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Progress on Chemistry and Application of Chitin and its Derivatives最新文献

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DEVELOPMENT OF MUCOADHESIVE CHITOSAN-BASED DRUG DELIVERY SYSTEM 粘固型壳聚糖给药系统的研制
IF 0.6 Q4 MATERIALS SCIENCE, BIOMATERIALS Pub Date : 2018-09-10 DOI: 10.15259/PCACD.23.10
M. Konovalova, B. Shagdarova, A. Zubareva, A. Generalov, M. Grechikhina, E. Svirshchevskaya
Chitosan is a highly versatile biopolymer characterised by low toxicity, biocompatibility, and slow but complete biodegradation in the human body, possessing multiple reactive groups. One of the most well-known properties of positively charged chitosan derivatives is their ability to bind mucous membranes. The aim of this work was the analysis of mucoadhesion of unmodified 20 kDa chitosan and its hydrophobic (HC) and hydrophobic quaternised (QHC) derivatives in vitro and ex vivo. Unmodified chitosan formed large aggregates in vitro in keratinocyte and colon cell cultures and ex vivo in murine small intestine and muscle explants. At the same time, HC and especially QHC bound cells in vitro and ex vivo in a fine dotted manner, as evidenced by confocal microscopy. Such a pattern of hydrophobic derivatives distribution provides the possibility to develop mucoadhesive drug delivery systems with increased local drug release and improved chitosan biodegradation.
壳聚糖是一种多用途的生物聚合物,具有低毒性、生物相容性好、在人体内生物降解缓慢但完全等特点。带正电荷的壳聚糖衍生物最著名的特性之一是它们结合粘膜的能力。本研究的目的是分析未经改性的20 kDa壳聚糖及其疏水衍生物(HC)和疏水季铵盐衍生物(QHC)在体外和离体的黏附性。未经修饰的壳聚糖在体外角质细胞和结肠细胞培养物以及离体小鼠小肠和肌肉外植体中形成大聚集体。同时,通过共聚焦显微镜观察,HC尤其是QHC在离体和体外结合细胞呈细点状。这种疏水衍生物的分布模式为开发具有增加局部药物释放和改善壳聚糖生物降解的黏附给药系统提供了可能性。
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引用次数: 2
THE INFLUENCE OF CHITIN AMINATION ON THE EFFECTIVENESS OF RB5 AND RY84 DYE SORPTION 几丁质胺化对rb5和ry84染料吸附效果的影响
IF 0.6 Q4 MATERIALS SCIENCE, BIOMATERIALS Pub Date : 2018-09-10 DOI: 10.15259/PCACD.23.006
U. Filipkowska, T. Jóźwiak, Paula Bugajska, M. Kuczajowska-Zadrożna
This article presents the influence of chitin amination on the effectiveness of RB5 and RY84 dye sorption. For chitin and chitin modified by amination, the optimal pH of sorption and the maximum sorption capacity were determined in relation to two reactive dyes: Reactive Black 5 (RB5) and Reactive Yellow 84 (RY84), differing in the active group and molecular weight. Three sorption models were used to describe the experimental data: Langmuir, Langmuir 2 and Freundlich. The highest sorption capacity was obtained for aminated chitin for both tested dyes: 386.53 mg/g for RB5 and 261.56 mg/g for RY84. In the case of sorption on unmodified chitin, the sorption capacities were lower: up to 235.65 mg/g.d.m. for RB5 and 208.88 mg/g.d.m. for RY84. The modification of chitin by amination has a beneficial effect on the amount of dye adsorbed in the process. The adsorptive capacity increased by 1.6-times in the case of RB5 and 1.25-times in case of RY84.
