- Email: [email protected]
Biomineralized hydrophobically modified alginate membrane for sustained drug delivery
Abstracts / Journal of Controlled Release 152 (2011) e1–e132
The combined results of Fig. 1b and d, show that the fabric surface had been coated with vitamin C–GA–chitosan microcapsules. Compared with the untreated (Fig. 1c) and treated (Fig. 1d) fabrics with microcapsules loaded with vitamin C, the structural stability and integrity of vitamin C can be identified by the use of 2, 6dichloroindophenol (DCP), inducing a fast change of the pink color to colorless. In the present study, GA was selected as the crosslinking agent to prepare vitamin C loaded GA–chitosan microcapsules. The crosslinking reaction between GA and chitosan proceeds rather fast due to the coexistence of amine and hydroxyl groups in the chitosan backbone. Therefore, the way to control the crosslinking reaction and/or the number of crosslinking sites is a crucial step in realizing the sustained release behavior of vitamin C. Fig. 2 represents the release profiles of vitamin C from GA– chitosan microcapsules. Fig. 2a shows that although the amount of the GA solution used for the crosslinking reaction was the same (0.5 mL), different release rates of vitamin C were obtained due to the different core contents (0.24 and 0.48 g) of vitamin C. With increasing loads of vitamin C, the release rates increase accordingly due to the thinner GA–chitosan polymer shell. On the other hand, the release rate of vitamin C decreased with increasing amounts of GA crosslinking agent (0.5 and 1 mL) (Fig. 2b). The release behavior of core ingredients from GA–chitosan microcapsules depends upon the density of GA–chitosan matrix materials, and the crosslinking density increases with increasing amounts of GA crosslinking agents. As a result, the release rate of vitamin C decreased, which is in agreement with the reports of Desai [2, 3] and Remunan-Lopez [5], who found that the release of the core ingredients from chitosan films decreased with increasing dosages of tripolyphosphate.
Cumulative Release, %
Acknowledgments The authors appreciated the National Natural Science Foundation of China (No. 20904040) and the Innovative Technology Funding of Hong Kong SAR government (ZP53 and ZR06) for their financial supports. References [1] H.F. Shi, John H. Xin, Cosmetic textiles: concepts, application and prospects, Proceeding in the 9th Asia Textile Conference, June 28–30, 2007, D01-14, TaiChun, Taiwan. [2] K.G. Desai, C. Liu, H.J. Park, Characteristics of vitamin C encapsulated tripolyphosphate– chitosan microspheres as affected by chitosan molecular weight, J. Microencapsul. 23 (2006) 79–90. [3] K.G. Desai, H.J. Park, Effect of manufacturing parameters on the characteristics of vitamin C encapsulated tripolyphosphate–chitosan microspheres prepared by spraydrying, J. Microencapsul. 23 (2006) 91–103. [4] M.S. Uddin, M.N.A. Hawlader, H.J. Zhu, Microencapsulation of ascorbic acid: effect of process variables on product characteristics, J. Microencapsul. 18 (2001) 199–209. [5] C. Remunan-Lopez, R. Bodmeier, Mechanical, water uptake and permeability properties of crosslinked chitosan glutamate and alginate films, J. Control. Release 44 (1997) 215–225.
Biomineralized hydrophobically modified alginate membrane for sustained drug delivery
80 60
Ximeng Sun, Jun Shi, Zhengzheng Zhang, Shaokui Cao School of Materials Science and Engineering, Zhengzhou University, Daxue Road 75, Zhengzhou 450052, China E-mail address: [email protected] (X. Sun).
40 20
Pristine Vitamin C Vc=0.48g Vc=0.24
0 0
1
2
3
4
5
6
Time, h
Cumulative Release, %
Conclusion Vitamin C encapsulated GA–chitosan microcapsules for modulated vitamin C release have been investigated by varying the crosslink density and the concentration of vitamin C. The study indicated that the vitamin C release rates decrease with increasing crosslink density of the capsules and increase with increasing concentration of vitamin C. The structural integrity of vitamin C after encapsulation proves that the interfacial/emulsion reaction is a good candidate for encapsulation of water-soluble ingredients into polymeric matrices.
doi:10.1016/j.jconrel.2011.08.135
a 100
b
e79
100 80
Abstract summary Biomineralized hydrophobically modified alginate membranes were prepared via a one step method. Characterization using SEM and FT-IR revealed that the prepared membranes are covered by a biomineralized polysaccharide layer. The swelling ratio decreased with the introduction of sodium palmitate (SP) into the biomineralized polysaccharide composition. Indomethacin release from the biomineralized hydrophobically modified membranes is around 70% within 720 min, while 100% release is obtained from the nonmodified membranes. Keywords: Alginate membrane, Hydrophobically modified, Biomineralization, Sustained drug delivery
60 40 20
Pristine Vitamin C X=0.5 ml X=1 ml
0 0
1
2
3
4
5
6
Time, h Fig. 2. The influence of manufacturing parameters on the release rate of vitamin C from GA–chitosan microcapsules. (a) varying the core content of vitamin C; (b) varying the crosslink density of chitosan.
