- Email: [email protected]
Nanogated vessel based on polypseudorotaxane-capped mesoporous silica via a highly acid-labile benzoic-imine linker
Abstracts / Journal of Controlled Release 152 (2011) e1–e132
Keywords: Mesoporous silica, Polypseudorotaxane, Acid-labile, Controlled release
100 80
Drug release (%)
e81
60 SA SA/SP SA/SP/BP
40 20 0 0
2
4
6
8
10
12
Time (h) Fig. 4. The sustained drug release profiles of the studied membranes.
Conclusion A series of biomineralized hydrophobically modified alginate membranes with sustained drug release properties was prepared in a one-step method. The results demonstrated that the interaction of the biomineralized polysaccharide composition and the hydrophobic chain could prevent the permeation of the encapsulated drug and endow the hydrophobically modified alginate membranes with sustained release properties.
Introduction pH-sensitive drug delivery vehicles have been widely used in the treatment of acidic targets, such as tumors and inflammatory tissues. So far, acid-dependent covalent bonds such as acetal [1], hydrazone [2], and orthoester [3], which dissociate rapidly in the endosomal compartment (pH ~ 5), are extensively researched in the construction of lipids, mesoporous silica, polymeric micelles, nanogels and prodrug conjugates as drug delivery carriers in acidic pH environments. However, tumor specificity has rarely been gained from the inclusion of these linkers, because normal cells also have the same endosomal acid pH (pH ~ 5). It is known that the extracellular pH of tumor tissue is slightly lower than that of the normal tissue. Most extracellular pH at a solid tumor site is 6.8, compared with the normal tissue (pH 7.4). Therefore, acid-labile linkage with more active and prompt response to a small drop of pH is needed for more effective and tumor-specific drug delivery. The benzoic-imine bond is highly pH-sensitive within a very narrow pH interval (7.4–5.0) [4]. Because of the proper π–π conjugation extent, it hydrolyzes under very slightly acidic conditions (e.g. extracellular pH of tumor tissue 6.8) whereas it is stable at neutral and basic pH. Herein, we report a new pH-responsive nanogated mesoporous silica system by capping PEG/α-CD polypseudorotaxanes onto the mesoporous silica through a highly acid-labile benzoic-imine linker (Scheme 1).
Acknowledgments This work was supported by the National Natural Science Foundation of China (No. 20874090). References [1] J. Shi, L.H. Liu, X.M. Sun, S.K. Cao, J.F. Mano, Biomineralized polysaccharide beads for dualstimuli-responsive drug delivery, Macromol. Biosci. 8 (2008) 260–267. [2] D.W. Green, I. Leveque, D. Walsh, D. Howard, X. Yang, K. Partridge, S. Mann, R.O.C. Oreffo, Biomineralized polysaccharide capsules for encapsulation, organization, and delivery of human cell types and growth factors, Adv. Funct. Mater. 15 (2005) 917–923. [3] D.W. Green, S. Mann, R.O.C. Oreffo, Mineralized polysaccharide capsules as biomimetic microenvironments for cell, gene and growth factor delivery in tissue engineering, Soft Matter 2 (2006) 732–737. [4] B. Nystrom, A.L. Kjoniksen, N. Beheshti, K.Z. Zhu, K.D. Knudsen, Rheological and structural aspects on association of hydrophobically modified polysaccharides, Soft Matter 5 (2009) 1328–1339. [5] J. Shi, X.P. Liu, S.K. Cao, Hybrid alginate membrane for multi-responsive controlled delivery, J. Membr. Sci. 352 (2010) 262–270.
doi:10.1016/j.jconrel.2011.08.136
Nanogated vessel based on polypseudorotaxane-capped mesoporous silica via a highly acid-labile benzoic-imine linker Yaohua Gao, Rujiang Ma, Yingli An, Linqi Shi Key Laboratory of Functional Polymer Materials, Ministry of Education, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China E-mail address: [email protected] (L. Shi). Abstract summary pH-responsive nanogated vessels based on polypseudorotaxanecapped mesoporous silica via a highly acid-labile benzoic-imine linker are prepared and used for controlled drug delivery. The benzoic-imine bond hydrolyzes under very slightly acidic conditions (e.g. extracellular pH of tumor tissue 6.8) whereas it is stable at neutral and basic pH. By changing the environmental pH from physiological pH to slightly acidic pH, i.e., 7.4 to 6.8, faster drug release can be clearly seen. Preliminary experiments showed that tumor specificity could be gained from the inclusion of the benzoicimine linker.
