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A dual inhibition of tumor growth and metastasis by CXCR-4 targeting based on redox sensitive dextrin nanogel
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Abstracts / Journal of Controlled Release 259 (2017) e5–e195
To achieve sustained-release of NGF from nerve conduits encounters a number of technical challenges. First, proteins are prone to denature when being encapsulated in a polymer device owning to their delicate conformation. In addition, the nerve conduit-forming polymeric fibers are up to a hundred nanometers in diameter, for which NGF protected in a particular form cannot be encapsulated for sustained-release. To resolve these thorny issues, we recognized luckily beaded fibers, a common substandard product in the polymeric fiber industry, as an ideal nerve conduit material to load NGF pre-formulated (protected) within polysaccharide particles. Experimentally, NGF was loaded in polysaccharide particles submicrons in diameter through an aqueous-aqueous emulsion to avoid denaturing due to contact of water-oil interface. Then the NGFprotected polysaccharide particles were suspended in a PLLA solution and subjected to a fiber-electrospinning machine under the condition to form fibers with bead-junctions. The relative surface tensions of the three phases (particle, fiber forming solution, and air) facilitated encapsulation of the polysaccharide particles by the bead-junctions of the fibers. A nerve regeneration assay using the nerve conduits made of the beaded fibers in animal model showed comparable recovery of damaged nerves to those treated by auto-grafting, suggesting the therapeutic feasibility of the present strategy.
Fig. 1. The graphical presentation of NGF-Dextran particles loaded PLLA fiber with bead structure.
Keywords: nerve conduit, beaded fibers, nerve growth factor, native conformation, sustained release Acknowledgements The presented study was supported by the grant of Nature Science Foundation of China (81102406). doi:10.1016/j.jconrel.2017.03.090
A dual inhibition of tumor growth and metastasis by CXCR-4 targeting based on redox sensitive dextrin nanogel Feiran Zhang, Siman Gong, Huipeng Li, David Oupicky, Minjie Sun⁎ State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China ⁎Corresponding author. E-mail addresses: [email protected] (F. Zhang), [email protected] (M. Sun) The metastasis of breast cancer is mainly regulated by chemokine receptors such as CXCR4. As reported, neutralizing the interactions of CXCL12/CXCR4 could significantly inhibit the metastasis of breast cancer cells to regional lymph nodes and lung [1]. Herein, a nanogel system to deliver chemical drug and CXCR4 antagonist, as a tool for the development of a new therapy for metastatic breast cancer, is designed and explored in this study. Dextrin is frequently chosen for nanogel formulating in order to circumvent the carrier toxicity [2]. A bioreducible cross-linked dextrin
nanogel coated with AMD3100, a relatively new CXCR4 antagonist, was constructed to possess dual function of anti-metastasis and reductionresponsive release of cargo intracellularly. In vitro flow cytometry and confocal laser scanning microscopy (CLSM) demonstrated the significantly enhanced cellular uptake of Dox/AMD3100 dextrin nanogels. Cytotoxicity results further confirmed the best inhibition of Dox/ AMD3100 dextrin nanogels against luc-4T1 cells owing to the synergistic efficacy of AMD3100 and doxorubicin. The Dox/AMD3100 dextrin nanogel also showed the distinct anti-metastasis effects in inhibiting CXCR4 internalization in U2OS cells and the cell invasion in the Matrigel. In the in vivo distribution study, the Cy7/AMD3100 nanogel exhibited stronger fluorescence density in comparison with other dextrin formulations. Finally, the breast cancer bearing Balb/C mice demonstrated that Dox/AMD3100 dextrin nanogel possessed superior anticancer activity and antimetastasis effect simultaneously.
Fig. 1. Illustration of antitumor efficacy of Dox/AMD3100 dextrin nanogel.
Keywords: dextrin nanogel, CXCR4 antagonist, redox sensitive, metastatic breast cancer Acknowledgements The authors are grateful for the financial support from the National Natural Science Foundation of China (No.81373983 and 81573377), Natural Science Foundation of Jiangsu Province (No.20141352). References [1] A. Müller, B. Homey, H. Soto, N. Ge, D. Catron, M.E. Buchanan, T. McClanahan, E. Murphy, W. Yuan, S.N. Wagner, J.L. Barrera, A. Mohar, E. Verástegui, A. Zlotnik, Involvement of chemokine receptors in breast cancer metastasis. Nature 410 (2001) 50-56. [2] S. Manchun, K. Cheewatanakornkool, C.R. Dass, P. Sriamornsak, Novel pHresponsive dextrin nanogels for doxorubicin delivery to cancer cells with reducedcy totoxicity to cardiomyocytes and stem cells, Carbohydr. Polym. 114 (2014) 78-86.
