- Email: [email protected]
Effect of resistant starch film properties on the colon-targeting release of drug from coated pellets
Abstracts / Journal of Controlled Release 152 (2011) e1–e132
The biodegradability and biocompatibility of N-Boc-histidinecapped PLGA–PEG–PLGA were proved by DLS, 1H NMR and MTT assay. Doxorubicin was used as a model anticancer drug. The in vitro DOX release (Fig. 1) was faster at pH 6.2, as compared to pH 7.4. The pH dependence release rate was due to the pH sensitivity of the micelles.
e5
with appropriate pKa. This polymer was used to form micelles which show an accelerate release of drugs at the slight acidic, tumor extracellular micro-environments. The basic properties of the new material and characteristic parameters of the formed micelles in water were evaluated. The in vitro release assays using DOX as a model drug validated the mode of drug release. The N-Boc-histidine capped PLGA–PEG–PLGA polymer may have potential as a biodegradable and biocompatible anticancer release carrier, which is sensitive to tumor extracellular pH. References
Fig. 1. In vitro release profiles of DOX from micelles at indicated pH values [12].
[1] E.S. Lee, Z.G. Gao, Y.H. Bae, Recent progress in tumor pH targeting nanotechnology, J. Control. Release 132 (2008) 164–170. [2] H.S. Yoo, E.A. Lee, T.G. Park, Doxorubicin-conjugated biodegradable polymeric micelles having acid-cleavable linkages, J. Control. Release 82 (2002) 17–27. [3] 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. [4] W. Chen, F.H. Meng, R. Cheng, Z.Y. Zhong, pH-Sensitive degradable polymersomes for triggered release of anticancer drugs: a comparative study with micelles, J. Control. Release 142 (2009) 40–46. [5] L. Yu, H. Zhang, J.D. Ding, A subtle end-group effect on macroscopic physical gelation of triblock copolymer aqueous solutions, Angew. Chem. Int. Ed. 45 (2006) 2232–2235. [6] L. Yu, G.T. Chang, H. Zhang, J.D. Ding, Temperature-induced spontaneous sol–gel transitions of poly(d, l-lactic acid-co-glycolic acid)–b-poly(ethylene glycol)–b-poly(d, llactic acid-co-glycolic acid) triblock copolymers and their end-capped derivatives in water, J. Polym. Sci. Polym. Chem. 45 (2007) 1122–1133. [7] L. Yu, G.T. Chang, H. Zhang, J.D. Ding, Injectable block copolymer hydrogels for sustained release of a PEGylated drug, Int. J. Pharm. 348 (2008) 95–106. [8] L. Yu, J.D. Ding, Injectable hydrogels as unique biomedical materials, Chem. Soc. Rev. 37 (2008) 1473–1481. [9] H. Zhang, L. Yu, J.D. Ding, Roles of hydrophilic homopolymers on the hydrophobicassociation-induced physical gelling of amphiphilic block copolymers in water, Macromolecules 41 (2008) 6493–6499. [10] L. Yu, Z. Zhang, H. Zhang, J.D. Ding, Mixing a sol and a precipitate of block copolymers with different block ratios leads to an injectable hydrogel, Biomacromolecules 10 (2009) 1547–1553. [11] G.T. Chang, L. Yu, Z.G. Yang, J.D. Ding, A delicate ionizable-group effect on selfassembly and thermogelling of amphiphilic block copolymers in water, Polymer 50 (2009) 6111–6120. [12] G.T. Chang, C. Li, W.Y. Lu, J.D. Ding, N-Boc-histidine-capped PLGA–PEG–PLGA as a smart polymer for drug delivery sensitive to tumor extracellular pH, Macromol. Biosci. doi:10.1002/mabi.201000117. [13] L.B. Wu, J.D. Ding, In vitro degradation of three-dimensional porous poly(d, l-lactideco-glycolide) scaffolds for tissue engineering, Biomaterials 25 (2004) 5821–5830. [14] L.B. Wu, J.D. Ding, Effects of porosity and pore size on in vitro degradation of threedimensional porous poly(d, l-lactide-co-glycolide) scaffolds for tissue engineering, J. Biomed. Mater. Res. A 75A (2005) 767–777.
doi:10.1016/j.jconrel.2011.08.086
Effect of resistant starch film properties on the colon-targeting release of drug from coated pellets
Fig. 2. Cellular uptake of DOX at indicated time and pH values. Human breast cancer cells MDA-MB-435 were used. Bars: 150 μm [12].