Scheme 1. Synthetic route of PEG-functionalized silica particles and illustration of pHresponsive release of guest molecules from the pores of mesoporous silica (MS).
The aim of this work is to design a novel pH-responsive drug delivery carrier with enhanced tumor specificity. Preliminary experiments in vitro showed that the tumor specificity could be improved by the incorporation of an acid-labile benzoic-imine linker. Experimental methods Synthesis of Methoxy Poly(ethylene glycol) Benzaldehyde(PEG-CHO). PEG-CHO was prepared according to the published methods with a yield of 80% [4]. Synthesis of MS-NH2. Bare MS particles were synthesized according to the literature [5]. By treatment with 3-aminopropyltriethoxysilane (APTES), amine groups were functionalized onto the silica surface to yield MS-NH2.
e82
Abstracts / Journal of Controlled Release 152 (2011) e1–e132
Synthesis of MS-PEG. MS-NH2 (150 mg) was dissolved in 6 mL of DMSO. Then PEG-CHO (0.72 g) which was dissolved in 12 mL of DMSO was added. The reaction mixture was stirred and kept at 40 °C for 4 h before purification by centrifugation. Results and discussion The morphology of MS was confirmed by TEM, E-SEM, N2 sorption measurements and PXRD. The mean diameter of the silica particles estimated by E-SEM was about 100 nm (Fig. 1a), and well-ordered mesopores could be clearly observed from the TEM image (Fig. 1b). PXRD results showed that the lattice spacing of the ordered pores with hexagonal structures was 4 nm. The N2 adsorption/desorption isotherms showed a typical MCM-41 structure (type IV) with a Brunauer– Emmett–Teller (BET) surface area of 1099 m2/g and pore volume of 1.09 cm3/g. A narrow pore size distribution of 2.4 nm was obtained for mesopores using the Barrett–Joiner–Halenda (BJH) method. The surface of MS was functionalized with amine groups by treatment with 3aminopropyltriethoxysilane (APTES) to yield MS-NH2. The MS-PEG was obtained by allowing MS-NH2 to react with PEG-CHO. The surface functionalization of MS was confirmed by FTIR spectroscopy.
To confirm the pH-dependent drug release profiles of the MS controlled release system, two additional control studies were carried out. One was that MS-PEG was used as a reservoir to trap the drug molecules without further capping by α-CDs. The other was that PEG/ CD polypseudorotaxane-capped MS was used to store the drug molecules. After the same washing procedure, no DOX release was observed at any pH in these two control studies, because, as to control study 1, absorbed molecules escaped from unguarded pores during the washing steps and as to study 2, DOX was not trapped into the mesopores at all due to the blockage of polypseudorotaxanes. Both of these again confirmed that the previously observed release was ascribed to the cleavage of the benzoic-imine linker at slightly acid environments. Conclusion A highly pH-responsive nanogated controlled release system was synthesized based on mesoporous silica capped by PEG/α-CD polypseudorotaxanes via a novel acid-labile benzoic-imine linker. This nanogated ensemble showed a distinct pH-dependent drug release characteristics at weakly acid conditions (e.g. pH 6.8), which makes it a promising candidate for future design of delivery systems with tumor-specific uptake and intracellular delivery ability. References
Fig. 1. E-SEM (a) and TEM (b) images of MS.
To investigate the pH-responsive gating behavior of the MS-based drug delivery system, doxorubicin (DOX) was loaded as guest molecule by soaking MS-PEG into a solution of DOX for two days. Then, α-CD was added into the mixture to cap the mesopores of the silica. The loading of DOX in MS-PEG was visualized by confocal laser scanning microscopy (CLSM). Fig. 2 shows the DOX release from the nanogated MS system at different pHs (7.4 and 6.8). The MS system showed distinguished pH-dependent drug release profiles. By changing the environmental pH from normal to slightly acidic, i.e., 7.4 to 6.8, accelerated DOX release could be clearly seen.