doi:10.1016/j.jconrel.2017.03.091
Polymer-grafted mesoporous silica hybrid nanoparticles as hypoxia-responsive drug carriers Feng Yu, Huijing Wu, Yufang Xu, Xuhong Qian, Weiping Zhu⁎ State Key Laboratory of Bioreactor Engineering, Shanghai Key Lab of Chemical Biology, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China ⁎Corresponding author. E-mail address: [email protected] (W. Zhu) In the recent years,the development of novel nanocarriers for biomedical applications, especially for cancer therapy, has strongly
Abstracts / Journal of Controlled Release 259 (2017) e5–e195
To achieve sustained-release of NGF from nerve conduits encounters a number of technical challenges. First, proteins are prone to denature when being encapsulated in a polymer device owning to their delicate conformation. In addition, the nerve conduit-forming polymeric fibers are up to a hundred nanometers in diameter, for which NGF protected in a particular form cannot be encapsulated for sustained-release. To resolve these thorny issues, we recognized luckily beaded fibers, a common substandard product in the polymeric fiber industry, as an ideal nerve conduit material to load NGF pre-formulated (protected) within polysaccharide particles. Experimentally, NGF was loaded in polysaccharide particles submicrons in diameter through an aqueous-aqueous emulsion to avoid denaturing due to contact of water-oil interface. Then the NGFprotected polysaccharide particles were suspended in a PLLA solution and subjected to a fiber-electrospinning machine under the condition to form fibers with bead-junctions. The relative surface tensions of the three phases (particle, fiber forming solution, and air) facilitated encapsulation of the polysaccharide particles by the bead-junctions of the fibers. A nerve regeneration assay using the nerve conduits made of the beaded fibers in animal model showed comparable recovery of damaged nerves to those treated by auto-grafting, suggesting the therapeutic feasibility of the present strategy.
Fig. 1. The graphical presentation of NGF-Dextran particles loaded PLLA fiber with bead structure.
Keywords: nerve conduit, beaded fibers, nerve growth factor, native conformation, sustained release Acknowledgements The presented study was supported by the grant of Nature Science Foundation of China (81102406). doi:10.1016/j.jconrel.2017.03.090
A dual inhibition of tumor growth and metastasis by CXCR-4 targeting based on redox sensitive dextrin nanogel Feiran Zhang, Siman Gong, Huipeng Li, David Oupicky, Minjie Sun⁎ State Key Laboratory of Natural Medicines and Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China ⁎Corresponding author. E-mail addresses: [email protected] (F. Zhang), [email protected] (M. Sun) The metastasis of breast cancer is mainly regulated by chemokine receptors such as CXCR4. As reported, neutralizing the interactions of CXCL12/CXCR4 could significantly inhibit the metastasis of breast cancer cells to regional lymph nodes and lung [1]. Herein, a nanogel system to deliver chemical drug and CXCR4 antagonist, as a tool for the development of a new therapy for metastatic breast cancer, is designed and explored in this study. Dextrin is frequently chosen for nanogel formulating in order to circumvent the carrier toxicity [2]. A bioreducible cross-linked dextrin
nanogel coated with AMD3100, a relatively new CXCR4 antagonist, was constructed to possess dual function of anti-metastasis and reductionresponsive release of cargo intracellularly. In vitro flow cytometry and confocal laser scanning microscopy (CLSM) demonstrated the significantly enhanced cellular uptake of Dox/AMD3100 dextrin nanogels. Cytotoxicity results further confirmed the best inhibition of Dox/ AMD3100 dextrin nanogels against luc-4T1 cells owing to the synergistic efficacy of AMD3100 and doxorubicin. The Dox/AMD3100 dextrin nanogel also showed the distinct anti-metastasis effects in inhibiting CXCR4 internalization in U2OS cells and the cell invasion in the Matrigel. In the in vivo distribution study, the Cy7/AMD3100 nanogel exhibited stronger fluorescence density in comparison with other dextrin formulations. Finally, the breast cancer bearing Balb/C mice demonstrated that Dox/AMD3100 dextrin nanogel possessed superior anticancer activity and antimetastasis effect simultaneously.
Fig. 1. Illustration of antitumor efficacy of Dox/AMD3100 dextrin nanogel.
Keywords: dextrin nanogel, CXCR4 antagonist, redox sensitive, metastatic breast cancer Acknowledgements The authors are grateful for the financial support from the National Natural Science Foundation of China (No.81373983 and 81573377), Natural Science Foundation of Jiangsu Province (No.20141352). References [1] A. Müller, B. Homey, H. Soto, N. Ge, D. Catron, M.E. Buchanan, T. McClanahan, E. Murphy, W. Yuan, S.N. Wagner, J.L. Barrera, A. Mohar, E. Verástegui, A. Zlotnik, Involvement of chemokine receptors in breast cancer metastasis. Nature 410 (2001) 50-56. [2] S. Manchun, K. Cheewatanakornkool, C.R. Dass, P. Sriamornsak, Novel pHresponsive dextrin nanogels for doxorubicin delivery to cancer cells with reducedcy totoxicity to cardiomyocytes and stem cells, Carbohydr. Polym. 114 (2014) 78-86.
doi:10.1016/j.jconrel.2017.03.091
Polymer-grafted mesoporous silica hybrid nanoparticles as hypoxia-responsive drug carriers Feng Yu, Huijing Wu, Yufang Xu, Xuhong Qian, Weiping Zhu⁎ State Key Laboratory of Bioreactor Engineering, Shanghai Key Lab of Chemical Biology, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China ⁎Corresponding author. E-mail address: [email protected] (W. Zhu) In the recent years,the development of novel nanocarriers for biomedical applications, especially for cancer therapy, has strongly