The pH-sensitive trend was also observed in cellular uptake of DOX from micelles investigated by microscopy. More DOX uptake was seen in the group of pH sensitive micelles at pH 6.2 than at pH 7.4 (Fig. 2). Conclusion By introducing the pH-sensitive moiety N-Boc-histidine into the ends of PLGA–PEG–PLGA, we synthesized a pH-sensitive polymer
Xiaoxi Li1, Peng Liu1, Ling Chen1, Long Yu1,2 1 Engineering Research Center of Starch & Protein Processing, Ministry of Education, South China University of Technology, Guangzhou 510640, China 2 Commonwealth Scientific and Industrial Research Organization, Materials Science and Engineering, Melbourne, Victoria 3169, Australia E-mail address: [email protected] (L. Chen). Abstract summary Resistant starch (RS) films were designed to target a protein to the colon by exploiting the colonic microbiota fermentative capacity. The RS films were coated to pellets and their mechanical resistance to the shear forces and the hydrostatic pressure within the pellets were investigated after contact with the gastrointestinal tract (GIT). In vitro tests showed that desired colon-targeted drug release can easily be obtained through controlling the proper relationship between enzymatic resistance and mechanical properties of RS film.
e6
Abstracts / Journal of Controlled Release 152 (2011) e1–e132
Keywords: Resistant starch film, Colon targeting, Mechanical properties, Controlled release, Pellets Introduction Oral colon-targeting drug delivery is an appealing method for oral protein and peptide delivery and many universal delivery systems have been investigated. RS escaping enzymatic digestion and acidolysis in the upper GIT but being degraded by microorganism in the colon is a potential carrier for oral colon-targeting drug delivery reported previously from our team and other researchers [1,2]. But the drawback of this polysaccharide is the easy swelling in aqueous conditions. RS with proper hydrophobic properties have been prepared in our lab by starch acetylation to overcome this drawback [2]. However, it is unclear whether RS films provide sufficient mechanical stability to withstand the shear stress in the upper GIT due to the gastrointestinal motility and to withstand the potentially significant hydrostatic pressure developed within the dosage forms due to water penetration into the systems upon contact with aqueous media. It was the aim of this study to elucidate these aspects and to investigate how the film coatings' properties affect the colon-targeted drug release. Experimental methods Preparation of RS film and its tensile properties. RS was prepared by esterification of high-amylose corn starch with acetic acid anhydride. RS film was prepared by solvent-casting from acetone. The resistance ability of RS to enzymatic and acid degradation was determined according to the Method 991.43 total dietary fiber of the Association of Official Analytical Chemists [3]. The tensile properties of the film were evaluated in accordance with ASTM D5938 standard on an Instron tensile testing apparatus (5565) at a crosshead speed of 10 mm/min under 30 °C and 30% relative humidity. In vitro drug release studies. Drug-loaded pellet cores (50% BSA, 50% microcrystalline cellulose) were prepared by extrusion and spheronization (Mini-250, Xinyite LTD, China) and then coated in a fluidized bed coater (WBF-1, Yingge LTD, Chongqing, China) with RS coating solution (3%, RS/acetone, w/w), until a proper weight gain was achieved. BSA release from the coated pellets in SGF, SIF and SCF was studied using a drug dissolution rate test apparatus 2(100 rpm, 37 °C) according to the USP23. 0.5 mL samples were taken over the course of time and the determination of BSA concentration was done using HPLC. The degradation and thermal mechanical properties of RS film in simulated digestive fluid. The films were incubated in simulated gastric fluid (SGF) for the first 2 h, and then in simulated intestinal fluid (SIF) for 6 h, afterwards in simulated colonic fluid (SCF) for an additional 40 h at 37 °C in sequence. The surface morphology and the thermal mechanical properties of films after each stage were investigated by scanning electron microscopy (SEM) (Nova NanoSEM430, FEI Co., The Netherlands) and dynamic mechanical analysis (DMA) (Diamond, PerkinElmer Co., USA) respectively. For DMA the tension measuring system was used. The temperature scanning range was from − 30 °C to 100 °C with the heating rate of 1 °C/min, and the force frequency is 0.5, 1, 2, 5, and 10 Hz, respectively. Results and discussion The RS film should have proper mechanical properties to resist the forces of the upper gastrointestinal tract when it is used as a carrier for an oral colon-targeting drug system, so its tensile properties should be evaluated. Table 1 illustrates the tensile properties of RS film. It can be seen that when RD increased from 82.9% to 99.9%, the tension strength increased from 4.73 MPa to 8.13 MPa, and the elongation from 5.35% to 15.25%. These properties meet the requirements for a drug coating-carrier.
