- Email: [email protected]
Hybrid polypeptide micelles loaded with indocyanine green for tumor imaging
Abstracts / Journal of Controlled Release 172 (2013) e14–e97
effect, and promptly unload the encapsulated drug to a desired therapeutic region with hyperthermia therapy. As most drug delivery carriers are taken up by endocytic pathways and end up inside the cell within endosomes; a pathway that prohibits efficient drug release into the cytosol, in this study direct delivery of the DOX of interest across the cell membrane into the cytosol is proposed. In vitro release study of this liposomal system revealed that a very fast and quantitative release was observed at 42 °C within 30 min and at a drug/lipid ratio of 0.02 (w/w), it showed a highest release, up to 89.8% in 6 h. In contrast, the system exhibited only a gradual release of DOX at 37 °C over 6 h. MTT assay using H460 cells suggest an efficient heat-triggered DOX release from ABC liposomes leading to the buildup of an intracellular drug concentration higher than the cell-killing threshold and thus to cell death, which was consistent with the flow cytometry study and confocal laser scanning microscopy observations. In summary, we have successfully developed a thermal-responsive liposome system containing ammonium bicarbonate and DOX that has a potential ability for cancer treatment by intracellular delivery of DOX to tumor cells.
e47
the concentration of drugs in the targeted tumor cells [1]. The folate receptor (FR) is a well-known high affinity folate-binding protein, which is overexpressed in a number of human tumors. A theoretical foundation of folate receptor-meditated targeting has been established. Cyclodextrin-based polyrotaxanes have been explored as polymer therapeutics, especially for controlled drug release due to their many unique structural features. They are nontoxic and biodegradable, can be easily chemically modified, and the threaded CDs can freely slide and rotate along the included polymer chain [2]. A type of PR-based triblock copolymer was synthesized via ATRP of poly(ethylene glycol) methyl ether methacrylate (PEGMA) initiated with polypseudorotaxanes self-assembled from a 2-bromoisobutyryl end-capped Pluronic F127 with β-CDs in aqueous medium. Folate acid was conjugated to both ends of the copolymers via “click chemistry” in DMF. With the unique amphiphilic structure, the obtained copolymers were self-assembled into nano-sized aggregates in aqueous medium. Dynamic light scattering (DLS) analysis and transmission electron microscopy (TEM) images suggested that after doxorubicin (DOX) was encapsulated, the size of the particles was increased from 150 nm to about 230 nm in diameter. A controlled and sustained release of DOX over a period of more than 3 days in a physiological neutral environment was obtained. These nano-particles modified with or without folate acid showed a lower cytotoxicity than the free drug to Hela cells, and as expected, the cytotoxicity of folate acid modified nano-particles was higher than that of the control nano-particles. The results have illustrated that PR-FA-DOX nano-particles are effective in targeted drug delivery of tumors.
Scheme 1. A schematic illustration showing the composition/structure of the thermalresponsive bubble-generating liposomes developed in this study and their working mechanism for DOX release.
Keywords: Liposomes, Drug delivery, Controlled release, Cancer therapy Acknowledgments This work was supported by a grant from the National Science Council (NSC 100-2120-M-007-003), Taiwan. References [1] G.N. Chiu, S.A. Abraham, L.M. Ickenstein, R. Ng, G. Karlsson, K. Edwards, E.K. Wasan, M.B. Bally, Encapsulation of doxorubicin into thermosensitive liposomes via complexation with the transition metal manganese, J. Control. Release 104 (2005) 271–288.
doi:10.1016/j.jconrel.2013.08.098
A tumor-targeted nano-drug delivery system based on amphiphilic polyrotaxane-based triblock copolymers
Fig. 1. Schematic diagrams of self-aggregation of the PR-FA-DOX nano-particles and cellular uptake behavior.
Keywords: Tumor targeting, Polyrotaxane, Drug delivery, Nanoparticle Acknowledgments The authors acknowledge the support from the Natural Science Foundation of China (No. 20974015), the Doctoral Program Foundation of Ministry of Education of China (No. 20091101110029). References [1] G.H. Sagar, M.A. Arunagirinathan, J.R. Bellare, Self-assembled surfactant nanostructures important in drug delivery: a review, Indian J. Exp. Biol. 45 (2007) 133–159. [2] X.W. Zhang, X.Q. Zhu, F.Y. Ke, L. Ye, E.Q. Chen, A.Y. Zhang, Z.G. Feng, Preparation and self-assembly of amphiphilic triblock copolymers with polyrotaxane as a middle block and their application as carrier for the controlled release of Amphotericin B, Polymer 50 (2009) 4343–4351.