Introduction Biomineralized polysaccharide (BP) hybrid materials [1–3] are likely to be of generic importance in the design of biocompatible microcapsules because they often exhibit complementary properties. On the other hand, the diffusion rate of drugs can be decreased by the introduction of hydrophobic components in the polysaccharidebased drug delivery system [4]. In this paper, we will describe a one-step method to prepare biomineralized polysaccharide hydrophobically modified (sodium palmitate, SP) membranes, in which the deposition of a porous alginate/chitosan layer around alginate membranes is coupled with the controlled precipitation of calcium
Abstracts / Journal of Controlled Release 152 (2011) e1–e132
phosphate arising from counter-diffusion of ions across the polysaccharide interface in hydrophobically modified alginate membranes as illustrated in Scheme 1. The purpose of this study is to prepare hybrid alginate membranes with multi-stimuli-responsive sustained release properties.
SA SA/SP
Transmittance
e80
SA/SP/BP
600 560
2850
1030
1635
4000 3500 3000 2500 2000 1500 1000
500
Wavenumbers (cm-1) Fig. 1. FTIR spectra of the samples.
Scheme 1. Schematic illustration of biomineralized hydrophobically modified membrane (a) and alginate membranes with incorporated SP (b).
Results and discussion Three samples were prepared in the experiments. SA, SA/SP and SA/SP/BP refer to sodium alginate membrane, sodium alginate/ sodium palmitate membrane and sodium alginate/sodium palmitate/biomineralized polysaccharide membrane, respectively. Fig. 1 presents the FT-IR spectra of the samples. After the formation of biomineralized polysaccharide, the absorption at 1620 cm− 1 corresponding to the carbonyl (CO) bond of sample SA was replaced by a new broad band at 1635 cm− 1 as a result of the interaction between the negatively charged −COO− groups of alginate and the positively charged −NH3+ groups of chitosan. Three strong absorptions around 1030 cm− 1, 600 cm− 1 and 560 cm− 1 assignable to the PO bonds also could be observed in sample SA/SP/BP, suggesting the formation of biomineralized component within the membrane. The peaks at 2850 cm− 1 are ascribed to−CH2 groups in SP. A progressive change in the texture of the outer space could be observed with the introduction of biomineralized composition as illustrated in Fig. 2. Many pores and cracks can be observed in the surface of samples SA and SA/SP (not presented here), while the biomineralized membranes showed a relatively flat and compact surface. The swelling ratio decreased progressively with the introduction of SP and the biomineralized polysaccharide composition (Fig. 3). Thus, it may be deduced that the biomineralized polysaccharide outer shell can prevent the water to penetrate into the membranes and then decrease the drug release. Fig. 3 also
Fig. 2. SEM micrographs of sample SA/SP/BP. Left and right refer to surface and cross section of the sample, respectively.
demonstrated the pH/temperature responsivity of the biomineralized polysaccharide membrane. Drug release results (Fig. 4) demonstrated that the drug release was around 70% within 720 min for the biomineralized polysaccharide hydrophobically modified membranes (sample SA/SP/BP) and that for the unmineralized ones (sample SA) it was almost 100%. The drug release of biomineralized polysaccharide membranes (without hydrophobic composition) was around 80% as discussed in other paper [5]. These results indicate that the interaction of the biomineralized and hydrophobic composition was successful in decreasing membrane permeability and accordingly the drug release. The interaction mechanism of the biomineralized and hydrophobic composition will be discussed in our following work.
30
Swelling ratio
Experimental methods Preparation of biomineralized hydrophobically modified polysaccharide membranes. Homogeneous aqueous solutions composed of sodium alginate (3%, w/v) containing PNIPAAm (PNIPAAm:alginate = 1:3 (w/w)), 4.5 g/L of SP, 20% (w/w) of indomethacin and 250 mM of Na2HPO4 were prepared. A homogeneous solution of chitosan (1% (v/v)) in 1% acetic acid containing 5% CaCl2 was used as a coagulation fluid. The homogeneous alginate solution was spread on a PTFE plate, and then immersed in the coagulation fluid to crosslink. The obtained membranes were vacuum dried at 40 °C for 24 h. Drug release behaviors were examined by using indomethacin as a model drug. Swelling and drug release studies were performed typically in triplicate.
37°C, pH7.4(PBS) 25°C, pH7.4(PBS) 37°C, pH2.1(HCl) 25°C, pH2.1(HCl)
20
10
0
SA
SA/SP
SA/SP/BP
Fig. 3. Equilibrium swelling ratio for the samples at different pH values and temperatures.
