.J. Stella, K.W. Nti-Addae, Prodrug strategies to overcome poor water solubility, Adv. Drug Deliv. Rev. 59 (2007) 677–694. [2] X.Q. Li, H.Y. Wen, H.Q. Dong, W.M. Xue, G.M. Pauletti, X.J. Cai, W.J. Xia, D. Shi, Y.Y. Li, Self-assembling nanomicelles of a novel camptothecin prodrug engineered with a redox-responsive release mechanism, Chem. Commun. 47 (2011) 8647–8649.
doi:10.1016/j.jconrel.2013.08.075
doi:10.1016/j.jconrel.2013.08.074
Redox-sensitive micelles based on PEG-Methotrexate prodrug with different hydrophilic/hydrophobic balance for drug delivery
Preparation and salt-responsive drug controlled release of complex nanoparticles of poly[(2-dimethylamino) ethyl methacrylate] and Alginic acid
Yongyong Li, Junping Ma, Haiqing Dong⁎ The Institute for Advanced Materials & Nanobiomedicine, Tongji University School of Medicine, Shanghai 200092, China E-mail address: [email protected] (H. Dong).
Hong Cai, Caihua Ni⁎, Liping Zhang School of Chemical and Material Engineering, Jiangnan University, Wuxi 214122, China E-mail address: [email protected] (C. Ni).
Abstracts / Journal of Controlled Release 172 (2013) e14–e97
The structures and properties of polyion complex nanoparticles are affected by external stimuli such as pH, ionic strength and temperature. Accordingly, investigating the influences is of great significance for controlled drug release [1,2]. To gain a better insight into the effects of pH and ionic strength on drug release we have prepared complex nanoparticles by selecting poly[(2-dimethylamino) ethyl methacrylate] (PDEMA) as cationic polyelectrolyte and Alginic acid (ALG-H) as anionic polyelectrolyte (Scheme 1). The drug (doxorubicin) release behavior in media with varying pH and ionic strength has been extensively investigated. The TEM of the nanoparticles indicates that particles with a spherical morphology with diameters around 240–260 nm can be formed only when the molar ratio of [COOH]:[NR2] is in the range of 6:4 to 4:6. The zeta potentials show that the nanoparticle surface is negatively or positively charged when the molar ratio of [COOH]:[NR2] is more than 6:4 or less than 5:5, respectively. MTT assays in 293T cells indicate that the nanoparticles are non-cytotoxic. The nanoparticles can be used as a drug vehicle for the controlled release of doxorubicin. The release rate increases as the concentration of NaCl gradually increases from 0.3 to 0.9 wt %, which demonstrates that the release can be controlled by the ionic strength.
e35
Nanoparticles have attracted intensive interest in biomedical applications as tumor diagnostics agents and drug delivery nanocarriers in cancer therapy because of the unique and tailorable properties.[1] Although benefited from the enhanced permeability and retention (EPR) effect, efficient cancer therapy is greatly challenged by the fact that the nanoparticles are rapidly removed from the blood and the majority of nanoparticles are accumulated in the organs of the reticuloendothelial system (RES) after intravenous injection (i.v.), leading to low particle concentration in blood and short contact time with the target tumor site subsequently [2]. In our work, a series of surface microphase separated mixed shell micelles (MSMs) were obtained with gradient hydrophilictity/ hydrophobicity, of which the weight ratio of PEG segment to PNIPAM segment (WPEG/WPNIPAM) were 10/0, 7/3, 5/5 and 3/7 respectively (MSMs-0, MSMs-30, MSMs-50 and MSMs-70 for short) (Fig. 1A). The in vivo biodistribution of the 125I-labeled MSMs was determined by Gamma counter and Gamma-camera imaging at various time points after i.v. in mice. Dramatic improvements in evading clearance during circulating were found that, compared with single PEGylated micelles, MSMs-50 accumulated in liver and spleen and their resident concentration in blood at 1 h after intravenous injection (i.v.), were proved to be more than 3 times lower and about 6 times higher, respectively (Fig. 1B–E). The results can give us a guideline for future development of nanomedicine for cancer.
Scheme 1. (a): The formation of complex nanoparticles based on poly[(2-dimethylamino) ethyl methacrylate] and Alginic acid, (b): Drug release at different NaCl concentrations.