doi:10.1016/j.jconrel.2013.08.099 ⁎
Lan Jiang, Ze-Ming Gao, Lin Ye, Ai-Ying Zhang, Zeng-Guo Feng School of Materials Science and Engineering, Beijing Institute of Technology, Beijing 100081, China E-mail addresses: [email protected] (L. Jiang), [email protected] (Z. Feng). Cancer treatment has been a global problem for a long time due to the fact that most of the chemotherapy drugs lack specificity, and that conventional chemotherapy in the treatment of many cancers usually leads to limited clinical success because of the severe side effects of cytotoxic agents. Tumor targeted drug delivery systems could overcome the shortcomings of the conventional chemotherapy to a certain extent. Receptor-mediated uptake can achieve specific transport of the drug to the receptor-bearing target tumor cells, which could increase
Hybrid polypeptide micelles loaded with indocyanine green for tumor imaging Lei Wu, Jizhe Deng, Qian Sun, Huqiang Yi, Shengtao Fang, Bing Liu, Lintao Cai⁎ Shenzhen Key Laboratory of Cancer Nanotechnology, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Shenzhen 518055, China E-mail address: [email protected] (L. Cai). Polymeric micelles have been widely used as vectors for drugs with poor water solubility in drug delivery systems. Indocyanine
e48
Abstracts / Journal of Controlled Release 172 (2013) e14–e97
green (ICG) is a near-infrared (NIR) fluorescence dye used extensively for biological applications, but has drawbacks with respect to poor aqueous stability in vitro, concentration-dependent aggregation, rapid elimination from the body, and lack of targeting specificity [1]. We here designed and synthesized a series of polymeric micelles based on hybrid polypeptide to overcome the limitations of ICG. A new type of amphiphilic PEG-polypeptide hybrid triblock copolymers was synthesized. The copolymers could self-assemble into micelles with PLLeu as the hydrophobic core and PEG as the hydrophilic shell [2]. The circular dichroism (CD) spectra showed that PLLeu segments had a unique α-helical conformation, which was found to play an important role in controlling drug release rate. The controlled ICG-release experiments and small animal imaging experiments indicated excellent ICG-release properties of micelles for cancer imaging.
by covalent linkage of the glucuronic acid moiety of the targeting ligand HA to the primary amine of DOPE of the preformed liposomal shell [2]. The particle size of HA-LCS-NPs was about 450 nm, with a zeta potential of about −20 mV. A cellular uptake study with ARPE-19 cells showed that HA-LCS-NPs with higher HA density exhibited about 1.6-fold higher uptake than those with low HA density. The use of a higher HA molecular weight (200–400 kDa) resulted in improved intracellular uptake (of about 1.5-fold increase). After pretreating the ARPE-19 cells with a saturable amount of free HA (200–400 kDa), the HA-LCS-NP uptake was significantly reduced. As shown in CLSM images, most HALCS-NPs overcome the vitreous barriers and pass through the inner limiting membrane. More red fluorescence appeared at the retinal pigment epithelium layer as compared with the CS-NPs and LCS-NP control groups. It is envisaged that HA-LCS-NPs with improved intracellular uptake and superior penetrating ability across the whole retina to RPE will be a promising efficient intravitreal drug delivery system.
Scheme 1. Schematic illustration of the self-assembly of polypeptide copolymers and ICG in aqueous solution. b. In vivo imaging of ICG-loaded micelles via tail vein injections in nude mice carrying human breast tumors.
Keywords: Hybrid polypeptide, Block copolymers, Polymeric micelle, Controlled release, Indocyanine green Acknowledgments This work was supported by the National Natural Science Foundation of China (Grant Nos. 81171446 and 81071249), the National Basic Research Program of China (973 Program, Grant No. 2011CB933600). References [1] M. Rudin, Noninvasive structural, functional, and molecular imaging in drug development, Curr. Opin. Chem. Biol. 13 (2009) 360–371. [2] A.L. Parker, L. Eckley, S. Singh, J.A. Preece, L. Collins, J.W. Fabre, (LYS)(16)based reducible polycations provide stable polyplexes with anionic fusogenic peptides and efficient gene delivery to post mitotic cells, Biochim. Biophys. Acta Gen. Subj. 1770 (2007) 1331–1337.