[1] Y. Chan, V. Bulmus, M. Hadi Zareie, F.L. Byrne, L. Barner, M. Kavallaris, Acid-cleavable polymeric coreshell particles for delivery of hydrophobic drugs, J. Control. Release 115 (2006) 197–207. [2] A. Kale, V.P. Torchilin, Design, synthesis, and characterization of pH-sensitive PEG-PE conjugates for stimuli-sensitive pharmaceutical nanocarriers: the effect of substitutes at the hydrazone linkage on the pH-stability of PEG-PE conjugates, Bioconjug. Chem. 18 (2007) 363–370. [3] S. Lin, F. Du, Y. Wang, S. Ji, D. Liang, L. Yu, Z. Li, An acid-labile block copolymer of PDMAEMA and PEG as potential carrier for intelligent gene delivery systems, Biomacromolecules 9 (2008) 109–115. [4] C.X. Ding, J.X. Gu, X.Z. Qu, Z.Z. Yang, Preparation of multifunctional drug carrier for tumor-specific uptake and enhanced intracellular delivery through the conjugation of weak acid labile linker, Bioconjug. Chem. 20 (2009) 1163–1170. [5] C. Park, K. Lee, C. Kim, Photo-responsive cyclodextrin-covered nano-containers and their sol–gel transition induced by molecular recognition, Angew. Chem. Int. Ed. 48 (2009) 1275–1278.
doi:10.1016/j.jconrel.2011.08.137
Dual drug release from coaxial electrospun nanofibers Yan Su, Xiumei Mo State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Chemistry & Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China Biomaterials and Tissue Engineering Laboratory, College of Chemistry & Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China E-mail address: [email protected] (Y. Su). Abstract summary The aim of this work was to develop a novel type of tissue engineering scaffold or drug delivery carrier with the capability of encapsulation and controlled release of dual drugs. Rhodamine B and bovine serum albumin (BSA) were successfully incorporated into nanofibers by means of blending and coaxial electrospinning. In vitro drug release from composite nanofibrous mats under different conditions was investigated. The results implied that drug and/or protein release profiles can be controlled by altering the coaxial electrospinning process.
Fig. 2. Cumulative release of doxorubicin from the nanogated MS system at pH 7.4 and 6.8.
Keywords: Dual drugs, Coaxial electrospinning, Nanofibers, Controlled release
Keywords: Mesoporous silica, Polypseudorotaxane, Acid-labile, Controlled release
100 80
Drug release (%)
e81
60 SA SA/SP SA/SP/BP
40 20 0 0
2
4
6
8
10
12
Time (h) Fig. 4. The sustained drug release profiles of the studied membranes.
Conclusion A series of biomineralized hydrophobically modified alginate membranes with sustained drug release properties was prepared in a one-step method. The results demonstrated that the interaction of the biomineralized polysaccharide composition and the hydrophobic chain could prevent the permeation of the encapsulated drug and endow the hydrophobically modified alginate membranes with sustained release properties.
Introduction pH-sensitive drug delivery vehicles have been widely used in the treatment of acidic targets, such as tumors and inflammatory tissues. So far, acid-dependent covalent bonds such as acetal [1], hydrazone [2], and orthoester [3], which dissociate rapidly in the endosomal compartment (pH ~ 5), are extensively researched in the construction of lipids, mesoporous silica, polymeric micelles, nanogels and prodrug conjugates as drug delivery carriers in acidic pH environments. However, tumor specificity has rarely been gained from the inclusion of these linkers, because normal cells also have the same endosomal acid pH (pH ~ 5). It is known that the extracellular pH of tumor tissue is slightly lower than that of the normal tissue. Most extracellular pH at a solid tumor site is 6.8, compared with the normal tissue (pH 7.4). Therefore, acid-labile linkage with more active and prompt response to a small drop of pH is needed for more effective and tumor-specific drug delivery. The benzoic-imine bond is highly pH-sensitive within a very narrow pH interval (7.4–5.0) [4]. Because of the proper π–π conjugation extent, it hydrolyzes under very slightly acidic conditions (e.g. extracellular pH of tumor tissue 6.8) whereas it is stable at neutral and basic pH. Herein, we report a new pH-responsive nanogated mesoporous silica system by capping PEG/α-CD polypseudorotaxanes onto the mesoporous silica through a highly acid-labile benzoic-imine linker (Scheme 1).