介绍了几丁质胺化对RB5和RY84染料吸附效果的影响。对甲壳素和胺化改性甲壳素,测定了活性基团和分子量不同的活性染料活性黑5 (RB5)和活性黄84 (RY84)的最佳吸附pH和最大吸附量。采用Langmuir、Langmuir 2和Freundlich三种吸附模型来描述实验数据。两种染料对胺化甲壳素的吸附量最高:RB5为386.53 mg/g, RY84为261.56 mg/g。在未改性甲壳素上吸附时,吸附量较低,可达235.65 mg/g.d.m。RB5和208.88 mg/g.d.m。RY84。氨基化改性甲壳素对染料吸附量有很大的影响。RB5的吸附量提高1.6倍,RY84的吸附量提高1.25倍。
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引用次数: 2
ATORVASTATIN ADSORPTION STUDIES ON CHITOSANS IN AN in vitro PHARMACEUTICAL MODEL 体外药物模型中阿托伐他汀在壳聚糖上的吸附研究
IF 0.6 Q4 MATERIALS SCIENCE, BIOMATERIALS Pub Date : 2018-09-10 DOI: 10.15259/PCACD.23.014
J. Meler, B. Grimling, M. Szcześniak, B. Karolewicz, Paweł Biernat
During the pharmacological therapy of specific diseases, drugs are used which, with other preparations or foods, can create connections, in many cases changing or even blocking their action. On the other hand, the use of unsuitable polymers as excipients may result in drug-polymer incompatibilities. Interactions consisting mainly of the occurrence of the adsorption phenomenon and on the formation of complex bonds that reduce the effect of the drugs are of particular importance.The aim of the study was to investigate whether the active substance atorvastatin is incompatible with dietary supplements containing chitosan.The phenomenon of the adsorption of the drug was examined using a static model of a pharmaceutical gastrointestinal tract, in the concentration range generally ingested in a single dose. Measurement results of the amount of bound drug were used to determine the average percentage of adsorbed drug dose. The results of the study prove that the anticholinesterase drug is adsorbed on chitosan in the pH ranges used, and that the binding capacity depends on the chitosan variety, which indirectly affects the reaction of the environment. It was observed that the average size of sorption depending on the chitosan variety ranged from 38% to 86%. The fact that the lowest value of adsorption was at pH 6.4 can be explained by the chemical properties of chitosan, which shows a charge only at pH >6.7. Under such conditions, the phenomenon of electrostatic adsorption may occur in relation to the healing substances of weak acids.At a pH above 7.6, corresponding to the intestinal fluid-filled intestine, the mean sorption for the highest dose of chitosan was from 38–86%. The increase in the adsorbed amount of anticholinesterase drugs on the polymer along with the increase in pH from 7.6 to 8.0 can be explained by the chitosan swelling properties, which increase with an increase in the pH.As a result, the specific surface area of the polymer and its sorption capacity increase. Based on the above considerations, it can be concluded that there is an antagonistic interaction between the drug and the polymer studied, which involves the adsorption of a drug from this group on the polymer (chitosan) and a decrease in its bioavailability.
在特定疾病的药理学治疗过程中,使用的药物与其他制剂或食物可以建立联系,在许多情况下改变甚至阻断其作用。另一方面,使用不合适的聚合物作为赋形剂可能导致药物-聚合物不相容。相互作用主要由吸附现象的发生和降低药物作用的复杂键的形成组成,这是特别重要的。本研究的目的是调查活性物质阿托伐他汀是否与含有壳聚糖的膳食补充剂不相容。使用药物胃肠道的静态模型,在通常以单剂量摄入的浓度范围内检查药物的吸附现象。结合药物量测定结果确定平均吸附药物剂量百分比。研究结果证明,抗胆碱酯酶药物在使用的pH范围内是吸附在壳聚糖上的,并且结合能力取决于壳聚糖的品种,间接影响反应的环境。结果表明,不同壳聚糖的平均吸附量在38% ~ 86%之间。壳聚糖的化学性质可以解释其在pH 6.4时的最低吸附值,壳聚糖仅在pH >6.7时才显示电荷。在这种条件下,与弱酸的愈合物质有关的静电吸附现象可能发生。当pH值高于7.6时,壳聚糖的平均吸收率为38% ~ 86%,与肠液填充的肠道相对应。当pH值从7.6增加到8.0时,抗胆碱酯酶药物在聚合物上的吸附量增加,这可以解释为壳聚糖的溶胀特性随着pH值的增加而增加,从而使聚合物的比表面积和吸附能力增加。基于以上考虑,可以得出结论,所研究的药物与聚合物之间存在拮抗相互作用,这涉及到从该基团中吸附药物在聚合物(壳聚糖)上并降低其生物利用度。