Table 1 The resistibility to digestion and mechanical properties of RS films. Sample
Resistibility to digestion (RD) (%)
Tensile strength (MPa)
Elongation (%)
1 2 3 4 5
82.9 ± 0.5 87.8 ± 1.0 92.7 ± 1.2 98.3 ± 1.5 99.9 ± 0.4
4.73 ± 1.01 5.53 ± 0.81 6.48 ± 3.32 7.11 ± 2.27 8.13 ± 1.10
5.35 ± 0.54 6.95 ± 0.48 9.94 ± 0.67 11.81 ± 0.29 15.25 ± 0.56
In order to evaluate the degradability of RS film in simulated digestive fluid, SEM was used to observe the surface morphology of films immersed into SGF, SIF and SCF for a certain time period (Fig. 1). It is shown that the RS film has good resistance to degradation for acid and enzymes in simulated upper GIT. So RS film exhibits good colon-targeting properties. Furthermore, with the increase of soaking time, holes and cracks emerge on the film surface, which can be applied for drug release in the colon.
(a)
(b)
(c)
(d)
(e)
Fig. 1. The surface change of RS film (RD is 92.7%) after incubation at different conditions of simulated digest tract fluid (10,000×). (a) original film; (b) 2 h in SGF; (c) 2 h in SGF plus 6 h in SIF; (d) 2 h in SGF, 6 h in SIF plus 16 h in SCF; and (e) 2 h in SGF, 6 h in SIF plus 40 h in SCF.
The drug release behavior of coated pellets by different RS film in simulated digestive fluid is shown in Fig. 2. Compared with uncoated pellets, the BSA release of pellets coated by RS film in simulated gastric and intestinal fluid was significantly decreased as the RD and hydrophobicity of RS film increased (Fig. 3). The released amounts of BSA were 5.4% and 24.2% after immersion for 2 and 8 h, respectively and the final amount was 76.3% with a film with RD of 92.7%. The results showed that the pellets coated by RS film can easily pass through the upper digestive tract and release drugs in the colon. It
Abstracts / Journal of Controlled Release 152 (2011) e1–e132
BSA Released(%)
was also shown that RD and hydrophobicity of RS film have a great impact on BSA colon-targeted releasing. To further investigate the effect of RS film properties on the colontargeted release of drug, the degradation and thermal mechanical properties of RS film in simulated digestive fluid was investigated by DMA after they were submersed in SGF, SIF and SCF for varying time periods. The results showed that the RS film storage modulus (E′) increased first and then decreased with immersion time and their Tg increased with immersion time (Fig. 4). The time at which the maximum E′ was reached and the increase of Tg as a function of time for the three films was different. This difference was caused by the differences in hydrophobic properties of the films. The film (RD = 87.8%) was more hydrophilic than film (RD = 98.3%), and the transfer of water into the former film was easier and faster than for the other (Fig. 3). In case of the more hydrophilic film more hydrogen bonds form with the hydroxyl groups of starch molecular chains, resulting in E′ and Tg increasing more rapidly finally leading to embrittlement of the RS film. The mechanical properties sufficient to withstand the hydrostatic pressure can be adjusted by varying the RD of RS films.
