壳聚糖改性及负载治疗PTCA术后再狭窄药物研究
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摘要
经皮冠状动脉成形术( percutaneous transluminal coronary angioplasty, PTCA )已成为冠心病治疗的主要手段,广为临床应用。PTCA拓宽了急性心肌梗死治疗的新领域,形成及时和更充分的再灌注,并可减少溶栓成功后的残余狭窄;但PTCA术后常发生冠状动脉再狭窄(restenosis,RS),造影随访其发生率达30%～40%。严重影响了PTCA和冠脉内支架的治愈率。为了提高PTCA术后再狭窄治愈率,必须提高在病变部位(再狭窄部位)的给药能力,同时降低药物对正常组织的毒性,因此能够同时满足治疗所需的药物释放浓度和作用时间的新型靶向性药物载体是解决问题的关键。在本课题研究中,我们合成了一系列具有良好生物相容性和靶向性的壳聚糖改性产物作为治疗PTCA术后再狭窄的药物载体,其中包括季铵盐改性壳聚糖、叶酸改性壳聚糖和葡萄糖酸改性壳聚糖,并研究了这些改性产物作为ASA、PRO和NO三种药物的载体对药物在体外释放性能的影响。壳聚糖改性产物本身都有一定的生物活性和药用价值,在人体内代谢后可以同时发挥负载药物和载体材料本身的生理调节作用。论文中主要对其合成方法、化学结构和释放性能进行了研究,主要内容包括以下几个方面:
1.季铵盐改性壳聚糖的抗氧化性能研究。本文从壳聚糖的改性入手,制备了不同类型的壳聚糖改性产物,并对其进行结构表征。不仅对C-2位上的活性胺基进行了不同的季胺化改性,而且在保护胺基的前提下对C-6位上的羟基也进行了相同的季胺化改性。系统地比较了不同季铵盐对壳聚糖相同或不同位点上改性后的抗氧化性的差异。通过对壳聚糖进行改性,进而研究改性后的产物对羟自由基、超氧阴离子和DPPH自由基的清除作用,为壳聚糖改性相关方面的研究、应用提供依据。
在C-2位胺基上接上季胺盐的效果略好于接在羟基上,可见羟基在抗氧化过程中起着相对重要的作用。根据各实验结果还可认为,由于反应位阻和分子缔合等原因,在去除·OH和O2-·上,大分子量壳聚糖的作用更强;而在去除DPPH时,则是小分子量壳聚糖能力更强;接上较小季胺基团的大分子量壳聚糖具有更强的抗氧化能力。
2.试验中合成了一种新型的壳聚糖季胺盐O-(2-羟基)丙基-3-三甲基氯化铵壳聚糖(O-HTCC),并对O-HTCC负载BSA的纳米粒子进行了详细的研究。详细的讨论了不同制备条件下形成的纳米粒子的形态和尺寸的变化;负载BSA的壳聚糖以及O-HTCC纳米粒子在模拟体内环境的体外释放规律;首次研究了BSA在纳米粒子中晶体结构的变化。
与壳聚糖纳米粒子相比,O-HTCC纳米粒子的包封率和载药量更大。当TPP浓度是2mg/mL,BSA浓度是1mg/mL时,BSA在O-HTCC纳米粒子中的包封率和载药量分别达到87.5%和99.5%。壳聚糖负载BSA后纳米粒子的尺寸比纯的壳聚糖纳米粒子要大,相反O-HTCC负载BSA后纳米粒子的尺寸比纯的O-HTCC的纳米粒子要小,随着BSA浓度的增大,负载BSA的壳聚糖或O-HTCC纳米粒子粒径都增大。BSA浓度对O-HTCC负载BSA纳米粒子的突释率也有很大影响,且随着BSA浓度的增大,O-HTCC负载BSA纳米粒子的包封率和载药量都增大。BSA包载到壳聚糖或O-HTCC纳米粒子中后,晶体结构发生了很大改变,这说明壳聚糖及其季铵盐改性产物O-HTCC的大分子在跟TPP发生离子交联的过程中,带正电的壳聚糖分子或O-HTCC分子能够引导BSA分子重新排列,使之出现新的晶体结构。
3.季铵盐壳聚糖(O-HTCC)同时负载阿司匹林(ASA)和普罗布考(PRO)两种固体药物的性能研究,以及作为气体药物NO的载体的研究。研究了分别负载ASA和PRO两种药物以及同时负载这两种药物的纳米粒子的形态和尺寸,及其外释放规律。结果显示:ASA和PRO在纳米粒子中的存在状态并不相同,亲水性的ASA是以非晶体状态存在,而亲油性的PRO是以晶体状态存在的。当同时负载这两种药物时,两者可以互相影响释放速率,并且释放速度都加快。另外,合成了壳聚糖季铵盐/NO加成物,对壳聚糖季铵盐/NO加成物的结构和性质进行了详细的讨论;研究了不同分子量和不同位点季铵盐改性壳聚糖对NO释放动力学的影响。结果显示:相对于HTCC来说,O-HTCC的NO负载量较大,释放速率也比较快;而对于同种载体而言,分子量大的季铵盐改性壳聚糖由于改性程度较差,所以与NO的反应能力也较差,同时也不利于NO的释放。
4.叶酸改性壳聚糖、羧甲基壳聚糖和O-HTCC的制备及改性产物负载NO的性能研究。制备了叶酸改性壳聚糖,叶酸改性O-羧甲基壳聚糖,叶酸改性O-HTCC等一系列合成产物,并对其进行了红外和核磁表征;与NO分子反应产生三种新型的亲核NO供体,对产物的结构进行表征,并研究它们的NO释放性能。研究表明:O-HTCC-FA-NO加成产物(摩尔比:O-HTCC/FA=2/1)有较长的NO释放半衰期,t1/2=0.866h;而CS-FA-NO加成产物有相对较短的半衰期,t1/2=0.248h(CS/FA=2/1)和t1/2=0.257h(CS/FA=1/2),但是可以看出,当FA和CS的摩尔比增大时,其合成产物NO加成物的半衰期和负载量都变大,如CS/FA=2/1的最大释放量是36.72nmol/mg,而CS/FA=1/2的最大释放量是84.3nmol/mg。
5.葡萄糖酸改性壳聚糖和改性羧甲基壳聚糖及其负载NO的性能研究。制备了葡萄糖酸改性壳聚糖,葡萄糖酸改性O-羧甲基壳聚糖等一系列合成产物,对其进行红外和核磁表征;与NO分子反应后产生两种新型亲核NO供体,对产物的结构进行表征,并研究了它们的NO释放性能。结果表明:分子量较小的CS生成的SBC-NO供体有较高的负载量;而相同分子量的情况下,CMCS生成的SBCS-NO比CS生成的SBC-NO有更长的释放半衰期。
本文的创新点:
本文主要合成了几种新型的药物载体,并对其性能进行了研究,主要创新点如下:
1.系统的比较了壳聚糖的不同位点季胺化改性产物对清除自由基(羟自由基·OH,超氧阴离子自由基氧O2·-和DPPH.自由基)的能力。研究了不同位点季胺盐改性的壳聚糖,季胺盐改性的不同分子量大小的壳聚糖以及相同位点不同季胺盐改性壳聚糖的抗氧化性差异。阐述了反应位阻和分子缔合以及分子量大小等原因跟清除自由基能力之间的密切关系。
2.以C-6位季胺盐改性壳聚糖为载体,研究了负载BSA药物的性能,同时研究了这些载药纳米粒子的形态和BSA在纳米粒子中晶体结构的变化,并研究了BSA的体外释放性能。
3.以季铵盐改性壳聚糖为载体,首次研究了同时负载阿斯匹林和普罗布考两种药物后的季铵盐改性壳聚糖纳米粒子的形态结构,以及药物在纳米粒子内的存在形态和体外释放性能。这种负载复合药物的纳米载药系统能够满足治疗心血管疾病所需要的药物释放速率和释放周期,具有重要的临床应用价值。
4.首次以季铵盐改性壳聚糖、叶酸改性壳聚糖和葡萄糖酸改性壳聚糖产物作为具有良好生物相容性的新的NO载体,合成出以下新的化合物:季铵盐改性壳聚糖/NO;叶酸改性壳聚糖/NO和葡萄糖酸改性壳聚糖/NO,并对每个产物的化学结构进行详细的表征,同时研究了它们NO的释放性能。
Blood flow through an obstructed coronary artery could be effectively restored by percutaneous transluminal coronary angioplasty (PTCA). Statistically, 30-40% of patients undergoing PTCA require additional surgical intervention because of a combination of factors including elastic recoil, thrombosis, vessel remodeling, local tissue inflammation, and neointima formation. The incidence of elastic recoil had been reduced by the postangioplasty deployment of vascular stents, which reduced the need for follow-up surgery by some 30%. However, even with stent implantation, restenosis was still a significant medical problem after PTCA. In order to improve the cure rate of restenosis after PTCA, new targeting drug carriers were the key to solve the problem, which could meet drug concentration of the treatment and time of drug release at the same time, while reducing toxicity of drugs on normal tissue. In the dissertation, the modified products of chitosan were used as biocompatible and targeting carrier in order to cure restenosis after PTCA. A series of novel chitosan modification were synthesized and characterized, including quaternized chitosan, chitosan modified by folic acid and chitosan modified by gluconic acid. In addition, the release properties of aspirin (ASA), probucol (PRO) and NO loaded in these chitosan modification carriers were investigated. The main content can be classified into five parts as follows:
1. Antioxidative activity of chitosans and novel quaternized chitosans with varying molecular weights. Different types of modified chitosans were prepared and characterized. Chitosan was not only modified by quaternization on the C-2 position, but slso modification happened on C-6 position of chitosan whose functional groups of the NH2 groups were protected in advance. The hydroxyl radical, superoxide anion and DPPH radical scavenging activities of quaternized chitosans with different modification position and different molecular weight were studied, which could also provide a basis for more application.
