Photopolymerization of Methacrylated Chitosan/PNIPAAm Hybrid Hydrogels PDF

International Journal of Biological Macromolecules 44 (2009) 229–235 Contents lists available at ScienceDirect International Journal of Biological Macromolecules...

International Journal of Biological Macromolecules 44 (2009) 229–235 Contents lists available at ScienceDirect International Journal of Biological Macromolecules journal homepage: www.elsevier.com/locate/ijbiomac Photopolymerization of methacrylated chitosan/PNIPAAm hybrid dual-sensitive hydrogels as carrier for drug delivery Jing Han, Kemin Wang, Dongzhi Yang, Jun Nie ∗ State Key Laboratory of Chemical Resource Engineering, The Key Laboratory of Beijing City on Preparation and Processing of Novel Polymer Materials, Beijing University of Chemical Technology, Beijing 100029, PR China a r t i c l e i n f o a b s t r a c t Article history: A series of hybrid hydrogels based on glycidyl methacrylated chitosan (CS-GMA) and N- Received 22 November 2008 isopropylacrylamide (NIPAAm) were designed and prepared via photopolymerization technology. The Received in revised form 11 December 2008 hydrogels were characterized by Fourier transform infrared (FT-IR), differential scanning calorimetry Accepted 15 December 2008 (DSC) and optical transmittance. The interior morphology of hydrogels was investigated by scanning Available online 25 December 2008 electron microscopy (SEM). The swelling experiment results revealed that hybrid hydrogel exhibited combined pH and temperature sensitivities. Acid orange 8 (AO8) and 5-flurouracil (5-Fu) were selected as Keywords: model drugs for examining their release from hydrogels. The results suggested that hydrogel composition Hybrid hydrogel Chitosan and pH value of buffer solution had great influences on release profiles. Poly(N-isopropylacrylamide) © 2008 Elsevier B.V. All rights reserved. Drug delivery 1. Introduction groups. Besides, chitosan has several favorable biological properties such as excellent biocompatibility, non-toxicity and biodegradabil- Over the last several decades, considerable research attention ity. Further, chitosan is natural cationic polyelectrolytes, which has been focused on hydrogel materials, especially environment could be used to synthesize gene carriers or drug carriers based on sensitive hydrogels (smart hydrogels or intelligent hydrogels), interaction of charges. which change their various properties in response to slight envi- Poly(N-isopropylacrylamide) (PNIPAAm) is one of the most ronmental stimuli such as pH , temperature , ionic strength well-known temperature sensitive polymer, exhibiting a lower crit- , light , electric field and magnetic field. These environ- ical solution temperature (LCST) at 32 ◦ C [16–18]. There exists ment sensitive hydrogels have potential applications in biomedical a hydrophilic/hydrophobic balance in the NIPAAm unit resulting and pharmaceutical areas. Intelligent hydrogels have been studied from the hydrophilic (amide group) and hydrophobic (isopropyl for controlled drug delivery , molecular separation and tissue group) regions of the PNIPAAm. Below the LCST, hydrogen bonding engineering. between hydrophilic segments and water molecules are domi- Among these smart hydrogels, pH and temperature sensitive nant, leading to enhanced dissolution or swelling in water. As the hydrogels have been most widely investigated because these two temperature increases, hydrophobic interactions among hydropho- factors are crucial to human body. For example, the large differences bic segments become strengthened, while the hydrogen bonding of pH value between stomach ( Sample C2 > Sample C1 due hybrid hydrogels were much faster that of PNIPAAm hydrogel. After to the different chitosan composition ratio. The result demonstrated 100 min in 37 ◦ C distilled water, the SR of Samples C1, C2 and that swelling rate and SReq could be controlled via composition ratio C3 reached 50, 75 and 140%, respectively. In the contrast, the SR of chitosan and NIPAAm. of PNIPAAm exhibited only approximately 10% within the same time frame. Although PNIPAAm owned hydrophilic amide groups, 3.7. pH and temperature dependence of SReq PNIPAAm hydrogel exhibited shrinking state at 37 ◦ C due to the dominant hydrophobic interaction. The introduction of chitosan Polyelectrolyte hydrogels show pH-sensitivity due to the ionic enhanced the SR of hybrid hydrogel at 37 ◦ C for hydrophilic nature reaction. In present work, the pH value of the external buffer solu- of chitosan bearing a large amount of hydrophilic groups including tion had been varied in the range from 2.2 to 8.0 and the effect on the hydroxyl and amino groups. Besides, covalently crosslinked struc- SReq of hybrid hydrogels was shown in Fig. 7. All hybrid hydrogels ture between chitosan and PNIPAAm chains would influence the (Samples C1, C2 and C3) had the similar swelling tendency: the SR of hydrophobic interaction between hydrophobic isopropyl groups. hybrid hydrogels decreased gradually as the pH value of buffer solu- tion increased from 2.2 to 8.0. However, the SR of PNIPAAm hydrogel (Sample B) did not exhibit obviously difference with the variation of Fig. 6. Swelling kinetics of various compositions hydrogels. Fig. 7. Equilibrium swelling ratio of hydrogels at different media value at 37 ◦ C. 234 J. Han et al. / International Journal of Biological Macromolecules 44 (2009) 229–235 the differences of SR of hybrid hydrogels between 25 and 37 ◦ C were affected by pH value of buffer solution. Generally, the differences of SR at acidic solution were more obvious than those at neu- tral solution. In hybrid hydrogels PNIPAAm chains behaviors were influenced by chitosan chains because of covalently crosslinked structure. In acidic solution, chitosan exhibited swelling state and thus the degree of freedom of PNIPAAm chains was bigger. As a result, the differences of SR between 25 and 37 ◦ C were larger than those at neutral solution. 