100 90 80 70 60 50 40 30 20 10 0
e7
Conclusion RS are highly promising film coating materials for advanced drug delivery systems allowing for colon targeting. Importantly, a desired colon-targeted drug delivery system can easily be obtained by controlling the proper relationship between the RD and the mechanical properties of RS film in GIT. Acknowledgements The authors are grateful for the financial support of the National Natural Science Foundation of China (20606014), the Fundamental Research Funds for the Central Universities, SCUT (2009ZZ0021), the National Key Technology R&D Program (2006BAD27B04) and Agricultural Science and Technology Achievements Transformation Funds (2009GB23600523). References [1] E.L. McConnell, M.D. Short, A.W. Basit, An in vivo comparison of intestinal pH and bacteria as physiological trigger mechanisms for colonic targeting in man, J. Control. Release 130 (2008) 154–160. [2] L. Chen, X. Li, Y. Pang, L. Li, X. Zhang, L. Yu, Resistant starch as a carrier for oral colontargeting drug matrix system, J. Mater. Sci. Mater. Med. 18 (2007) 2199–2203. [3] AOAC, Method 991.43 Total Dietary Fiber, 17th ed., The Association of Official Analytical Chemists, Gaitherburg, MD, 2000.
doi:10.1016/j.jconrel.2011.08.087
Rapidly pH-responsive degradable polymersomes for triggered release of hydrophilic and hydrophobic anticancer drugs
no coating RD=87.8%
Wei Chen, Fenghua Meng, Ru Cheng, Zhiyuan Zhong Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Organic Chemistry, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China E-mail addresses: [email protected] (F. Meng), [email protected] (Z. Zhong).
RD=92.7% RD=98.3% RD=99.9%
0
10
20
30
40
50
Time(h) Fig. 2. BSA release from pellets coated by different RS films.
Abstract summary Rapidly pH-responsive biodegradable polymersomes were prepared from block copolymers composed of poly(ethylene glycol) (PEG) and an acid-labile polycarbonate, poly(2,4,6-trimethoxybenzylidene-pentaerythritol carbonate) (PTMBPEC). The obtained polymersomes had average sizes of 100–200 nm. These polymersomes though sufficiently stable at pH 7.4 were prone to fast hydrolysis at mildly acidic pH of 4.0 and 5.0. These polymersomes were able to simultaneously load paclitaxel (PTX, hydrophobic) and doxorubicin hydrochloride (DOX⋅HCl, hydrophilic). The in vitro release studies demonstrated that both PTX and DOX⋅HCl were released in a pHdependent manner. Keywords: pH-sensitive, Biodegradable, Polymersomes, Drug delivery
Fig. 3. The effect of water on the RS molecule.
60 3
50
Tg (oC)
E' (GPa)
40 2
RD=98.3% RD=92.7% RD=87.8%
1
0
0
10
20
30
Time (h)
40
30 20 10
RD=87.8% RD=92.7% RD=98.3%
0 -10 50
-20
0
10
20
30
40
50
Time (h)
Fig. 4. DMA results (E′ and Tg) of RS film immersed into SGF, SIF and SCF at 0.5 Hz and 37 °C.
Introduction Polymersomes have attracted rapidly growing interest due to their intriguing aggregation phenomena, cell and virus-mimicking dimensions and functions, as well as tremendous potential applications in medicine, pharmacy, and biotechnology [1,2]. Polymersomes have the ability of simultaneous loading and release of both hydrophilic and hydrophobic drugs which is particularly interesting in combination therapy for cancers. Recently we have developed pH-sensitive biodegradable micelles based on an amphiphilic copolymer containing an acid-labile polycarbonate (PTMBPEC) hydrophobic block [3]. These micelles showed a high drug loading capacity for hydrophobic anticancer drugs and a significantly faster drug release at endosomal pH than at physiological pH.