C-2 quternized chitosan was better than C-6 quternized chitosan in antioxidant capacity, which suggested C-2 hydroxy-antioxidant activity of chitosan played a relatively important role. According to the experimental results, some resistance and molecular reaction of association and other reasons were related to some facts that chitosan with the higher molecular weight had the stronger capacity in the superoxide and hydroxyl radical scavenging activities, on the contrary, chitosan with the lower molecular weight had the stronger capacity in the DPPH radical scavenging. In addition, chitosan with higher molecular weight modified by larger quaternary ammonium salt had the higher antioxidant capacity.
2. O-(2-hydroxy)propyl-3-trimethylammonium chloride chitosan (O-HTCC) was synthesized and characterized, and also BSA loaded O-HTCC nanoparticles was studied. The size and morphology changes of nanoparticles under the different formation conditions were discussed in detail. In vitro release properties of the BSA were studied, at the same time, the changes of BSA crystal in the chitosan and O-HTCC nanoparticles were first characterized.
BSA encapsulation efficiency and BSA loading capacity of O-HTCC nanoparticles were much larger than that of chitosan nanoparticles. When the TPP concentration was 2mg/mL and BSA concentration was 1mg/mL, BSA encapsulation efficiency and BSA loading capacity of O-HTCC nanoparticles reached to 87.5% and 99.5%, respectively. After loaded BSA, the size of BSA loaded chitosan nanoparticles was larger than that of pure chitosan nanoparticles. By contrast, BSA loaded O-HTCC nanoparticles was smaller than that of pure O-HTCC nanoparticles, and also with the BSA concentration increasing, not only the size of BSA loaded chitosan, but the size of BSA loaded O-HTCC nanoparticles became larger. BSA concentration also had a great influence on the BSA burst release in BSA loaded O-HTCC nanoparticles, and with the BSA concentration increasing, BSA encapsulation efficiency and BSA loading capacity increased. The crystal structure of BSA had undergone great change after loaded in the chitosan and O-HTCC nanoparticles, which showed that during the process of cross-linking between cationic macromolecules and TPP, a new crystal structure of BSA occurred.
3. Preparation and characterization of nanoparticles containing aspirin (ASA) and probucol (PRO) based on quant ammonium salt modified and study on quaternized chitosans’NO adducts properties. Only one drug loaded O-HTCC nanoparticles was compared with ASA and PRO combined drugs loaded O-HTCC nanoparticles at the same time, consisted of nanoparticles size and morphology and in vitro release. The results showed that: the presence states of ASA and PRO in the nanoparticles were different, hydrophilicity of the ASA was in the existence of non-state crystal, and lipophilic PRO was in the crystal state. When ASA and PRO were loaded at the same time, both drugs could affect one another in release rate, and speed up the release of their speed. In addition, the quaternary ammonium chitosan salt/NO adducts were synthesized, and the structure and properties of different quaternary ammonium chitosans/NO adducts were discussed in detail, as well as the influence of quaternary ammonium chitosan salt with different molecular weights and different site modification on the release kinetics of NO. These results showed that: Compared with HTCC, O-HTCC had the higher NO loading capacity and also had the higher release rate. As far as quaternized chitosans with the same modification and with the different molecular weight, quaternized chitosan with the higher molecular weight had the poorer NO loading capacity.