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.
The combined results of Fig. 1b and d, show that the fabric surface had been coated with vitamin C–GA–chitosan microcapsules. Compared with the untreated (Fig. 1c) and treated (Fig. 1d) fabrics with microcapsules loaded with vitamin C, the structural stability and integrity of vitamin C can be identified by the use of 2, 6dichloroindophenol (DCP), inducing a fast change of the pink color to colorless. In the present study, GA was selected as the crosslinking agent to prepare vitamin C loaded GA–chitosan microcapsules. The crosslinking reaction between GA and chitosan proceeds rather fast due to the coexistence of amine and hydroxyl groups in the chitosan backbone. Therefore, the way to control the crosslinking reaction and/or the number of crosslinking sites is a crucial step in realizing the sustained release behavior of vitamin C. Fig. 2 represents the release profiles of vitamin C from GA– chitosan microcapsules. Fig. 2a shows that although the amount of the GA solution used for the crosslinking reaction was the same (0.5 mL), different release rates of vitamin C were obtained due to the different core contents (0.24 and 0.48 g) of vitamin C. With increasing loads of vitamin C, the release rates increase accordingly due to the thinner GA–chitosan polymer shell. On the other hand, the release rate of vitamin C decreased with increasing amounts of GA crosslinking agent (0.5 and 1 mL) (Fig. 2b). The release behavior of core ingredients from GA–chitosan microcapsules depends upon the density of GA–chitosan matrix materials, and the crosslinking density increases with increasing amounts of GA crosslinking agents. As a result, the release rate of vitamin C decreased, which is in agreement with the reports of Desai [2, 3] and Remunan-Lopez [5], who found that the release of the core ingredients from chitosan films decreased with increasing dosages of tripolyphosphate.
Cumulative Release, %
Acknowledgments The authors appreciated the National Natural Science Foundation of China (No. 20904040) and the Innovative Technology Funding of Hong Kong SAR government (ZP53 and ZR06) for their financial supports. References [1] H.F. Shi, John H. Xin, Cosmetic textiles: concepts, application and prospects, Proceeding in the 9th Asia Textile Conference, June 28–30, 2007, D01-14, TaiChun, Taiwan. [2] K.G. Desai, C. Liu, H.J. Park, Characteristics of vitamin C encapsulated tripolyphosphate– chitosan microspheres as affected by chitosan molecular weight, J. Microencapsul. 23 (2006) 79–90. [3] K.G. Desai, H.J. Park, Effect of manufacturing parameters on the characteristics of vitamin C encapsulated tripolyphosphate–chitosan microspheres prepared by spraydrying, J. Microencapsul. 23 (2006) 91–103. [4] M.S. Uddin, M.N.A. Hawlader, H.J. Zhu, Microencapsulation of ascorbic acid: effect of process variables on product characteristics, J. Microencapsul. 18 (2001) 199–209. [5] C. Remunan-Lopez, R. Bodmeier, Mechanical, water uptake and permeability properties of crosslinked chitosan glutamate and alginate films, J. Control. Release 44 (1997) 215–225.
Biomineralized hydrophobically modified alginate membrane for sustained drug delivery
80 60
Ximeng Sun, Jun Shi, Zhengzheng Zhang, Shaokui Cao School of Materials Science and Engineering, Zhengzhou University, Daxue Road 75, Zhengzhou 450052, China E-mail address: [email protected] (X. Sun).
40 20
Pristine Vitamin C Vc=0.48g Vc=0.24
0 0
1
2
3
4
5
6
Time, h
Cumulative Release, %
Conclusion Vitamin C encapsulated GA–chitosan microcapsules for modulated vitamin C release have been investigated by varying the crosslink density and the concentration of vitamin C. The study indicated that the vitamin C release rates decrease with increasing crosslink density of the capsules and increase with increasing concentration of vitamin C. The structural integrity of vitamin C after encapsulation proves that the interfacial/emulsion reaction is a good candidate for encapsulation of water-soluble ingredients into polymeric matrices.
doi:10.1016/j.jconrel.2011.08.135
a 100
b
e79
100 80
Abstract summary Biomineralized hydrophobically modified alginate membranes were prepared via a one step method. Characterization using SEM and FT-IR revealed that the prepared membranes are covered by a biomineralized polysaccharide layer. The swelling ratio decreased with the introduction of sodium palmitate (SP) into the biomineralized polysaccharide composition. Indomethacin release from the biomineralized hydrophobically modified membranes is around 70% within 720 min, while 100% release is obtained from the nonmodified membranes. Keywords: Alginate membrane, Hydrophobically modified, Biomineralization, Sustained drug delivery
60 40 20
Pristine Vitamin C X=0.5 ml X=1 ml
0 0
1
2
3
4
5
6
Time, h Fig. 2. The influence of manufacturing parameters on the release rate of vitamin C from GA–chitosan microcapsules. (a) varying the core content of vitamin C; (b) varying the crosslink density of chitosan.