The biodegradability and biocompatibility of N-Boc-histidinecapped PLGA–PEG–PLGA were proved by DLS, 1H NMR and MTT assay. Doxorubicin was used as a model anticancer drug. The in vitro DOX release (Fig. 1) was faster at pH 6.2, as compared to pH 7.4. The pH dependence release rate was due to the pH sensitivity of the micelles.
e5
with appropriate pKa. This polymer was used to form micelles which show an accelerate release of drugs at the slight acidic, tumor extracellular micro-environments. The basic properties of the new material and characteristic parameters of the formed micelles in water were evaluated. The in vitro release assays using DOX as a model drug validated the mode of drug release. The N-Boc-histidine capped PLGA–PEG–PLGA polymer may have potential as a biodegradable and biocompatible anticancer release carrier, which is sensitive to tumor extracellular pH. References
Fig. 1. In vitro release profiles of DOX from micelles at indicated pH values [12].
[1] E.S. Lee, Z.G. Gao, Y.H. Bae, Recent progress in tumor pH targeting nanotechnology, J. Control. Release 132 (2008) 164–170. [2] H.S. Yoo, E.A. Lee, T.G. Park, Doxorubicin-conjugated biodegradable polymeric micelles having acid-cleavable linkages, J. Control. Release 82 (2002) 17–27. [3] 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. [4] W. Chen, F.H. Meng, R. Cheng, Z.Y. Zhong, pH-Sensitive degradable polymersomes for triggered release of anticancer drugs: a comparative study with micelles, J. Control. Release 142 (2009) 40–46. [5] L. Yu, H. Zhang, J.D. Ding, A subtle end-group effect on macroscopic physical gelation of triblock copolymer aqueous solutions, Angew. Chem. Int. Ed. 45 (2006) 2232–2235. [6] L. Yu, G.T. Chang, H. Zhang, J.D. Ding, Temperature-induced spontaneous sol–gel transitions of poly(d, l-lactic acid-co-glycolic acid)–b-poly(ethylene glycol)–b-poly(d, llactic acid-co-glycolic acid) triblock copolymers and their end-capped derivatives in water, J. Polym. Sci. Polym. Chem. 45 (2007) 1122–1133. [7] L. Yu, G.T. Chang, H. Zhang, J.D. Ding, Injectable block copolymer hydrogels for sustained release of a PEGylated drug, Int. J. Pharm. 348 (2008) 95–106. [8] L. Yu, J.D. Ding, Injectable hydrogels as unique biomedical materials, Chem. Soc. Rev. 37 (2008) 1473–1481. [9] H. Zhang, L. Yu, J.D. Ding, Roles of hydrophilic homopolymers on the hydrophobicassociation-induced physical gelling of amphiphilic block copolymers in water, Macromolecules 41 (2008) 6493–6499. [10] L. Yu, Z. Zhang, H. Zhang, J.D. Ding, Mixing a sol and a precipitate of block copolymers with different block ratios leads to an injectable hydrogel, Biomacromolecules 10 (2009) 1547–1553. [11] G.T. Chang, L. Yu, Z.G. Yang, J.D. Ding, A delicate ionizable-group effect on selfassembly and thermogelling of amphiphilic block copolymers in water, Polymer 50 (2009) 6111–6120. [12] G.T. Chang, C. Li, W.Y. Lu, J.D. Ding, N-Boc-histidine-capped PLGA–PEG–PLGA as a smart polymer for drug delivery sensitive to tumor extracellular pH, Macromol. Biosci. doi:10.1002/mabi.201000117. [13] L.B. Wu, J.D. Ding, In vitro degradation of three-dimensional porous poly(d, l-lactideco-glycolide) scaffolds for tissue engineering, Biomaterials 25 (2004) 5821–5830. [14] L.B. Wu, J.D. Ding, Effects of porosity and pore size on in vitro degradation of threedimensional porous poly(d, l-lactide-co-glycolide) scaffolds for tissue engineering, J. Biomed. Mater. Res. A 75A (2005) 767–777.
doi:10.1016/j.jconrel.2011.08.086
Effect of resistant starch film properties on the colon-targeting release of drug from coated pellets
Fig. 2. Cellular uptake of DOX at indicated time and pH values. Human breast cancer cells MDA-MB-435 were used. Bars: 150 μm [12].