Acknowledgments This work was supported by the National Natural Science Foundation of China (No. 20874090). References [1] J. Shi, L.H. Liu, X.M. Sun, S.K. Cao, J.F. Mano, Biomineralized polysaccharide beads for dualstimuli-responsive drug delivery, Macromol. Biosci. 8 (2008) 260–267. [2] D.W. Green, I. Leveque, D. Walsh, D. Howard, X. Yang, K. Partridge, S. Mann, R.O.C. Oreffo, Biomineralized polysaccharide capsules for encapsulation, organization, and delivery of human cell types and growth factors, Adv. Funct. Mater. 15 (2005) 917–923. [3] D.W. Green, S. Mann, R.O.C. Oreffo, Mineralized polysaccharide capsules as biomimetic microenvironments for cell, gene and growth factor delivery in tissue engineering, Soft Matter 2 (2006) 732–737. [4] B. Nystrom, A.L. Kjoniksen, N. Beheshti, K.Z. Zhu, K.D. Knudsen, Rheological and structural aspects on association of hydrophobically modified polysaccharides, Soft Matter 5 (2009) 1328–1339. [5] J. Shi, X.P. Liu, S.K. Cao, Hybrid alginate membrane for multi-responsive controlled delivery, J. Membr. Sci. 352 (2010) 262–270.
doi:10.1016/j.jconrel.2011.08.136
Nanogated vessel based on polypseudorotaxane-capped mesoporous silica via a highly acid-labile benzoic-imine linker Yaohua Gao, Rujiang Ma, Yingli An, Linqi Shi Key Laboratory of Functional Polymer Materials, Ministry of Education, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China E-mail address: [email protected] (L. Shi). Abstract summary pH-responsive nanogated vessels based on polypseudorotaxanecapped mesoporous silica via a highly acid-labile benzoic-imine linker are prepared and used for controlled drug delivery. The benzoic-imine bond hydrolyzes under very slightly acidic conditions (e.g. extracellular pH of tumor tissue 6.8) whereas it is stable at neutral and basic pH. By changing the environmental pH from physiological pH to slightly acidic pH, i.e., 7.4 to 6.8, faster drug release can be clearly seen. Preliminary experiments showed that tumor specificity could be gained from the inclusion of the benzoicimine linker.
Scheme 1. Synthetic route of PEG-functionalized silica particles and illustration of pHresponsive release of guest molecules from the pores of mesoporous silica (MS).
The aim of this work is to design a novel pH-responsive drug delivery carrier with enhanced tumor specificity. Preliminary experiments in vitro showed that the tumor specificity could be improved by the incorporation of an acid-labile benzoic-imine linker. Experimental methods Synthesis of Methoxy Poly(ethylene glycol) Benzaldehyde(PEG-CHO). PEG-CHO was prepared according to the published methods with a yield of 80% [4]. Synthesis of MS-NH2. Bare MS particles were synthesized according to the literature [5]. By treatment with 3-aminopropyltriethoxysilane (APTES), amine groups were functionalized onto the silica surface to yield MS-NH2.
e82
Abstracts / Journal of Controlled Release 152 (2011) e1–e132
Synthesis of MS-PEG. MS-NH2 (150 mg) was dissolved in 6 mL of DMSO. Then PEG-CHO (0.72 g) which was dissolved in 12 mL of DMSO was added. The reaction mixture was stirred and kept at 40 °C for 4 h before purification by centrifugation. Results and discussion The morphology of MS was confirmed by TEM, E-SEM, N2 sorption measurements and PXRD. The mean diameter of the silica particles estimated by E-SEM was about 100 nm (Fig. 1a), and well-ordered mesopores could be clearly observed from the TEM image (Fig. 1b). PXRD results showed that the lattice spacing of the ordered pores with hexagonal structures was 4 nm. The N2 adsorption/desorption isotherms showed a typical MCM-41 structure (type IV) with a Brunauer– Emmett–Teller (BET) surface area of 1099 m2/g and pore volume of 1.09 cm3/g. A narrow pore size distribution of 2.4 nm was obtained for mesopores using the Barrett–Joiner–Halenda (BJH) method. The surface of MS was functionalized with amine groups by treatment with 3aminopropyltriethoxysilane (APTES) to yield MS-NH2. The MS-PEG was obtained by allowing MS-NH2 to react with PEG-CHO. The surface functionalization of MS was confirmed by FTIR spectroscopy.
