- Email: [email protected]
Dinuclear platinum (II) loaded micelles directed to reduce systemic toxicity and enhance antitumor activity
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Abstracts / Journal of Controlled Release 172 (2013) e14–e97
National University YangSan Hospital, Beomeo-ri, Mulgeum-eup, Yangsan, Gyeongnam, Republic of Korea E-mail addresses: [email protected] (X. Huang), [email protected] (I. Kim). In photodynamic therapy, 5-aminolevulinic acid (ALA) is injected into the patient, where it circulates in the body and allows accumulation in diseased cells and generally changes to a kind of photosensitizer protoporphyrin IX (PpIX) that absorbs energy from light and uses this energy to enable chemical reactions to take place [1]. However, ALA is too hydrophilic to penetrate the mucous layer in the bile duct and most of it is excreted before photo-treatment. Dendritic hyperbranched polyglycidol (HBP) with multihydroxyl groups, with robust adhesion and cohesive integrity represents valuable characteristics of a medical adhesive for applications requiring long-term performance [2]. Here, we have prepared an acid sensitive HBP-ALA prodrug (Fig. 1). The HBP-ALA prodrug is utilized to formulate PpIX and to measure the resulting uptake, intracellular distribution, and effectiveness in photodynamic therapy against human cholangiocarcinoma cell (HuCC-T1), human gastric epithelial cell (AGS), and human colorectal carcinoma (HCT116) under acid conditions. The HBP-ALA is an effective alternative to ALA for enhancing the PpIX production efficiency in a controlled way and the selectivity of the phototoxic effect in tumor cells.
cationic polysaccharide in the world, has been hydrophobically modified and utilized as drug carrier because of its intrinsic advantages such as biocompatibility and biodegradability [1,2]. We have synthesized a series of water-soluble amphiphilic CS derivatives (HTsGs-CS-DCAs) by grafting deoxycholic acid, glycidyltrimethylammounium chloride and glycidol. As the surface charge of nanocarriers for drug delivery is very important, we report here the effect of surface charge of nanocarriers on drug release behavior. The surface charges ranging from 20 mV to nearly neutral could be easily adjusted by controlling the degree of substitution (DS) of hydrophilic molecules. Paclitaxel (PTX) was loaded with encapsulation efficiency around 80% and when PTX-HTsGs-CS-DCA nanocarriers were exposed to PBS at pH 7.4 a sustained slow release was observed. Moreover, the release rate of PTX obviously slowed down with the decrease of the surface charge of the nanocarriers (Fig. 1).
Fig. 1. The size and zeta potential of HTsGs-CS-DCA3.0 nanocarriers. Fig. 1. The release of ALA from HBP-ALA conjugates and transfer to PpIX as PDT in vitro at acid condition.
Keywords: Drug delivery, 5-Aminolevulinic acid, Photodynamic therapy, Hyperbranched polyglycidol, Photosensitizer, Protoporphyrin IX Acknowledgements This work was supported by grants-in-aid for the World Class University Program (No. R32-2008-000-10174-0). References
Keywords: Amphiphilic chitosan nanocarriers, Surface charge, In vitro release behavior Acknowledgments The authors are thankful for the financial support from the National Natural Science Foundation of China (20876018) and the Scientific Research Foundation for the Returned Overseas Chinese Scholars State Education Ministry. References
[1] Y.N. Konan, R. Gurny, E. Allemann, State of the art in the delivery of photosensitizers for photodynamic therapy, J. Photochem. Photobiol. 66 (2002) 89–109. [2] C.E. Brubaker, H. Kissler, L.J. Wang, D.B. Kaufman, P.B. Messersmith, Biological performance of mussel-inspired adhesive in extrahepatic islet transplantation, Biomaterials 31 (2010) 420–427.
[1] N. Wiradharma, Y. Zhang, S. Venkataraman, J.L. Hedrick, Y.Y. Yang, Selfassembled polymer nanostructures for delivery of anticancer therapeutics, Nano Today 4 (2009) 302–317. [2] H.F. Zhou, W.T. Yu, X. Guo, X.D. Liu, N. Li, Y. Zhang, X.J. Ma, Synthesis and characterization of amphiphilic glycidol-chitosan-deoxycholic acid nanoparticles as drug carrier for doxorubicin, Biomacromolecules 11 (2010) 3480–3486.
doi:10.1016/j.jconrel.2013.08.159
doi:10.1016/j.jconrel.2013.08.160
Effect of surface charge of amphiphlic chitosan nanocarriers on drug release behavior
Dinuclear platinum (II) loaded micelles directed to reduce systemic toxicity and enhance antitumor activity
Xiudong Liua,⁎, Huofei Zhoub, Weiting Yub, Xiaojun Mab,⁎ a College of Environment and Chemical Engineering, Dalian University, Dalian Economic Technological Development Zone, Dalian 116622, China b Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China E-mail addresses: [email protected] (X. Liu), [email protected] (X. Ma).