Keywords: Complex nanoparticles, Alginic acid, Doxorubicin, Drug release Acknowledgement We are gratefccbvul for the support of the State Key Laboratory of Hydrology-Water Resources and Hydraulic Engineering, Hohai University (No. 2010490911) and the National Natural Science Foundation of China (NSFC 10974044). References [1] R.C. Nagarwal, S. Kant, P.N. Singh, Polymeric nanoparticulate system: a potential approach for ocular drug delivery, J. Control. Release 136 (2009) 2–13. [2] Y. Lee, S. Fukushima, Y. Bae, S. Hiki, T. Ishii, K. Kataoka, A protein nanocarrier from charge-conversion polymer in response to endosomal pH, J. Am. Chem. Soc. 129 (2007) 5362–5363.
Fig. 1. (A) General illustration of formation of the MSMs, the in vivo biodistribution of four MSMs (MSMs-0, MSMs-30, MSMs-50, and MSMs-70) in specific tissues (B) liver, (C) spleen, (D) blood) and (E) the blood clearance curves of corresponding MSMs.
Keywords: Polymeric micelles, Enhanced permeability and retention effect, Biodistribution, Microphase separation Acknowledgements This work was supported by the Science Foundation of China (No. 91127045, 50830103, 20904025 and 81171371) and the National Basic Research Program of China (973 Program, No. 2011CB932500) through their financial support. References
doi:10.1016/j.jconrel.2013.08.076
[1] K. Riehemann, S.W. Schneider, T.A. Luger, B. Godin, M. Ferrari, H. Fuchs, Nanomedicine—challenge and perspectives, Angew. Chem. Int. Ed. 48 (2009) 872–897. [2] Y.H. Bae, K. Park, Targeted drug delivery to tumors: myths, reality and possibility, J. Control. Release 153 (2011) 198–205.
In vivo biodistribution of polymeric micelles with microphase separated surface
doi:10.1016/j.jconrel.2013.08.077
Hongjun Gaoa, Jie Xionga, Tangjian Chenga, Jinjian Liub, Liping Chub, Jianfeng Liub,⁎, Rujiang Maa, Zhenkun Zhanga, Yingli Ana, Linqi Shia,⁎ a Key Laboratory of Functional Polymer Materials, Ministry of Education, and Institute of Polymer Chemistry, Nankai University, Tianjin 300071, China b Tianjin Key Laboratory of Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China E-mail address: [email protected] (L. Shi).
Electrospun silk fibroin composite nanofibrous mats loaded with vitamin A and E Xiao-Yue Shenga, Lin-Peng Fana, Xiu-Mei Moa,b,c, Chuang-Long Hea,b,c, Hong-Sheng Wanga,b,c,⁎ a Biomaterials and Tissue Engineering Lab, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China
Abstracts / Journal of Controlled Release 172 (2013) e14–e97
the acidic micro-environment in early endosome and late endosome/ lysosome, here, we report pH-responsive poly(ethylene glycol)block-poly(2-diisopropylamino ethyl methacrylate) (PEG-b-PDPA) wormlike micelles for the delivery of hydrophobic drugs. To exploit the pH-responsiveness of PEG-b-PDPA wormlike micelles, the PDPA segment was functionalized with hydroxyl pendant groups, and then labeled with a pH non-responsive fluorescence dye of tetramethyl rhodamine (TMR). Fluorescence images of a series of micellar solutions were taken at different pHs. At pHs above 6.3, the micellar solution produced negligible fluorophore signal owing to aggregation of TMR molecules inside the micelle core. At pHs below 6.3, the PDPA block was protonated and became water-soluble, thus leading to micelle disassembly and dramatic increase in fluorescence emission (Scheme 1) [1]. The TMR-conjugated wormlike micelles were further investigated for their intracellular uptake and activation in A-549 lung cancer cells. Punctuated fluorescence dots appeared inside the cells 30 min after micelle incubation, indicating the efficient uptake and activation of the TMR-labeled micelles inside the acidic endosomes. The number of red fluorescence dots increased gradually due to cellular accumulation of the wormlike micelles. All these data indicated that the pH-responsive wormlike micelles are potent candidates for intracellular delivery of hydrophobic drugs.