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引用次数: 0
THE INFLUENCE OF THE DEACETYLATION DEGREE OF CHITOSAN IN THE FORM OF FLAKES ON THE EFFECTIVENESS OF NITRATES V SORPTION FROM AQUEOUS SOLUTIONS 壳聚糖薄片脱乙酰程度对硝酸盐吸附效果的影响
IF 0.6 Q4 MATERIALS SCIENCE, BIOMATERIALS Pub Date : 2018-09-10 DOI: 10.15259/PCACD.23.008
T. Jóźwiak, U. Filipkowska, Paula Bugajska, M. Kuczajowska-Zadrożna, A. Mielcarek
The influence of the degree of deacetylation of chitosan from the range of DD = 75–90% on the effectiveness of sorption of nitrates from aqueous solutions was investigated. The scope of the research included: determining the effect of pH on the effectiveness of N-NO3 binding on chitosan sorbents and determining the sorption capacity of chitosan sorbents with different degrees of deacetylation after 5, 15, 30 and 60 minutes.The effectiveness of sorption of nitrates on chitosan sorbents increased in the series DD=75% < DD=85% < DD=90%. Regardless of the degree of deacetylation, the sorption effectiveness of nitrates on chitosan was the highest at pH 4. The amount of nitrate-related sorbents was the highest after 30 min of sorption. A process time which was too long resulted in desorption of nitrates. The maximum sorption capacity for chitosan with the degree of deacetylation DD = 75, 85 and 90% was 0.59 mg N-NO3/g, 0.60 mg N-NO3/g and 0.87 mg N-NO3/g, respectively.
研究了壳聚糖脱乙酰度在DD=75-90%范围内对硝酸盐从水溶液中吸附效果的影响。研究范围包括:测定pH对N-NO3与壳聚糖吸附剂结合效果的影响,以及测定不同脱乙酰度的壳聚糖吸附物在5、15、30和60分钟后的吸附能力。硝酸盐在壳聚糖吸附剂上的吸附效率在DD=75%
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引用次数: 0
FUNCTIONAL THREE-COMPONENT POLYMERIC BIOCOMPOSITES FOR THE TREATMENT OF BEDSORES 治疗褥疮的功能性三组分高分子生物复合材料
IF 0.6 Q4 MATERIALS SCIENCE, BIOMATERIALS Pub Date : 2018-09-10 DOI: 10.15259/PCACD.23.019
M. Wiśniewska-Wrona, M. E. Fray
Presented here are the results of investigations into the preparation of three-component dressing materials from various biopolymers in the form of a single-layer film which is suitable as a carrier for pain-relieving (lidocaine) and bacteriostatic (sulphanilamid) therapeutic agents. Physical-chemical, biological and usable properties of the prepared materials were tested and assessed. The amount of added active substance was adopted based on the dose recommended by the Polish Pharmacopeia for external medicinal preparations.Antibacterial activity against gram (-) Escherichia coli and gram (+) Staphylococcus aureus was assessed in some of the biocomposites by quantitative methods. The cytotoxic action in direct contact with the mouse fibroblast NCTC clone 929 was also estimated.Thermal analysis (DSC), infrared spectrophotometry (FTIR) and nuclear magnetic resonance spectroscopy were employed to investigate the impact of the variable contents of chitosan, alginate, carboxymethyl cellulose (CMC), and the active substance upon the chemical- and phase-structure of the prepared three-component polymeric biocomposites.It was found that the quantitative composition of the biocomposites and the additive of active substances lidocaine and sulphanilamide exert a vital impact upon their physical-mechanical and usable properties (imbibition, absorption). Investigations into the release of the medicinal substance from the investigated biocomposites to an acceptor fluid led to the conclusion that the kinetics of the process may be described by a complex first order rate equation with two exponential functions.