doi:10.1016/j.jconrel.2013.08.100
HA-modified core–shell liponanoparticles for efficient intravitreal drug delivery Li Gana, Jing Wanga,b, Jianping Liua,b, Yong Gana,⁎ a Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China b School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China E-mail address: [email protected] (L. Gan). Most of the vision-threatening eye conditions, such as uveitis, agerelated macular degeneration, and diabetic retinopathy are related to the retina. Till now, intravitreous injection is still most favorable in the clinic to deliver therapeutic agents to the retina. However, many obstacles, such as short intraocular retention time and non-targeted biodistribution to the retina, have not been overcome [1]. Based on these considerations, we are trying to formulate novel HA-modified core–shell liponanoparticles to achieve efficient intravitreal drug delivery. Core–shell liponanoparticles (LCS-NPs) were prepared by hydrating a dried lipid film with chitosan nanoparticles (CS-NPs) solution. Hyaluronan-conjugated liponanoparticles (HA-LCS-NPs) were obtained
Scheme 1. HA-modified core–shell liponanoparticles exhibit superior penetrating ability across the whole retina to RPE.
Keywords: Core-shell, Hyaluronan, Liponanoparticles, ARPE, Intravitreal movement Acknowledgements This work was supported by the Natural Sciences Foundation of Shanghai China (No. 11ZR1444700) and the National Natural Sciences Foundation of China (No. 81102387). References [1] H. Koo, H. Moon, H. Han, J.H. Na, M.S. Huh, J.H. Park, S.J. Woo, K.H. Park, I. Chan Kwon, K. Kim, H. Kim, The movement of self-assembled amphiphilic polymeric nanoparticles in the vitreous and retina after intravitreal injection, Biomaterials 33 (2012) 3485–3493. [2] H.S. Qhattal, X. Liu, Characterization of CD44-mediated cancer cell uptake and intracellular distribution of hyaluronan-grafted liposomes, Mol. Pharm. 8 (2011) 1233–1246.
doi:10.1016/j.jconrel.2013.08.101
Controlled release of ibuprofen from biodegradable depsipeptide-based copolymers Li Zhanga, Yakai Fenga,b,c, Hongfei Caoa, Jintang Guoa,b,c, Musammir Khana a School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China b Helmholtz-Zentrum Geesthacht, Joint Laboratory for Biomaterials and Regenerative Medicine, Kantstr. 55, 14513 Teltow, Germany c Tianjin University, Joint Laboratory for Biomaterials and Regenerative Medicine, Weijin Road 92, Tianjin 300072, China E-mail addresses: [email protected] (L. Zhang), [email protected] (Y. Feng). Currently, amphiphilic block copolymers with good biocompatibility and biodegradability have attracted more and more attention
effect, and promptly unload the encapsulated drug to a desired therapeutic region with hyperthermia therapy. As most drug delivery carriers are taken up by endocytic pathways and end up inside the cell within endosomes; a pathway that prohibits efficient drug release into the cytosol, in this study direct delivery of the DOX of interest across the cell membrane into the cytosol is proposed. In vitro release study of this liposomal system revealed that a very fast and quantitative release was observed at 42 °C within 30 min and at a drug/lipid ratio of 0.02 (w/w), it showed a highest release, up to 89.8% in 6 h. In contrast, the system exhibited only a gradual release of DOX at 37 °C over 6 h. MTT assay using H460 cells suggest an efficient heat-triggered DOX release from ABC liposomes leading to the buildup of an intracellular drug concentration higher than the cell-killing threshold and thus to cell death, which was consistent with the flow cytometry study and confocal laser scanning microscopy observations. In summary, we have successfully developed a thermal-responsive liposome system containing ammonium bicarbonate and DOX that has a potential ability for cancer treatment by intracellular delivery of DOX to tumor cells.
e47
the concentration of drugs in the targeted tumor cells [1]. The folate receptor (FR) is a well-known high affinity folate-binding protein, which is overexpressed in a number of human tumors. A theoretical foundation of folate receptor-meditated targeting has been established. Cyclodextrin-based polyrotaxanes have been explored as polymer therapeutics, especially for controlled drug release due to their many unique structural features. They are nontoxic and biodegradable, can be easily chemically modified, and the threaded CDs can freely slide and rotate along the included polymer chain [2]. A type of PR-based triblock copolymer was synthesized via ATRP of poly(ethylene glycol) methyl ether methacrylate (PEGMA) initiated with polypseudorotaxanes self-assembled from a 2-bromoisobutyryl end-capped Pluronic F127 with β-CDs in aqueous medium. Folate acid was conjugated to both ends of the copolymers via “click chemistry” in DMF. With the unique amphiphilic structure, the obtained copolymers were self-assembled into nano-sized aggregates in aqueous medium. Dynamic light scattering (DLS) analysis and transmission electron microscopy (TEM) images suggested that after doxorubicin (DOX) was encapsulated, the size of the particles was increased from 150 nm to about 230 nm in diameter. A controlled and sustained release of DOX over a period of more than 3 days in a physiological neutral environment was obtained. These nano-particles modified with or without folate acid showed a lower cytotoxicity than the free drug to Hela cells, and as expected, the cytotoxicity of folate acid modified nano-particles was higher than that of the control nano-particles. The results have illustrated that PR-FA-DOX nano-particles are effective in targeted drug delivery of tumors.