Xiuli Hu, Haihua Xiao, Zhigang Xie, Xiabin Jing⁎ State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China E-mail addresses: [email protected] (X. Hu), [email protected] (X. Jing).
Amphiphilic polymers can easily form micelles, or micelle-like aggregates with a hydrophobic core and a hydrophilic surface based on self-assembly in aqueous media. Chitosan (CS), the only naturally
Cisplatin, carboplatin, oxaliplatin and other platinum(II)-based drugs play an important role in clinical cancer chemotherapy. However, the application of these drugs has been greatly hampered by drug resistance and severe side effects. Multinuclear platinum complexes containing two or more linked platinum centers represent a novel class
Abstracts / Journal of Controlled Release 172 (2013) e14–e97
of promising candidates for cancer chemotherapy and recently there are some promising reports which indicate that multinuclear platinum complexes have a higher cytotoxicity than mononuclear platinum complexes [1,2]. These reported multinuclear platinum complexes react with DNA more rapidly than cisplatin and its analogues and produce characteristic long-range (Pt,Pt) interstrand cross-linked DNA adducts and they are promising to reduce the drug resistance. In this work, a dinuclear monofunctional Pt(II) complex {[cisPt(NH3)2(Cl)2(NH2)2(CH2)6]}(NO3)2 was synthesized and charac1 terized by H NMR, and electrospray mass spectrometry. Diblock copolymer poly(ethylene glycol)-b-poly(glutamic acid), the most investigated carrier for drug delivery, was selected and complexed with synthesized dinuclear monofunctional Pt(II) complex as shown in Scheme 1. In this way, the water-soluble poly(glutanic acid) becomes hydrophobic and the complex can self-assemble into nanoscale micelles with the Pt complexes in the core part of the micelles and thus effectively protected. These Pt-bearing micelles are expected to be internalized by the cancer cells via endocytosis. The Pt species would be released from the polymer backbones and play their role of anti-tumor agent, while the polymer carrier itself can be excreted from the body.
e79
Poly(N-isopropylacrylamide) (PNIPAAm) containing both hydrophilic and hydrophobic segments has attracted much attention as carrier for drug delivery systems [1]. It is expected that blends of PNIPAAm with poly (caprolactone)-based polyurethane (PU) will be biocompatible and also thermo-sensitive. The lower critical solution temperature (LCST) of these blends can be modulated near to the body's physiological temperature, which is important for biological applications. Moreover, electrospun multifunctional PNIPAAm/PU nanofibers with a high surface area to volume ratio are also interesting for controlled drug release applications [2]. PNIPAAm and PU were dissolved in DMF to form uniform solutions (12% w/w). By using nifedipine (NIF) as model drug with a concentration of 13% (w/w), the drug release behavior was investigated. Smooth and non-beaded surfaces of PNIPAAm/PU with NIF composite nanofibers were obtained. The addition of PU indeed influenced the wettability of the nanofibers. The release rates depended largely on the temperature of the medium and the microstructure of the composite nanofibers. When the properties of the nanofibers were switched from hydrophilic to hydrophobic, the amount of released NIF decreased and could be controlled. Thermo-sensitive PNIPAAm/PU nanofibers were fabricated successfully by electrospinning and the LCST could be modulated. After the introduction of NIF into the nanofibers it was demonstrated that such nanofibers were good carriers for the release of water-insoluble drugs. Controlled drug release could be obtained by varying the temperature around the LCST.
Scheme 1. Block copolymer PEG-b-PGA complexing with dinuclear monofunctional Pt(II) complex to form micelles that have long circulation time and systemic stability.