本文介绍了由各种生物聚合物以单层膜的形式制备三组分敷料的研究结果,单层膜适合作为止痛(利多卡因)和抑菌(磺胺胺)治疗剂的载体。对制备的材料的物理化学、生物和可用性能进行了测试和评估。活性物质的添加量是根据《波兰药典》推荐的外用药物制剂的剂量采用的。通过定量方法评估了一些生物复合材料对革兰氏(-)大肠杆菌和革兰氏(+)金黄色葡萄球菌的抗菌活性。还估计了与小鼠成纤维细胞NCTC克隆929直接接触的细胞毒性作用。采用热分析法(DSC)、红外光谱法(FTIR)和核磁共振光谱法研究了壳聚糖、海藻酸盐、羧甲基纤维素(CMC)和活性物质的不同含量对所制备的三组分聚合物生物复合材料的化学结构和相结构的影响。研究发现,生物复合材料的定量组成以及活性物质利多卡因和磺胺的添加剂对其物理机械和可用性能(吸收、吸收)产生了至关重要的影响。对药物从所研究的生物复合材料释放到受体流体的研究得出结论,该过程的动力学可以用具有两个指数函数的复杂一阶速率方程来描述。
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引用次数: 1
SCREENING OF THE CATALYTIC ACTIVITY OF Pd0 AND Pd2+- SUPPORTED ON CHITOSAN BEADS AND CRYOGELS 壳聚糖微球和冷藏箱负载Pd0和Pd2+催化活性的筛选
IF 0.6 Q4 MATERIALS SCIENCE, BIOMATERIALS Pub Date : 2018-09-10 DOI: 10.15259/PCACD.23.015
A. Pestov, A. V. Mekhaev, Y. Privar, N. Prokuda, E. Modin, S. Bratskaya
Here, we report the results of screening of the catalytic activity of Pd-containing chitosan beads and cryogels in the cross-coupling reaction, hydrogenation of alkenes, nitro-, and carbonyl compounds and the hydrodechlorination of chlorophenols. Pd0-containing chitosan beads and cryogels show moderate catalytic activity in the reduction of alkenes and nitroaromatics. The conversion of nitroaromatics decreases for substrates with electron-withdrawing substituents, while the conversion of alkenes increases with the activation of carbon-carbon double bonds. For several substrates, a significant difference in kinetics and conversion degrees was observed for Pd nanoparticles supported on chitosan beads and cryogels. It was found that conversion in the hydrodechlorination reaction depends on substrate structure, being higher for substrates containing substituents with a positive mesomeric effect. Pd2+-chitosan catalysts showed high catalytic activity in cross-coupling (Heck reaction) offering the following advantages over known catalytic systems: lower reaction temperature, the selective functionalisation of C-I bonds, and the possibility to perform reactions with iodobenzene without base addition.
本文报道了含pd壳聚糖微球和低温凝胶在交叉偶联反应、烯烃、硝基和羰基化合物加氢反应和氯酚加氢脱氯反应中的催化活性的筛选结果。含pd0的壳聚糖微球和低温剂对烯烃和硝基芳烃的还原具有中等的催化活性。硝基芳烃的转化率随着吸电子取代基的激活而降低,而烯烃的转化率随着碳碳双键的激活而提高。对于几种底物,壳聚糖微球和冷藏箱负载的钯纳米颗粒在动力学和转化程度上有显著差异。研究发现,加氢脱氯反应的转化率取决于底物的结构,对于含有具有正中间体效应取代基的底物,转化率更高。Pd2+-壳聚糖催化剂在交叉偶联(Heck反应)中表现出较高的催化活性,与已知的催化体系相比,具有以下优点:较低的反应温度,C-I键的选择性功能化,以及与碘苯进行反应而不需要碱加成的可能性。
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引用次数: 1
WETTING PROPERTIES OF CHITOSAN-MODIFIED AND PLASMA-TREATED PEEK SURFACES 壳聚糖改性和等离子体处理PEEK表面的润湿性能
IF 0.6 Q4 MATERIALS SCIENCE, BIOMATERIALS Pub Date : 2018-09-10 DOI: 10.15259/PCACD.23.016
K. Przykaza, M. Jurak, A. Wiącek
In this paper, the wettability of chitosan/phospholipid (1,2-dipalmitoyl-sn-glycero-3-phosphocholine – DPPC), chitosan/lipid (cholesterol – Chol) and chitosan/protein (cyclosporine A – CsA) films on air plasma activated polyetheretherketone (PEEK) plates was studied. The layers were prepared using the solution spreading technique and their surface wetting properties were determined based on the measurements of the advancing and receding contact angles of water, formamide and diiodomethane. Moreover, based on the contact angle hysteresis model of Chibowski, values of total surface free energy were estimated. Significant changes in PEEK polarity were observed after plasma activation and modifications with Ch/DPPC, Ch/Chol and Ch/CsA layers. These molecules modulate the chitosan film surface by changing the type and magnitude of interactions, which is revealed in the values of surface free energy. These results may be important for the development and implementation of highly biocompatible bone substitution polymers coated with chitosan film with anti-fungal and anti-bactericidal properties. Those systems based on chitosan may also carry and release biologically active substances which could be relevant in the new generation of drug delivery systems.