Scheme 1. A schematic illustration showing the composition/structure of the thermalresponsive bubble-generating liposomes developed in this study and their working mechanism for DOX release.
Keywords: Liposomes, Drug delivery, Controlled release, Cancer therapy Acknowledgments This work was supported by a grant from the National Science Council (NSC 100-2120-M-007-003), Taiwan. References [1] G.N. Chiu, S.A. Abraham, L.M. Ickenstein, R. Ng, G. Karlsson, K. Edwards, E.K. Wasan, M.B. Bally, Encapsulation of doxorubicin into thermosensitive liposomes via complexation with the transition metal manganese, J. Control. Release 104 (2005) 271–288.
doi:10.1016/j.jconrel.2013.08.098
A tumor-targeted nano-drug delivery system based on amphiphilic polyrotaxane-based triblock copolymers
Fig. 1. Schematic diagrams of self-aggregation of the PR-FA-DOX nano-particles and cellular uptake behavior.
Keywords: Tumor targeting, Polyrotaxane, Drug delivery, Nanoparticle Acknowledgments The authors acknowledge the support from the Natural Science Foundation of China (No. 20974015), the Doctoral Program Foundation of Ministry of Education of China (No. 20091101110029). References [1] G.H. Sagar, M.A. Arunagirinathan, J.R. Bellare, Self-assembled surfactant nanostructures important in drug delivery: a review, Indian J. Exp. Biol. 45 (2007) 133–159. [2] X.W. Zhang, X.Q. Zhu, F.Y. Ke, L. Ye, E.Q. Chen, A.Y. Zhang, Z.G. Feng, Preparation and self-assembly of amphiphilic triblock copolymers with polyrotaxane as a middle block and their application as carrier for the controlled release of Amphotericin B, Polymer 50 (2009) 4343–4351.
doi:10.1016/j.jconrel.2013.08.099 ⁎
Lan Jiang, Ze-Ming Gao, Lin Ye, Ai-Ying Zhang, Zeng-Guo Feng School of Materials Science and Engineering, Beijing Institute of Technology, Beijing 100081, China E-mail addresses: [email protected] (L. Jiang), [email protected] (Z. Feng). Cancer treatment has been a global problem for a long time due to the fact that most of the chemotherapy drugs lack specificity, and that conventional chemotherapy in the treatment of many cancers usually leads to limited clinical success because of the severe side effects of cytotoxic agents. Tumor targeted drug delivery systems could overcome the shortcomings of the conventional chemotherapy to a certain extent. Receptor-mediated uptake can achieve specific transport of the drug to the receptor-bearing target tumor cells, which could increase
Hybrid polypeptide micelles loaded with indocyanine green for tumor imaging Lei Wu, Jizhe Deng, Qian Sun, Huqiang Yi, Shengtao Fang, Bing Liu, Lintao Cai⁎ Shenzhen Key Laboratory of Cancer Nanotechnology, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Shenzhen 518055, China E-mail address: [email protected] (L. Cai). Polymeric micelles have been widely used as vectors for drugs with poor water solubility in drug delivery systems. Indocyanine
e48
Abstracts / Journal of Controlled Release 172 (2013) e14–e97
green (ICG) is a near-infrared (NIR) fluorescence dye used extensively for biological applications, but has drawbacks with respect to poor aqueous stability in vitro, concentration-dependent aggregation, rapid elimination from the body, and lack of targeting specificity [1]. We here designed and synthesized a series of polymeric micelles based on hybrid polypeptide to overcome the limitations of ICG. A new type of amphiphilic PEG-polypeptide hybrid triblock copolymers was synthesized. The copolymers could self-assemble into micelles with PLLeu as the hydrophobic core and PEG as the hydrophilic shell [2]. The circular dichroism (CD) spectra showed that PLLeu segments had a unique α-helical conformation, which was found to play an important role in controlling drug release rate. The controlled ICG-release experiments and small animal imaging experiments indicated excellent ICG-release properties of micelles for cancer imaging.