The prodrug strategy has been shown to be a powerful tool for drug delivery and has led to widespread clinical use. The main advantages of prodrugs include increased solubility, improved specificity and reduced toxicity [1]. Micelles characterized by a core shell nanostructure represent another promising tool for drug delivery. We are interested at developing prodrug based micelles [2].These novel nano-formulations are expected to provide benefits like enhanced drug loading efficiency, potential combinational drug delivery by loading other drugs and facilitating the enhanced permeability and retention (EPR) effect due to their size range within 10–100 nm. Herein we designed two prodrugs of mPEG-Methotrexate (mPEG(CH2)12-SS-MTX) and mPEG-SS-MTX. A dodecyl chain difference in the structures can be used for varying the hydrophilic/hydrophobic balance for optimized micelle stability. TEM observations showed both micelles with regular and spherical shape (Fig. 1). However, a remarkable difference was observed with respect to their critical micelle concentrations (CMC). mPEG-(CH2)12-SS-MTX micelles showed an obviously lower CMC (23 mg/L) than mPEG-SS-MTX micelles (102 mg/L). A micelle stability assay against large volume dilution to 100 times demonstrated that mPEG-(CH2)12-SS-MTX micelles show no significant changes while mPEG-SS-MTX micelles were hardly detected indicating the excellent stability of the former micelles. Interestingly, in vitro MTX release studies revealed a redox responsive release while dodecyl chain incorporation showed no negative impact (Fig. 1). Thus, we concluded that the mPEG-(CH2)12-SS-MTX prodrugs represent a promising class of new drug carriers.
Fig. 1. (a) TEM images and CMC of mPEG-(CH2)12-SS-MTX prodrug micelles; (b) Redox sensitive release of MTX using glutathione (GSH) with different concentrations in PBS (7.4) at 37 °C.
Scheme 1. Representation of intracellular acidic pH-mediated activation of PEG-bPDPA wormlike micelles.
Keywords: Drug delivery, Wormlike micelles, pH-responsive, Intracellular-activation Acknowledgements This project was supported by the World Premier International Research Center Initiative (WPI), MEXT, Japan, and the National Basic Research Program of China (2013CB932704, 2009CB930304). References [1] H.J. Yu, Y.L. Zou, Y.G. Wang, X.N. Huang, G. Huang, B.D. Sumer, D.A. Boothman, J.M. Gao, Overcoming endosomal barrier by amphotericin B-loaded dual pH-responsive PDMA-b-PDPA micelleplexes for siRNA delivery, ACS Nano 5 (2011) 9246–9255.
Keywords: Drug delivery, Prodrug, Hydrophilic/hydrophobic balance, Micellar stability Acknowledgements This work was financially supported by the National Natural Science Foundation of China (21104059 and 21004045) and the Fundamental Research Funds for the Central Universities. References [1] V.J. Stella, K.W. Nti-Addae, Prodrug strategies to overcome poor water solubility, Adv. Drug Deliv. Rev. 59 (2007) 677–694. [2] X.Q. Li, H.Y. Wen, H.Q. Dong, W.M. Xue, G.M. Pauletti, X.J. Cai, W.J. Xia, D. Shi, Y.Y. Li, Self-assembling nanomicelles of a novel camptothecin prodrug engineered with a redox-responsive release mechanism, Chem. Commun. 47 (2011) 8647–8649.
doi:10.1016/j.jconrel.2013.08.075
doi:10.1016/j.jconrel.2013.08.074
Redox-sensitive micelles based on PEG-Methotrexate prodrug with different hydrophilic/hydrophobic balance for drug delivery
Preparation and salt-responsive drug controlled release of complex nanoparticles of poly[(2-dimethylamino) ethyl methacrylate] and Alginic acid
Yongyong Li, Junping Ma, Haiqing Dong⁎ The Institute for Advanced Materials & Nanobiomedicine, Tongji University School of Medicine, Shanghai 200092, China E-mail address: [email protected] (H. Dong).
Hong Cai, Caihua Ni⁎, Liping Zhang School of Chemical and Material Engineering, Jiangnan University, Wuxi 214122, China E-mail address: [email protected] (C. Ni).
Abstracts / Journal of Controlled Release 172 (2013) e14–e97
The structures and properties of polyion complex nanoparticles are affected by external stimuli such as pH, ionic strength and temperature. Accordingly, investigating the influences is of great significance for controlled drug release [1,2]. To gain a better insight into the effects of pH and ionic strength on drug release we have prepared complex nanoparticles by selecting poly[(2-dimethylamino) ethyl methacrylate] (PDEMA) as cationic polyelectrolyte and Alginic acid (ALG-H) as anionic polyelectrolyte (Scheme 1). The drug (doxorubicin) release behavior in media with varying pH and ionic strength has been extensively investigated. The TEM of the nanoparticles indicates that particles with a spherical morphology with diameters around 240–260 nm can be formed only when the molar ratio of [COOH]:[NR2] is in the range of 6:4 to 4:6. The zeta potentials show that the nanoparticle surface is negatively or positively charged when the molar ratio of [COOH]:[NR2] is more than 6:4 or less than 5:5, respectively. MTT assays in 293T cells indicate that the nanoparticles are non-cytotoxic. The nanoparticles can be used as a drug vehicle for the controlled release of doxorubicin. The release rate increases as the concentration of NaCl gradually increases from 0.3 to 0.9 wt %, which demonstrates that the release can be controlled by the ionic strength.