To confirm the pH-dependent drug release profiles of the MS controlled release system, two additional control studies were carried out. One was that MS-PEG was used as a reservoir to trap the drug molecules without further capping by α-CDs. The other was that PEG/ CD polypseudorotaxane-capped MS was used to store the drug molecules. After the same washing procedure, no DOX release was observed at any pH in these two control studies, because, as to control study 1, absorbed molecules escaped from unguarded pores during the washing steps and as to study 2, DOX was not trapped into the mesopores at all due to the blockage of polypseudorotaxanes. Both of these again confirmed that the previously observed release was ascribed to the cleavage of the benzoic-imine linker at slightly acid environments. Conclusion A highly pH-responsive nanogated controlled release system was synthesized based on mesoporous silica capped by PEG/α-CD polypseudorotaxanes via a novel acid-labile benzoic-imine linker. This nanogated ensemble showed a distinct pH-dependent drug release characteristics at weakly acid conditions (e.g. pH 6.8), which makes it a promising candidate for future design of delivery systems with tumor-specific uptake and intracellular delivery ability. References
Fig. 1. E-SEM (a) and TEM (b) images of MS.
To investigate the pH-responsive gating behavior of the MS-based drug delivery system, doxorubicin (DOX) was loaded as guest molecule by soaking MS-PEG into a solution of DOX for two days. Then, α-CD was added into the mixture to cap the mesopores of the silica. The loading of DOX in MS-PEG was visualized by confocal laser scanning microscopy (CLSM). Fig. 2 shows the DOX release from the nanogated MS system at different pHs (7.4 and 6.8). The MS system showed distinguished pH-dependent drug release profiles. By changing the environmental pH from normal to slightly acidic, i.e., 7.4 to 6.8, accelerated DOX release could be clearly seen.
[1] Y. Chan, V. Bulmus, M. Hadi Zareie, F.L. Byrne, L. Barner, M. Kavallaris, Acid-cleavable polymeric coreshell particles for delivery of hydrophobic drugs, J. Control. Release 115 (2006) 197–207. [2] A. Kale, V.P. Torchilin, Design, synthesis, and characterization of pH-sensitive PEG-PE conjugates for stimuli-sensitive pharmaceutical nanocarriers: the effect of substitutes at the hydrazone linkage on the pH-stability of PEG-PE conjugates, Bioconjug. Chem. 18 (2007) 363–370. [3] S. Lin, F. Du, Y. Wang, S. Ji, D. Liang, L. Yu, Z. Li, An acid-labile block copolymer of PDMAEMA and PEG as potential carrier for intelligent gene delivery systems, Biomacromolecules 9 (2008) 109–115. [4] C.X. Ding, J.X. Gu, X.Z. Qu, Z.Z. Yang, Preparation of multifunctional drug carrier for tumor-specific uptake and enhanced intracellular delivery through the conjugation of weak acid labile linker, Bioconjug. Chem. 20 (2009) 1163–1170. [5] C. Park, K. Lee, C. Kim, Photo-responsive cyclodextrin-covered nano-containers and their sol–gel transition induced by molecular recognition, Angew. Chem. Int. Ed. 48 (2009) 1275–1278.
doi:10.1016/j.jconrel.2011.08.137
Dual drug release from coaxial electrospun nanofibers Yan Su, Xiumei Mo State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Chemistry & Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China Biomaterials and Tissue Engineering Laboratory, College of Chemistry & Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China E-mail address: [email protected] (Y. Su). Abstract summary The aim of this work was to develop a novel type of tissue engineering scaffold or drug delivery carrier with the capability of encapsulation and controlled release of dual drugs. Rhodamine B and bovine serum albumin (BSA) were successfully incorporated into nanofibers by means of blending and coaxial electrospinning. In vitro drug release from composite nanofibrous mats under different conditions was investigated. The results implied that drug and/or protein release profiles can be controlled by altering the coaxial electrospinning process.
Fig. 2. Cumulative release of doxorubicin from the nanogated MS system at pH 7.4 and 6.8.
Keywords: Dual drugs, Coaxial electrospinning, Nanofibers, Controlled release