Introduction Biomineralized polysaccharide (BP) hybrid materials [1–3] are likely to be of generic importance in the design of biocompatible microcapsules because they often exhibit complementary properties. On the other hand, the diffusion rate of drugs can be decreased by the introduction of hydrophobic components in the polysaccharidebased drug delivery system [4]. In this paper, we will describe a one-step method to prepare biomineralized polysaccharide hydrophobically modified (sodium palmitate, SP) membranes, in which the deposition of a porous alginate/chitosan layer around alginate membranes is coupled with the controlled precipitation of calcium
Abstracts / Journal of Controlled Release 152 (2011) e1–e132
phosphate arising from counter-diffusion of ions across the polysaccharide interface in hydrophobically modified alginate membranes as illustrated in Scheme 1. The purpose of this study is to prepare hybrid alginate membranes with multi-stimuli-responsive sustained release properties.
SA SA/SP
Transmittance
e80
SA/SP/BP
600 560
2850
1030
1635
4000 3500 3000 2500 2000 1500 1000
500
Wavenumbers (cm-1) Fig. 1. FTIR spectra of the samples.
Scheme 1. Schematic illustration of biomineralized hydrophobically modified membrane (a) and alginate membranes with incorporated SP (b).
Results and discussion Three samples were prepared in the experiments. SA, SA/SP and SA/SP/BP refer to sodium alginate membrane, sodium alginate/ sodium palmitate membrane and sodium alginate/sodium palmitate/biomineralized polysaccharide membrane, respectively. Fig. 1 presents the FT-IR spectra of the samples. After the formation of biomineralized polysaccharide, the absorption at 1620 cm− 1 corresponding to the carbonyl (CO) bond of sample SA was replaced by a new broad band at 1635 cm− 1 as a result of the interaction between the negatively charged −COO− groups of alginate and the positively charged −NH3+ groups of chitosan. Three strong absorptions around 1030 cm− 1, 600 cm− 1 and 560 cm− 1 assignable to the PO bonds also could be observed in sample SA/SP/BP, suggesting the formation of biomineralized component within the membrane. The peaks at 2850 cm− 1 are ascribed to−CH2 groups in SP. A progressive change in the texture of the outer space could be observed with the introduction of biomineralized composition as illustrated in Fig. 2. Many pores and cracks can be observed in the surface of samples SA and SA/SP (not presented here), while the biomineralized membranes showed a relatively flat and compact surface. The swelling ratio decreased progressively with the introduction of SP and the biomineralized polysaccharide composition (Fig. 3). Thus, it may be deduced that the biomineralized polysaccharide outer shell can prevent the water to penetrate into the membranes and then decrease the drug release. Fig. 3 also
Fig. 2. SEM micrographs of sample SA/SP/BP. Left and right refer to surface and cross section of the sample, respectively.
demonstrated the pH/temperature responsivity of the biomineralized polysaccharide membrane. Drug release results (Fig. 4) demonstrated that the drug release was around 70% within 720 min for the biomineralized polysaccharide hydrophobically modified membranes (sample SA/SP/BP) and that for the unmineralized ones (sample SA) it was almost 100%. The drug release of biomineralized polysaccharide membranes (without hydrophobic composition) was around 80% as discussed in other paper [5]. These results indicate that the interaction of the biomineralized and hydrophobic composition was successful in decreasing membrane permeability and accordingly the drug release. The interaction mechanism of the biomineralized and hydrophobic composition will be discussed in our following work.
30
Swelling ratio
Experimental methods Preparation of biomineralized hydrophobically modified polysaccharide membranes. Homogeneous aqueous solutions composed of sodium alginate (3%, w/v) containing PNIPAAm (PNIPAAm:alginate = 1:3 (w/w)), 4.5 g/L of SP, 20% (w/w) of indomethacin and 250 mM of Na2HPO4 were prepared. A homogeneous solution of chitosan (1% (v/v)) in 1% acetic acid containing 5% CaCl2 was used as a coagulation fluid. The homogeneous alginate solution was spread on a PTFE plate, and then immersed in the coagulation fluid to crosslink. The obtained membranes were vacuum dried at 40 °C for 24 h. Drug release behaviors were examined by using indomethacin as a model drug. Swelling and drug release studies were performed typically in triplicate.
37°C, pH7.4(PBS) 25°C, pH7.4(PBS) 37°C, pH2.1(HCl) 25°C, pH2.1(HCl)
20
10
0
SA
SA/SP
SA/SP/BP
Fig. 3. Equilibrium swelling ratio for the samples at different pH values and temperatures.
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.