本文研究了壳聚糖/磷脂(1,2-二棕榈酰- cn -甘油-3-磷脂胆碱- DPPC)、壳聚糖/脂(胆固醇- Chol)和壳聚糖/蛋白(环孢素A - CsA)薄膜在空气等离子体活化聚醚醚酮(PEEK)板上的润湿性。采用溶液铺展法制备了膜层,并通过测定水、甲酰胺和二碘甲烷的进后退接触角来确定膜层的表面润湿性能。此外,基于Chibowski的接触角迟滞模型,估计了总表面自由能的值。在等离子体活化和Ch/DPPC、Ch/Chol和Ch/CsA层修饰后,PEEK极性发生了显著变化。这些分子通过改变相互作用的类型和大小来调节壳聚糖膜表面,这体现在表面自由能的值上。这些结果可能对开发和实现具有抗真菌和抗菌性能的壳聚糖膜包覆的高生物相容性骨替代聚合物具有重要意义。这些基于壳聚糖的系统还可以携带和释放生物活性物质,这可能与新一代的药物传递系统有关。
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引用次数: 1
PROCEDURE FOR DETERMINATION OF THE MOLECULAR WEIGHT OF CHITOSAN BY VISCOMETRY 粘度法测定壳聚糖分子量的方法
IF 0.6 Q4 MATERIALS SCIENCE, BIOMATERIALS Pub Date : 2018-09-10 DOI: 10.15259/PCACD.23.004
Renata Czechowska-Biskup, R. Wach, J. Rosiak, P. Ulański
The aim of this publication is to facilitate the estimation of chitosan molecular weight (MW) in laboratories with no access to sophisticated analytical instruments, by applying the easily accessible and economical capillary viscometry. The procedure of viscosity-average molecular weight (Mv) determination is described in details. The examples provided encompass testing of the experimental procedure for determination of the Mv of chitosan with a low-molecular weight of 7.7 kDa and 88 kDa, after verification with a high-molecular weight polymer (477 kDa). The experimental work demonstrated the importance of the initial concentration of low-MW chitosan for the accurate determination of intrinsic viscosity and, as a consequence, the viscosity-average molecular weight.
本出版物的目的是为了方便估计壳聚糖分子量(MW)在实验室没有访问复杂的分析仪器,通过应用容易获得和经济的毛细管粘度法。详细介绍了粘度-平均分子量(Mv)测定方法。所提供的例子包括测定低分子量(7.7 kDa)和88 kDa的壳聚糖的Mv的实验程序,并与高分子量(477 kDa)的聚合物进行验证。实验证明了低分子量壳聚糖的初始浓度对于准确测定其特性粘度的重要性,从而确定其粘度-平均分子量。
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引用次数: 18
THE INFLUENCE OF CHITOSAN FLAKE DEACETYLATION DEGREE ON ORTHOPHOSPHATE SORPTION EFFICIENCY FROM AQUEOUS SOLUTIONS 壳聚糖片脱乙酰度对水溶液中正磷酸盐吸附效率的影响
IF 0.6 Q4 MATERIALS SCIENCE, BIOMATERIALS Pub Date : 2018-09-10 DOI: 10.15259/PCACD.23.003
Paula Bugajska, U. Filipkowska, T. Jóźwiak, M. Kuczajowska-Zadrożna
The article presents the effectiveness of orthophosphate sorption from aqueous solutions depending on the deacetylation degree of chitosan flakes.The first stage of the research was to determine the pH value at which the sorption process was the most effective (from the pH range 2–11). In the second stage, research was carried out to determine the maximum sorption capacities of chitosan with deacetylation degrees of 75%, 85% and 90% in relation to PO43-. The highest effectiveness of orthophosphate removal on chitosan, regardless of its deacetylation degree, was obtained at pH 4. At pH 2 and 3, the chitosan flakes dissolved. This study showed that the sorption effectiveness of phosphorus compounds depends on the deacetylation degree of chitosan. Along with the increase in deacetylation degree, the sorption capacity of chitosan also increases in relation to orthophosphates. It is related to the higher number of amino groups in the structure of chitosan, which are responsible for the sorption of pollutants in the form of anions. The maximum sorption capacity of chitosan-DD = 75% in relation to biogen was 5.13 mg/g, chitosan-DD = 85% was 5.65 mg/g, and chitosan-DD = 90% was 5.91 mg/g.After 60 minutes, the desorption process had begun and was most likely caused by an increase in the pH of the solution. Due to chitosan's ability to neutralise the sample and the associated risk of desorption, the time of sorbent contact with sewage cannot be longer than 60 minutes.