The pH-sensitive trend was also observed in cellular uptake of DOX from micelles investigated by microscopy. More DOX uptake was seen in the group of pH sensitive micelles at pH 6.2 than at pH 7.4 (Fig. 2). Conclusion By introducing the pH-sensitive moiety N-Boc-histidine into the ends of PLGA–PEG–PLGA, we synthesized a pH-sensitive polymer
Xiaoxi Li1, Peng Liu1, Ling Chen1, Long Yu1,2 1 Engineering Research Center of Starch & Protein Processing, Ministry of Education, South China University of Technology, Guangzhou 510640, China 2 Commonwealth Scientific and Industrial Research Organization, Materials Science and Engineering, Melbourne, Victoria 3169, Australia E-mail address: [email protected] (L. Chen). Abstract summary Resistant starch (RS) films were designed to target a protein to the colon by exploiting the colonic microbiota fermentative capacity. The RS films were coated to pellets and their mechanical resistance to the shear forces and the hydrostatic pressure within the pellets were investigated after contact with the gastrointestinal tract (GIT). In vitro tests showed that desired colon-targeted drug release can easily be obtained through controlling the proper relationship between enzymatic resistance and mechanical properties of RS film.
e6
Abstracts / Journal of Controlled Release 152 (2011) e1–e132
Keywords: Resistant starch film, Colon targeting, Mechanical properties, Controlled release, Pellets Introduction Oral colon-targeting drug delivery is an appealing method for oral protein and peptide delivery and many universal delivery systems have been investigated. RS escaping enzymatic digestion and acidolysis in the upper GIT but being degraded by microorganism in the colon is a potential carrier for oral colon-targeting drug delivery reported previously from our team and other researchers [1,2]. But the drawback of this polysaccharide is the easy swelling in aqueous conditions. RS with proper hydrophobic properties have been prepared in our lab by starch acetylation to overcome this drawback [2]. However, it is unclear whether RS films provide sufficient mechanical stability to withstand the shear stress in the upper GIT due to the gastrointestinal motility and to withstand the potentially significant hydrostatic pressure developed within the dosage forms due to water penetration into the systems upon contact with aqueous media. It was the aim of this study to elucidate these aspects and to investigate how the film coatings' properties affect the colon-targeted drug release. Experimental methods Preparation of RS film and its tensile properties. RS was prepared by esterification of high-amylose corn starch with acetic acid anhydride. RS film was prepared by solvent-casting from acetone. The resistance ability of RS to enzymatic and acid degradation was determined according to the Method 991.43 total dietary fiber of the Association of Official Analytical Chemists [3]. The tensile properties of the film were evaluated in accordance with ASTM D5938 standard on an Instron tensile testing apparatus (5565) at a crosshead speed of 10 mm/min under 30 °C and 30% relative humidity. In vitro drug release studies. Drug-loaded pellet cores (50% BSA, 50% microcrystalline cellulose) were prepared by extrusion and spheronization (Mini-250, Xinyite LTD, China) and then coated in a fluidized bed coater (WBF-1, Yingge LTD, Chongqing, China) with RS coating solution (3%, RS/acetone, w/w), until a proper weight gain was achieved. BSA release from the coated pellets in SGF, SIF and SCF was studied using a drug dissolution rate test apparatus 2(100 rpm, 37 °C) according to the USP23. 0.5 mL samples were taken over the course of time and the determination of BSA concentration was done using HPLC. The degradation and thermal mechanical properties of RS film in simulated digestive fluid. The films were incubated in simulated gastric fluid (SGF) for the first 2 h, and then in simulated intestinal fluid (SIF) for 6 h, afterwards in simulated colonic fluid (SCF) for an additional 40 h at 37 °C in sequence. The surface morphology and the thermal mechanical properties of films after each stage were investigated by scanning electron microscopy (SEM) (Nova NanoSEM430, FEI Co., The Netherlands) and dynamic mechanical analysis (DMA) (Diamond, PerkinElmer Co., USA) respectively. For DMA the tension measuring system was used. The temperature scanning range was from − 30 °C to 100 °C with the heating rate of 1 °C/min, and the force frequency is 0.5, 1, 2, 5, and 10 Hz, respectively. Results and discussion The RS film should have proper mechanical properties to resist the forces of the upper gastrointestinal tract when it is used as a carrier for an oral colon-targeting drug system, so its tensile properties should be evaluated. Table 1 illustrates the tensile properties of RS film. It can be seen that when RD increased from 82.9% to 99.9%, the tension strength increased from 4.73 MPa to 8.13 MPa, and the elongation from 5.35% to 15.25%. These properties meet the requirements for a drug coating-carrier.