Keywords: Poly(glutamic acid), Micelles, Multinuclear platinum, Drug delivery, Passive targeting Acknowledgements Financial support was provided by the National Natural Science Foundation of China (Project No. 21004062, 51103148). References [1] D.M. Fan, X.L. Yang, X.Y. Wang, S.C. Zhang, J.F. Mao, J. Ding, L.P. Lin, Z.J. Guo, A, dinuclear monofunctional platinum(II) complex with an aromatic linker shows low reactivity towards glutathione but high DNA binding ability and antitumor activity, J. Biol. Inorg. Chem. 12 (2007) 655–665. [2] N. Farrell, Polynuclear platinum drugs, Met. Ions. Biol. Syst. 42 (2004) 251–296.
doi:10.1016/j.jconrel.2013.08.161
Fig. 1. Temperature dependence of the water CAs for PNIPAAm/PU nanofibers (the inset photographs were the water-droplet shape on the PNIPAAm/PU nanofibers within 10 s a) 26 °C, b) 40 °C and SEM images of c) PNIPAAm/PU nanofibers, d) PNIPAAm/PU with NIF nanofibers touching with water).
Keywords: Electrospun, Thermo-sensitive, Nanofibers, Controlled drug release Acknowledgements The authors gratefully acknowledge the Program for New Century Excellent Talents in University of China (NCET-08-0165) for financial support. References
Controllable drug release from electrospun thermo-sensitive poly(n-isopropylacrylamide)/poly(ε-caprolactone)-based polyurethane nanofibers Xiuling Lina,b, Dongyan Tanga, Haofei Dua Department of Chemistry, Harbin Institute of Technology, Harbin 150001, China b Department of Materials Science and Engineering, Anhui University of Science and Technology, Huainan 232001, China E-mail address: [email protected] (X. Lin).
a
[1] S.Q. Liu, Y.W. Tong, Y.Y. Yang, Incorporation and in vitro release of doxorubicin in thermally sensitive micelles made from poly(N-isopropylacrylamide-co-N, Ndimethylacrylamide)-b-poly(D, L-lactide-co-glycolide) with varying compositions, Biomaterials 26 (2005) 5064–5074. [2] G. Verreck, I. Chun, J. Rosenblatt, J. Peeters, A.V. Dijck, J. Mensch, M. Noppe, M.E. Brewster, Incorporation of drugs in an amorphous state into electrospun nanofibers composed of a water-insoluble, nonbiodegradable polymer, J. Control. Release 92 (2003) 349–360.
doi:10.1016/j.jconrel.2013.08.162
Abstracts / Journal of Controlled Release 172 (2013) e14–e97
National University YangSan Hospital, Beomeo-ri, Mulgeum-eup, Yangsan, Gyeongnam, Republic of Korea E-mail addresses: [email protected] (X. Huang), [email protected] (I. Kim). In photodynamic therapy, 5-aminolevulinic acid (ALA) is injected into the patient, where it circulates in the body and allows accumulation in diseased cells and generally changes to a kind of photosensitizer protoporphyrin IX (PpIX) that absorbs energy from light and uses this energy to enable chemical reactions to take place [1]. However, ALA is too hydrophilic to penetrate the mucous layer in the bile duct and most of it is excreted before photo-treatment. Dendritic hyperbranched polyglycidol (HBP) with multihydroxyl groups, with robust adhesion and cohesive integrity represents valuable characteristics of a medical adhesive for applications requiring long-term performance [2]. Here, we have prepared an acid sensitive HBP-ALA prodrug (Fig. 1). The HBP-ALA prodrug is utilized to formulate PpIX and to measure the resulting uptake, intracellular distribution, and effectiveness in photodynamic therapy against human cholangiocarcinoma cell (HuCC-T1), human gastric epithelial cell (AGS), and human colorectal carcinoma (HCT116) under acid conditions. The HBP-ALA is an effective alternative to ALA for enhancing the PpIX production efficiency in a controlled way and the selectivity of the phototoxic effect in tumor cells.
cationic polysaccharide in the world, has been hydrophobically modified and utilized as drug carrier because of its intrinsic advantages such as biocompatibility and biodegradability [1,2]. We have synthesized a series of water-soluble amphiphilic CS derivatives (HTsGs-CS-DCAs) by grafting deoxycholic acid, glycidyltrimethylammounium chloride and glycidol. As the surface charge of nanocarriers for drug delivery is very important, we report here the effect of surface charge of nanocarriers on drug release behavior. The surface charges ranging from 20 mV to nearly neutral could be easily adjusted by controlling the degree of substitution (DS) of hydrophilic molecules. Paclitaxel (PTX) was loaded with encapsulation efficiency around 80% and when PTX-HTsGs-CS-DCA nanocarriers were exposed to PBS at pH 7.4 a sustained slow release was observed. Moreover, the release rate of PTX obviously slowed down with the decrease of the surface charge of the nanocarriers (Fig. 1).