本文介绍了壳聚糖薄片脱乙酰度对水溶液中正磷酸盐吸附的有效性。研究的第一阶段是确定吸附过程最有效的pH值(pH范围为2-11)。在第二阶段,研究了脱乙酰度分别为75%、85%和90%的壳聚糖对PO43-的最大吸附能力。无论脱乙酰度如何,在pH值为4时,壳聚糖对正磷酸盐的去除效果最高。在pH为2和3时,壳聚糖薄片溶解。研究表明,壳聚糖对磷化合物的吸附效果与脱乙酰度有关。随着脱乙酰度的增加,壳聚糖对正磷酸盐的吸附能力也增加。这与壳聚糖结构中氨基数量较高有关,氨基负责以阴离子形式吸附污染物。壳聚糖DD=75%相对于生物源的最大吸附能力为5.13mg/g,壳聚糖DD=85%为5.65mg/g,壳聚糖DD=90%为5.91mg/g。60分钟后,解吸过程已经开始,很可能是由溶液pH值的增加引起的。由于壳聚糖具有中和样品的能力以及相关的解吸风险,吸附剂与污水接触的时间不能超过60分钟。
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引用次数: 1
THE INHIBITION OF HUMAN PLATELET AGGREGATION BY A LOW-MOLECULAR WEIGHT CHITOSAN 低分子量壳聚糖对人血小板聚集的抑制作用
IF 0.6 Q4 MATERIALS SCIENCE, BIOMATERIALS Pub Date : 2018-09-10 DOI: 10.15259/PCACD.23.005
N. Drozd, Yu.S. Logvinova, B. Shagdarova, A. Il’ina, V. Varlamov
Chitosan derivatives were obtained by chemical (MW of 6 kDa, DD 99% - Ch6/99; MW13 kDa, DD 98% - Ch13/98) and enzymatic (MW of 5 kDa, DD 85% - Ch5/85; MW of 10 kDa, DD 85% - Ch10/85) depolymeri-sation of chitosan with a MW of 334 and 1000 kDa. Chitosan derivatives (almost identical MW pairs and different DD) possessed insignificant an-ticoagulant activity, did not promote human platelet aggregation and re-duced ADP or collagen-induced platelet aggregation. The studied sam-ples at a concentration of 2 mg/ml reduced the aggregation of platelets more than twice induced in 2x10-6M and 1x10-5M concentrations; at weak activation in 2x10-6M, the Ch10/85 sample was the most effective. The Ch6/99 and Ch13/98 samples were 20 times more effective at the inhibi-tion of collagen-induced platelet aggregation than the Ch10/85 sample. The latter can be explained by the greater value of positive charge (DD) and polydispersity (Mw/Mn) of chitosan samples obtained by chemical de-polymerisation.
化学反应得到壳聚糖衍生物(分子量为6 kDa, DD为99% - Ch6/99;MW13 kDa, DD 98% - Ch13/98)和酶(MW为5 kDa, DD 85% - Ch5/85;分子量为10 kDa, DD为85% - Ch10/85),分子量为334和1000 kDa的壳聚糖解聚。壳聚糖衍生物(几乎相同的分子量对和不同的DD)具有不显著的抗凝血活性,不促进人血小板聚集和降低ADP或胶原诱导的血小板聚集。在2 mg/ml浓度下,所研究的样品使2x10-6M和1x10-5M浓度诱导的血小板聚集减少了两倍以上;在2x10-6M弱活化条件下,Ch10/85样品最有效。Ch6/99和Ch13/98样品对胶原诱导的血小板聚集的抑制效果是Ch10/85样品的20倍。后者可以用化学解聚得到的壳聚糖样品的正电荷(DD)值和多分散性(Mw/Mn)来解释。
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引用次数: 0
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Progress on Chemistry and Application of Chitin and its Derivatives
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