by covalent linkage of the glucuronic acid moiety of the targeting ligand HA to the primary amine of DOPE of the preformed liposomal shell [2]. The particle size of HA-LCS-NPs was about 450 nm, with a zeta potential of about −20 mV. A cellular uptake study with ARPE-19 cells showed that HA-LCS-NPs with higher HA density exhibited about 1.6-fold higher uptake than those with low HA density. The use of a higher HA molecular weight (200–400 kDa) resulted in improved intracellular uptake (of about 1.5-fold increase). After pretreating the ARPE-19 cells with a saturable amount of free HA (200–400 kDa), the HA-LCS-NP uptake was significantly reduced. As shown in CLSM images, most HALCS-NPs overcome the vitreous barriers and pass through the inner limiting membrane. More red fluorescence appeared at the retinal pigment epithelium layer as compared with the CS-NPs and LCS-NP control groups. It is envisaged that HA-LCS-NPs with improved intracellular uptake and superior penetrating ability across the whole retina to RPE will be a promising efficient intravitreal drug delivery system.
Scheme 1. Schematic illustration of the self-assembly of polypeptide copolymers and ICG in aqueous solution. b. In vivo imaging of ICG-loaded micelles via tail vein injections in nude mice carrying human breast tumors.
Keywords: Hybrid polypeptide, Block copolymers, Polymeric micelle, Controlled release, Indocyanine green Acknowledgments This work was supported by the National Natural Science Foundation of China (Grant Nos. 81171446 and 81071249), the National Basic Research Program of China (973 Program, Grant No. 2011CB933600). References [1] M. Rudin, Noninvasive structural, functional, and molecular imaging in drug development, Curr. Opin. Chem. Biol. 13 (2009) 360–371. [2] A.L. Parker, L. Eckley, S. Singh, J.A. Preece, L. Collins, J.W. Fabre, (LYS)(16)based reducible polycations provide stable polyplexes with anionic fusogenic peptides and efficient gene delivery to post mitotic cells, Biochim. Biophys. Acta Gen. Subj. 1770 (2007) 1331–1337.
doi:10.1016/j.jconrel.2013.08.100
HA-modified core–shell liponanoparticles for efficient intravitreal drug delivery Li Gana, Jing Wanga,b, Jianping Liua,b, Yong Gana,⁎ a Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China b School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China E-mail address: [email protected] (L. Gan). Most of the vision-threatening eye conditions, such as uveitis, agerelated macular degeneration, and diabetic retinopathy are related to the retina. Till now, intravitreous injection is still most favorable in the clinic to deliver therapeutic agents to the retina. However, many obstacles, such as short intraocular retention time and non-targeted biodistribution to the retina, have not been overcome [1]. Based on these considerations, we are trying to formulate novel HA-modified core–shell liponanoparticles to achieve efficient intravitreal drug delivery. Core–shell liponanoparticles (LCS-NPs) were prepared by hydrating a dried lipid film with chitosan nanoparticles (CS-NPs) solution. Hyaluronan-conjugated liponanoparticles (HA-LCS-NPs) were obtained
Scheme 1. HA-modified core–shell liponanoparticles exhibit superior penetrating ability across the whole retina to RPE.
Keywords: Core-shell, Hyaluronan, Liponanoparticles, ARPE, Intravitreal movement Acknowledgements This work was supported by the Natural Sciences Foundation of Shanghai China (No. 11ZR1444700) and the National Natural Sciences Foundation of China (No. 81102387). References [1] H. Koo, H. Moon, H. Han, J.H. Na, M.S. Huh, J.H. Park, S.J. Woo, K.H. Park, I. Chan Kwon, K. Kim, H. Kim, The movement of self-assembled amphiphilic polymeric nanoparticles in the vitreous and retina after intravitreal injection, Biomaterials 33 (2012) 3485–3493. [2] H.S. Qhattal, X. Liu, Characterization of CD44-mediated cancer cell uptake and intracellular distribution of hyaluronan-grafted liposomes, Mol. Pharm. 8 (2011) 1233–1246.
doi:10.1016/j.jconrel.2013.08.101
Controlled release of ibuprofen from biodegradable depsipeptide-based copolymers Li Zhanga, Yakai Fenga,b,c, Hongfei Caoa, Jintang Guoa,b,c, Musammir Khana a School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China b Helmholtz-Zentrum Geesthacht, Joint Laboratory for Biomaterials and Regenerative Medicine, Kantstr. 55, 14513 Teltow, Germany c Tianjin University, Joint Laboratory for Biomaterials and Regenerative Medicine, Weijin Road 92, Tianjin 300072, China E-mail addresses: [email protected] (L. Zhang), [email protected] (Y. Feng). Currently, amphiphilic block copolymers with good biocompatibility and biodegradability have attracted more and more attention