Table 1 The resistibility to digestion and mechanical properties of RS films. Sample
Resistibility to digestion (RD) (%)
Tensile strength (MPa)
Elongation (%)
1 2 3 4 5
82.9 ± 0.5 87.8 ± 1.0 92.7 ± 1.2 98.3 ± 1.5 99.9 ± 0.4
4.73 ± 1.01 5.53 ± 0.81 6.48 ± 3.32 7.11 ± 2.27 8.13 ± 1.10
5.35 ± 0.54 6.95 ± 0.48 9.94 ± 0.67 11.81 ± 0.29 15.25 ± 0.56
In order to evaluate the degradability of RS film in simulated digestive fluid, SEM was used to observe the surface morphology of films immersed into SGF, SIF and SCF for a certain time period (Fig. 1). It is shown that the RS film has good resistance to degradation for acid and enzymes in simulated upper GIT. So RS film exhibits good colon-targeting properties. Furthermore, with the increase of soaking time, holes and cracks emerge on the film surface, which can be applied for drug release in the colon.
(a)
(b)
(c)
(d)
(e)
Fig. 1. The surface change of RS film (RD is 92.7%) after incubation at different conditions of simulated digest tract fluid (10,000×). (a) original film; (b) 2 h in SGF; (c) 2 h in SGF plus 6 h in SIF; (d) 2 h in SGF, 6 h in SIF plus 16 h in SCF; and (e) 2 h in SGF, 6 h in SIF plus 40 h in SCF.
The drug release behavior of coated pellets by different RS film in simulated digestive fluid is shown in Fig. 2. Compared with uncoated pellets, the BSA release of pellets coated by RS film in simulated gastric and intestinal fluid was significantly decreased as the RD and hydrophobicity of RS film increased (Fig. 3). The released amounts of BSA were 5.4% and 24.2% after immersion for 2 and 8 h, respectively and the final amount was 76.3% with a film with RD of 92.7%. The results showed that the pellets coated by RS film can easily pass through the upper digestive tract and release drugs in the colon. It
Abstracts / Journal of Controlled Release 152 (2011) e1–e132
BSA Released(%)
was also shown that RD and hydrophobicity of RS film have a great impact on BSA colon-targeted releasing. To further investigate the effect of RS film properties on the colontargeted release of drug, the degradation and thermal mechanical properties of RS film in simulated digestive fluid was investigated by DMA after they were submersed in SGF, SIF and SCF for varying time periods. The results showed that the RS film storage modulus (E′) increased first and then decreased with immersion time and their Tg increased with immersion time (Fig. 4). The time at which the maximum E′ was reached and the increase of Tg as a function of time for the three films was different. This difference was caused by the differences in hydrophobic properties of the films. The film (RD = 87.8%) was more hydrophilic than film (RD = 98.3%), and the transfer of water into the former film was easier and faster than for the other (Fig. 3). In case of the more hydrophilic film more hydrogen bonds form with the hydroxyl groups of starch molecular chains, resulting in E′ and Tg increasing more rapidly finally leading to embrittlement of the RS film. The mechanical properties sufficient to withstand the hydrostatic pressure can be adjusted by varying the RD of RS films.