Fig. 1. The size and zeta potential of HTsGs-CS-DCA3.0 nanocarriers. Fig. 1. The release of ALA from HBP-ALA conjugates and transfer to PpIX as PDT in vitro at acid condition.
Keywords: Drug delivery, 5-Aminolevulinic acid, Photodynamic therapy, Hyperbranched polyglycidol, Photosensitizer, Protoporphyrin IX Acknowledgements This work was supported by grants-in-aid for the World Class University Program (No. R32-2008-000-10174-0). References
Keywords: Amphiphilic chitosan nanocarriers, Surface charge, In vitro release behavior Acknowledgments The authors are thankful for the financial support from the National Natural Science Foundation of China (20876018) and the Scientific Research Foundation for the Returned Overseas Chinese Scholars State Education Ministry. References
[1] Y.N. Konan, R. Gurny, E. Allemann, State of the art in the delivery of photosensitizers for photodynamic therapy, J. Photochem. Photobiol. 66 (2002) 89–109. [2] C.E. Brubaker, H. Kissler, L.J. Wang, D.B. Kaufman, P.B. Messersmith, Biological performance of mussel-inspired adhesive in extrahepatic islet transplantation, Biomaterials 31 (2010) 420–427.
[1] N. Wiradharma, Y. Zhang, S. Venkataraman, J.L. Hedrick, Y.Y. Yang, Selfassembled polymer nanostructures for delivery of anticancer therapeutics, Nano Today 4 (2009) 302–317. [2] H.F. Zhou, W.T. Yu, X. Guo, X.D. Liu, N. Li, Y. Zhang, X.J. Ma, Synthesis and characterization of amphiphilic glycidol-chitosan-deoxycholic acid nanoparticles as drug carrier for doxorubicin, Biomacromolecules 11 (2010) 3480–3486.
doi:10.1016/j.jconrel.2013.08.159
doi:10.1016/j.jconrel.2013.08.160
Effect of surface charge of amphiphlic chitosan nanocarriers on drug release behavior
Dinuclear platinum (II) loaded micelles directed to reduce systemic toxicity and enhance antitumor activity
Xiudong Liua,⁎, Huofei Zhoub, Weiting Yub, Xiaojun Mab,⁎ a College of Environment and Chemical Engineering, Dalian University, Dalian Economic Technological Development Zone, Dalian 116622, China b Laboratory of Biomedical Material Engineering, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China E-mail addresses: [email protected] (X. Liu), [email protected] (X. Ma).
Xiuli Hu, Haihua Xiao, Zhigang Xie, Xiabin Jing⁎ State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China E-mail addresses: [email protected] (X. Hu), [email protected] (X. Jing).
Amphiphilic polymers can easily form micelles, or micelle-like aggregates with a hydrophobic core and a hydrophilic surface based on self-assembly in aqueous media. Chitosan (CS), the only naturally
Cisplatin, carboplatin, oxaliplatin and other platinum(II)-based drugs play an important role in clinical cancer chemotherapy. However, the application of these drugs has been greatly hampered by drug resistance and severe side effects. Multinuclear platinum complexes containing two or more linked platinum centers represent a novel class
Abstracts / Journal of Controlled Release 172 (2013) e14–e97
of promising candidates for cancer chemotherapy and recently there are some promising reports which indicate that multinuclear platinum complexes have a higher cytotoxicity than mononuclear platinum complexes [1,2]. These reported multinuclear platinum complexes react with DNA more rapidly than cisplatin and its analogues and produce characteristic long-range (Pt,Pt) interstrand cross-linked DNA adducts and they are promising to reduce the drug resistance. In this work, a dinuclear monofunctional Pt(II) complex {[cisPt(NH3)2(Cl)2(NH2)2(CH2)6]}(NO3)2 was synthesized and charac1 terized by H NMR, and electrospray mass spectrometry. Diblock copolymer poly(ethylene glycol)-b-poly(glutamic acid), the most investigated carrier for drug delivery, was selected and complexed with synthesized dinuclear monofunctional Pt(II) complex as shown in Scheme 1. In this way, the water-soluble poly(glutanic acid) becomes hydrophobic and the complex can self-assemble into nanoscale micelles with the Pt complexes in the core part of the micelles and thus effectively protected. These Pt-bearing micelles are expected to be internalized by the cancer cells via endocytosis. The Pt species would be released from the polymer backbones and play their role of anti-tumor agent, while the polymer carrier itself can be excreted from the body.
