Preparation Of Xylan-based Temperature/pH Responsive Intelligent Hydrogels And Their Drug Release Property

The environmental responsive hydrogels(intelligent hydrogels) especially for temperature and pH sensitive hydrogels have been extensively studied for application in tissue engineering, drug delivery and biomedical fields. Recently, natural macromolecules like cellulose, chitosan and starch based hydrogels have aroused broad interest of researchers due to their excellent biocompatibility and biodegradability. Hemicellulose is one of three main components of lignocelluloses, next to cellulose in abundance. Xylan-type hemicellulose not only has advantages of abundance, non-toxicity, low cost and biodegradability, but also has unique physiological characteristics which show competitive advantages, including anti-inflammation, inhibiting cell mutation, promoting cell adhesion and proliferation,innate immunological defense and anti-cancer effect, etc. Therefore, xylan has been attracted great attention of domestic and overseas researchers currently. Xylan based hydrogels have potential applications in bio-pharmaceuticals especially in drug controlled release fields. The presence of active hydroxyl and partial carboxylic groups on the xylan chains make them suitable for chemical or enzymatic modification and impart them new functionalities which could further broaden the application of xylan. This article investigated the preparation of temperature and pH responsive xylan based hydrogels and their application in drug controlled release. The effect of different modified xylan, different content of crosslinker and monomers on mechanical properties and drug release of hydrogels were investigated.(1) Xylan-based temperature/pH sensitive hydrogels were prepared by the crosslinking copolymerization of xylan with N-isopropylacrylamide(NIPAm) and acrylic acid(AA) using N,N′-methylenebis-acrylamide(MBA) as a cross-linker and2,2-dimethoxy-2-phenylacetophenone(DMPA) as a photoinitiator via ultraviolet irradiation.The effect of different temperature and pH on the swelling properties of xylan based hydrogels were discussed as well as the effect of monomers and crosslinkers contents. The hydrogels were characterized by SEM, FTIR, DSC, etc. The resulting hydrogels had excellent porous structure and temperture/pH responsive behaviors. Moreover, the hydrogels had good swelling and deswelling properties in the stimulated intestinal and gastric fluid. The liquid nitrogen freezing dried hydrogels showed well-organized honeycomb-like structure. The different momoners and crosslinkers contents had an important impact on the mechanical capacities of hydrogels. The lower critical solution temperature(LCST) of hydrogels emerged at around 34 oC and increased with increasing the AA content. The maximumdrug encapsulation efficiency of hydrogels reached to 97.6%. The drug delivery in vitro experiment indicated the maximum cumulative release rate of acetylsalicylic acid as drug model was 90.12% and 26.35% in the intestinal and gastric fluid, respectively. Xylan-based hydrogels were proved to be biocompatible with NIH3T3 cell by MTT assay.(2) In order to improve the reactivity of xylan, glycidyl methacrylate(GMA) was introduced onto the xylan chains by the transesterification reaction, xylan possessing methacryloyl groups which is easy to be polymerized was obtained. The temperature and pH sensitive xylan based hydrogels and GMAX based hydrogels were prepared by the crosslinking polymerization of NIPAm and AM with xylan and GMAX under the presence of MBA via UV irradiation. Comparative study was conducted about the xylan based hydrogels and GMAX based hydrogels under the same conditions. The equilibrium swelling ratio,temperature/pH sensitive property, morphological and crystalline structure, drug controlled behaviors and cell biocompatibility of hydrogels were comparatively discussed. The results were found that GMAX based hydrogels had denser honeycomb-like network structure and stronger compressive ability(the compressive stress reached to 37.03 kPa when the strain was50%) than pure xylan based hydrogels due to the introduction of methacryloyl groups on xylan. Both LCST of two types of hydrogels emerged at 35 oC. GMAX-based hydrogels had a drug encapsulation efficiency of 95.21%. The maximum cumulative release rate of acetylsalicylic acid for GMAX-based hydrogels and xylan-based hydrogels reached to 84.2%and 77.5% in the intestinal fluid, respectively. Cell proliferation experiment showed GMAX based hydrogels had better cell biocompatibility. Hence, GMAX based hydrogels possessed the excellent intestinal-targeted behaviors as acetylsalicylic acid encapsulation carriers.(3) The maleic anhydride modified xylan(MAHX) based P(NIPAm-co-AA) hydrogels were prepared by the crosslinking polymerization under UV light. The gel-1, gel-2, gel-3 and gel-4 were prepared using different MAHX as raw materials(DS of MAHX was 0.12, 0.28,0.48, 0.65) weight ratio was 1:1, 2:1, 3:1 and 4:1).The effect of different degree of substitution(DS) of MAHX on the properties of hydrogels was investigated. The swelling ability, morphological and crystalline structure of hydrogels were studied. The resulting hydrogels had good swelling properties, porous structure and temperature/pH dual sensitivity.The swelling ratio order of hydrogels at pH7.4, 37 o C was: gel-3﹥gel-4﹥gel-2﹥gel-1. The equilibrium swelling ratios of gel-3 in the solution of stimulated intestinal(pH 7.4) and gastric(pH 1.5) fluids were 30 g/g and 4.3 g/g. There was no obvious difference after repeating three times. The LCST of hydrogels was about 34 oC. Compared the acetylsalicylic acid with theophylline as drug models in vitro release, the cumulative release rate ofacetylsalicylic acid for MAHX based hydrogels was higher than that of theophylline(Cumulative release rate of acetylsalicylic acid was 94.56% after sustained release time for 8h in the stimulated intestinal fluid). This was indicated that drug release was based on both properties of hydrogels and drugs. The gastric-intestinal sustained drug release study was found that the drug release rate was extremely slow at intial 3 h in the gastric fluid(maximum release rate: 24.26%), and then cumulative release rate reached to 90.5% after sustained release for 5 h in the stimulated intestinal fluid. This indicated that MAHX-based hydrogels as drug carriers had favorable intestinal-targeted behaviors. The cytotoxicity determination demonstrated that MAHX based hydrogels could promote cell proliferation and had satisfactory biocompatibility with NIH3T3 cells.