100 90 80 70 60 50 40 30 20 10 0
e7
Conclusion RS are highly promising film coating materials for advanced drug delivery systems allowing for colon targeting. Importantly, a desired colon-targeted drug delivery system can easily be obtained by controlling the proper relationship between the RD and the mechanical properties of RS film in GIT. Acknowledgements The authors are grateful for the financial support of the National Natural Science Foundation of China (20606014), the Fundamental Research Funds for the Central Universities, SCUT (2009ZZ0021), the National Key Technology R&D Program (2006BAD27B04) and Agricultural Science and Technology Achievements Transformation Funds (2009GB23600523). References [1] E.L. McConnell, M.D. Short, A.W. Basit, An in vivo comparison of intestinal pH and bacteria as physiological trigger mechanisms for colonic targeting in man, J. Control. Release 130 (2008) 154–160. [2] L. Chen, X. Li, Y. Pang, L. Li, X. Zhang, L. Yu, Resistant starch as a carrier for oral colontargeting drug matrix system, J. Mater. Sci. Mater. Med. 18 (2007) 2199–2203. [3] AOAC, Method 991.43 Total Dietary Fiber, 17th ed., The Association of Official Analytical Chemists, Gaitherburg, MD, 2000.
doi:10.1016/j.jconrel.2011.08.087
Rapidly pH-responsive degradable polymersomes for triggered release of hydrophilic and hydrophobic anticancer drugs
no coating RD=87.8%
Wei Chen, Fenghua Meng, Ru Cheng, Zhiyuan Zhong Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Organic Chemistry, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China E-mail addresses: [email protected] (F. Meng), [email protected] (Z. Zhong).
RD=92.7% RD=98.3% RD=99.9%
0
10
20
30
40
50
Time(h) Fig. 2. BSA release from pellets coated by different RS films.
Abstract summary Rapidly pH-responsive biodegradable polymersomes were prepared from block copolymers composed of poly(ethylene glycol) (PEG) and an acid-labile polycarbonate, poly(2,4,6-trimethoxybenzylidene-pentaerythritol carbonate) (PTMBPEC). The obtained polymersomes had average sizes of 100–200 nm. These polymersomes though sufficiently stable at pH 7.4 were prone to fast hydrolysis at mildly acidic pH of 4.0 and 5.0. These polymersomes were able to simultaneously load paclitaxel (PTX, hydrophobic) and doxorubicin hydrochloride (DOX⋅HCl, hydrophilic). The in vitro release studies demonstrated that both PTX and DOX⋅HCl were released in a pHdependent manner. Keywords: pH-sensitive, Biodegradable, Polymersomes, Drug delivery
Fig. 3. The effect of water on the RS molecule.
60 3
50
Tg (oC)
E' (GPa)
40 2
RD=98.3% RD=92.7% RD=87.8%
1
0
0
10
20
30
Time (h)
40
30 20 10
RD=87.8% RD=92.7% RD=98.3%
0 -10 50
-20
0
10
20
30
40
50
Time (h)
Fig. 4. DMA results (E′ and Tg) of RS film immersed into SGF, SIF and SCF at 0.5 Hz and 37 °C.
Introduction Polymersomes have attracted rapidly growing interest due to their intriguing aggregation phenomena, cell and virus-mimicking dimensions and functions, as well as tremendous potential applications in medicine, pharmacy, and biotechnology [1,2]. Polymersomes have the ability of simultaneous loading and release of both hydrophilic and hydrophobic drugs which is particularly interesting in combination therapy for cancers. Recently we have developed pH-sensitive biodegradable micelles based on an amphiphilic copolymer containing an acid-labile polycarbonate (PTMBPEC) hydrophobic block [3]. These micelles showed a high drug loading capacity for hydrophobic anticancer drugs and a significantly faster drug release at endosomal pH than at physiological pH.