e79
Poly(N-isopropylacrylamide) (PNIPAAm) containing both hydrophilic and hydrophobic segments has attracted much attention as carrier for drug delivery systems [1]. It is expected that blends of PNIPAAm with poly (caprolactone)-based polyurethane (PU) will be biocompatible and also thermo-sensitive. The lower critical solution temperature (LCST) of these blends can be modulated near to the body's physiological temperature, which is important for biological applications. Moreover, electrospun multifunctional PNIPAAm/PU nanofibers with a high surface area to volume ratio are also interesting for controlled drug release applications [2]. PNIPAAm and PU were dissolved in DMF to form uniform solutions (12% w/w). By using nifedipine (NIF) as model drug with a concentration of 13% (w/w), the drug release behavior was investigated. Smooth and non-beaded surfaces of PNIPAAm/PU with NIF composite nanofibers were obtained. The addition of PU indeed influenced the wettability of the nanofibers. The release rates depended largely on the temperature of the medium and the microstructure of the composite nanofibers. When the properties of the nanofibers were switched from hydrophilic to hydrophobic, the amount of released NIF decreased and could be controlled. Thermo-sensitive PNIPAAm/PU nanofibers were fabricated successfully by electrospinning and the LCST could be modulated. After the introduction of NIF into the nanofibers it was demonstrated that such nanofibers were good carriers for the release of water-insoluble drugs. Controlled drug release could be obtained by varying the temperature around the LCST.
Scheme 1. Block copolymer PEG-b-PGA complexing with dinuclear monofunctional Pt(II) complex to form micelles that have long circulation time and systemic stability.
Keywords: Poly(glutamic acid), Micelles, Multinuclear platinum, Drug delivery, Passive targeting Acknowledgements Financial support was provided by the National Natural Science Foundation of China (Project No. 21004062, 51103148). References [1] D.M. Fan, X.L. Yang, X.Y. Wang, S.C. Zhang, J.F. Mao, J. Ding, L.P. Lin, Z.J. Guo, A, dinuclear monofunctional platinum(II) complex with an aromatic linker shows low reactivity towards glutathione but high DNA binding ability and antitumor activity, J. Biol. Inorg. Chem. 12 (2007) 655–665. [2] N. Farrell, Polynuclear platinum drugs, Met. Ions. Biol. Syst. 42 (2004) 251–296.
doi:10.1016/j.jconrel.2013.08.161
Fig. 1. Temperature dependence of the water CAs for PNIPAAm/PU nanofibers (the inset photographs were the water-droplet shape on the PNIPAAm/PU nanofibers within 10 s a) 26 °C, b) 40 °C and SEM images of c) PNIPAAm/PU nanofibers, d) PNIPAAm/PU with NIF nanofibers touching with water).
Keywords: Electrospun, Thermo-sensitive, Nanofibers, Controlled drug release Acknowledgements The authors gratefully acknowledge the Program for New Century Excellent Talents in University of China (NCET-08-0165) for financial support. References
Controllable drug release from electrospun thermo-sensitive poly(n-isopropylacrylamide)/poly(ε-caprolactone)-based polyurethane nanofibers Xiuling Lina,b, Dongyan Tanga, Haofei Dua Department of Chemistry, Harbin Institute of Technology, Harbin 150001, China b Department of Materials Science and Engineering, Anhui University of Science and Technology, Huainan 232001, China E-mail address: [email protected] (X. Lin).
a
[1] S.Q. Liu, Y.W. Tong, Y.Y. Yang, Incorporation and in vitro release of doxorubicin in thermally sensitive micelles made from poly(N-isopropylacrylamide-co-N, Ndimethylacrylamide)-b-poly(D, L-lactide-co-glycolide) with varying compositions, Biomaterials 26 (2005) 5064–5074. [2] G. Verreck, I. Chun, J. Rosenblatt, J. Peeters, A.V. Dijck, J. Mensch, M. Noppe, M.E. Brewster, Incorporation of drugs in an amorphous state into electrospun nanofibers composed of a water-insoluble, nonbiodegradable polymer, J. Control. Release 92 (2003) 349–360.
doi:10.1016/j.jconrel.2013.08.162