e35
Nanoparticles have attracted intensive interest in biomedical applications as tumor diagnostics agents and drug delivery nanocarriers in cancer therapy because of the unique and tailorable properties.[1] Although benefited from the enhanced permeability and retention (EPR) effect, efficient cancer therapy is greatly challenged by the fact that the nanoparticles are rapidly removed from the blood and the majority of nanoparticles are accumulated in the organs of the reticuloendothelial system (RES) after intravenous injection (i.v.), leading to low particle concentration in blood and short contact time with the target tumor site subsequently [2]. In our work, a series of surface microphase separated mixed shell micelles (MSMs) were obtained with gradient hydrophilictity/ hydrophobicity, of which the weight ratio of PEG segment to PNIPAM segment (WPEG/WPNIPAM) were 10/0, 7/3, 5/5 and 3/7 respectively (MSMs-0, MSMs-30, MSMs-50 and MSMs-70 for short) (Fig. 1A). The in vivo biodistribution of the 125I-labeled MSMs was determined by Gamma counter and Gamma-camera imaging at various time points after i.v. in mice. Dramatic improvements in evading clearance during circulating were found that, compared with single PEGylated micelles, MSMs-50 accumulated in liver and spleen and their resident concentration in blood at 1 h after intravenous injection (i.v.), were proved to be more than 3 times lower and about 6 times higher, respectively (Fig. 1B–E). The results can give us a guideline for future development of nanomedicine for cancer.
Scheme 1. (a): The formation of complex nanoparticles based on poly[(2-dimethylamino) ethyl methacrylate] and Alginic acid, (b): Drug release at different NaCl concentrations.
Keywords: Complex nanoparticles, Alginic acid, Doxorubicin, Drug release Acknowledgement We are gratefccbvul for the support of the State Key Laboratory of Hydrology-Water Resources and Hydraulic Engineering, Hohai University (No. 2010490911) and the National Natural Science Foundation of China (NSFC 10974044). References [1] R.C. Nagarwal, S. Kant, P.N. Singh, Polymeric nanoparticulate system: a potential approach for ocular drug delivery, J. Control. Release 136 (2009) 2–13. [2] Y. Lee, S. Fukushima, Y. Bae, S. Hiki, T. Ishii, K. Kataoka, A protein nanocarrier from charge-conversion polymer in response to endosomal pH, J. Am. Chem. Soc. 129 (2007) 5362–5363.
Fig. 1. (A) General illustration of formation of the MSMs, the in vivo biodistribution of four MSMs (MSMs-0, MSMs-30, MSMs-50, and MSMs-70) in specific tissues (B) liver, (C) spleen, (D) blood) and (E) the blood clearance curves of corresponding MSMs.
Keywords: Polymeric micelles, Enhanced permeability and retention effect, Biodistribution, Microphase separation Acknowledgements This work was supported by the Science Foundation of China (No. 91127045, 50830103, 20904025 and 81171371) and the National Basic Research Program of China (973 Program, No. 2011CB932500) through their financial support. References
doi:10.1016/j.jconrel.2013.08.076
[1] K. Riehemann, S.W. Schneider, T.A. Luger, B. Godin, M. Ferrari, H. Fuchs, Nanomedicine—challenge and perspectives, Angew. Chem. Int. Ed. 48 (2009) 872–897. [2] Y.H. Bae, K. Park, Targeted drug delivery to tumors: myths, reality and possibility, J. Control. Release 153 (2011) 198–205.
In vivo biodistribution of polymeric micelles with microphase separated surface
doi:10.1016/j.jconrel.2013.08.077
Hongjun Gaoa, Jie Xionga, Tangjian Chenga, Jinjian Liub, Liping Chub, Jianfeng Liub,⁎, Rujiang Maa, Zhenkun Zhanga, Yingli Ana, Linqi Shia,⁎ a Key Laboratory of Functional Polymer Materials, Ministry of Education, and Institute of Polymer Chemistry, Nankai University, Tianjin 300071, China b Tianjin Key Laboratory of Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin 300192, China E-mail address: [email protected] (L. Shi).
Electrospun silk fibroin composite nanofibrous mats loaded with vitamin A and E Xiao-Yue Shenga, Lin-Peng Fana, Xiu-Mei Moa,b,c, Chuang-Long Hea,b,c, Hong-Sheng Wanga,b,c,⁎ a Biomaterials and Tissue Engineering Lab, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China