3.8. Drug release analysis Hydrogels are widely used in drug delivery systems for their excellent biocompatibility and permeability. Drug release from hydrogel matrices is influenced by many factors including the pro- cesses of swelling, diffusion and erosion therefore its assessment is complicated by the limitations of the in vitro evaluation proce- dures. Drug–polymer interactions, network porosity, and degree of hydrophilicity of the matrix are also important factors influencing Fig. 8. Comparison of swelling ratio of hybrid hydrogels in different external condi- controlled release. tions. In this paper, AO8, and 5-Fu were selected as controlled release model drugs and their molecule structures are shown in Fig. 9. AO8 as an acid dye bearing sulfonate group might bound to chitosan pH value at 37 ◦ C. Chitosan derivate (CS-GMA) as cationic polyelec- due to ionic interaction as reported. The binding of drug to chi- trolytes bearing a large amount of amino groups dissolved more or tosan is dependent on pH value of condition, which influences the swelled more if crosslinked at low pH value due to amino ioniza- release behavior. 5-Fu is a commonly used anticancer drug for tion. The amino group protonated from NH2 to NH3 + with pH value a variety of malignancies, including cancers of the colon, head and ranging from 8.0 to 2.2, which changed the electrostatic repulsion neck, breast and skin. The sustained releases of 5-Fu are desirable among charges present on chitosan chains and thus influenced the in cancer therapy and have been investigated widely [32–34]. SR of hydrogels. Fig. 7 also implied the dependence of SReq on the Release kinetics of AO8 from hybrid hydrogel (Sample C2) in composition of CS-GMA/PNIPAAm hybrid hydrogel at 37 ◦ C. The SR buffer solution (pH 2.2 and 7.4) at 37 ◦ C was depicted in Fig. 10. Evi- of hydrogels reduced in the order Sample C3 > Sample C2 > Sample dently, the release of AO8 was strongly dependent on pH value. At C1 > Sample B in various buffer solution. The reduction in SR from pH 7.4, AO8 released gradually from hydrogel; whereas the release Sample C3 to Sample B was attributed to the decrease of chitosan rate was rather low in pH 2.2 buffer solutions. Such release behavior derivative composition ratio. The hydrophilic nature of chitosan could be explained by the pH-dependent interaction between AO8 contributed to SR of hybrid hydrogels. At 37 ◦ C, hydrophobic inter- and hydrogel. At pH 2.2 the sulfonate group of AO8 dissociated and action among hydrophobic segments in PNIPAAm was dominant was converted to dye anions, while at pH 7.4 AO8 existed in the form which led to the shrinking state of PNIPAAm. Thus PNIPAAm chain of undissociated molecule. In acid solution chitosan behaved as contributed little to SR of hybrid hydrogels at 37 ◦ C. Therefore, the a cationic polyelectrolyte due to protonation of the amino groups. reduction of chitosan derivative in composition caused the decline It is reported the amino groups of the chitosan are at pH 4.2 pro- of SR. At the same time, the reduction of CS-GMA led to the decrease tonated to form cationic amino groups, but chitosan should have of amino groups which influence the pH sensitivity of hybrid hydro- very low positive charge at pH 6.5. Therefore, the interaction gels. based on the formation of chitosan–NH3 +/− O3 S-dye exited in acid The temperature dependence of SR of hydrogels was illustrated solution. There was a lack of strong interaction of AO8 with chitosan in Fig. 8. Though Sample C2 did not exhibit obvious phase transition measuring by DSC and optical transmittance, the SReq of Sample C2 was greatly dependent on temperature as well as Sample C1 in buffer solution with various pH values. At 25 ◦ C both Samples C1 and C2 showed higher SR than those of them at 37 ◦ C. At 25 ◦ C, PNIPAAm chains exhibited swelling state due to the strong hydrogen bond interaction between amide group and water molecules. At 37 ◦ C, PNIPAAm chains showed shrinking state because of the strength- ened hydrophobic interaction between hydrophobic groups among PNIPAAm chains which led to sharp decline of SR. It was found that Fig. 9. The molecule structures of model drugs. Fig. 10. Cumulative release profiles of AO8 from hybrid hydrogels in different media.  J. Han et al. / International Journal of Biological Macromolecules 44 (2009) 229–235 235 of hydrogels. 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