4. The study of folic acid modified chitosan, CMCS and O-HTCC and their NO adducts properties. Chitosan, CMCS and O-HTCC modified by folic acid were synthesized and reacted with nitric oxide to form novel nitric oxide donors. The synthesized method was carried out: folic acid was actived by N-Hydroxysuccinimide (NHS) and 1-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDC), then reacted with the amine groups on chitosan, CMCS and O-HTCC. The chemical structures of the products were characterized by FTIR, UV spectrum, and NMR. The results showed that: folic acid modified chitosan, CMCS and O-HTCC at C2 position could be prepared by this method. The maximum NO release and half life of O-HTCC-FA-NO (molar ratio: O-HTCC/FA=2/1), CS-FA-NO (CS/FA=2/1) and CS-FA-NO (CS/FA=1/2) were 52.3nmol/mg (t1/2=0.866h), 36.72nmol/mg (t1/2=0.248h) and 84.3nmol/mg (t1/2=0.257h), respectively. The reasons of these differences were attributed to the different of degree of substitution of folic acid and the obstacle in space of folic acid.
5. Gluconic acid modified chitosan and carboxymethyl chitosan and their NO adducts properties. A series of gluconic acid modified chitosan (SBC) and gluconic acid modified CMCS (SBCS) as new NO adducts were prepared and characterized, as well as NO in vitro release properties were studied. The results showed that: SBC-NO adducts obtained by chitosan modification with the smaller molecular weight had the higher loading capacity, on the contrary, with the same molecular weight, the release half-life of SBCS-NO adducts was much longer than that of SBC-NO adducts.
1.季铵盐改性壳聚糖的抗氧化性能研究。本文从壳聚糖的改性入手,制备了不同类型的壳聚糖改性产物,并对其进行结构表征。不仅对C-2位上的活性胺基进行了不同的季胺化改性,而且在保护胺基的前提下对C-6位上的羟基也进行了相同的季胺化改性。系统地比较了不同季铵盐对壳聚糖相同或不同位点上改性后的抗氧化性的差异。通过对壳聚糖进行改性,进而研究改性后的产物对羟自由基、超氧阴离子和DPPH自由基的清除作用,为壳聚糖改性相关方面的研究、应用提供依据。
在C-2位胺基上接上季胺盐的效果略好于接在羟基上,可见羟基在抗氧化过程中起着相对重要的作用。根据各实验结果还可认为,由于反应位阻和分子缔合等原因,在去除·OH和O2-·上,大分子量壳聚糖的作用更强;而在去除DPPH时,则是小分子量壳聚糖能力更强;接上较小季胺基团的大分子量壳聚糖具有更强的抗氧化能力。
2.试验中合成了一种新型的壳聚糖季胺盐O-(2-羟基)丙基-3-三甲基氯化铵壳聚糖(O-HTCC),并对O-HTCC负载BSA的纳米粒子进行了详细的研究。详细的讨论了不同制备条件下形成的纳米粒子的形态和尺寸的变化;负载BSA的壳聚糖以及O-HTCC纳米粒子在模拟体内环境的体外释放规律;首次研究了BSA在纳米粒子中晶体结构的变化。
与壳聚糖纳米粒子相比,O-HTCC纳米粒子的包封率和载药量更大。当TPP浓度是2mg/mL,BSA浓度是1mg/mL时,BSA在O-HTCC纳米粒子中的包封率和载药量分别达到87.5%和99.5%。壳聚糖负载BSA后纳米粒子的尺寸比纯的壳聚糖纳米粒子要大,相反O-HTCC负载BSA后纳米粒子的尺寸比纯的O-HTCC的纳米粒子要小,随着BSA浓度的增大,负载BSA的壳聚糖或O-HTCC纳米粒子粒径都增大。BSA浓度对O-HTCC负载BSA纳米粒子的突释率也有很大影响,且随着BSA浓度的增大,O-HTCC负载BSA纳米粒子的包封率和载药量都增大。BSA包载到壳聚糖或O-HTCC纳米粒子中后,晶体结构发生了很大改变,这说明壳聚糖及其季铵盐改性产物O-HTCC的大分子在跟TPP发生离子交联的过程中,带正电的壳聚糖分子或O-HTCC分子能够引导BSA分子重新排列,使之出现新的晶体结构。
3.季铵盐壳聚糖(O-HTCC)同时负载阿司匹林(ASA)和普罗布考(PRO)两种固体药物的性能研究,以及作为气体药物NO的载体的研究。研究了分别负载ASA和PRO两种药物以及同时负载这两种药物的纳米粒子的形态和尺寸,及其外释放规律。结果显示:ASA和PRO在纳米粒子中的存在状态并不相同,亲水性的ASA是以非晶体状态存在,而亲油性的PRO是以晶体状态存在的。当同时负载这两种药物时,两者可以互相影响释放速率,并且释放速度都加快。另外,合成了壳聚糖季铵盐/NO加成物,对壳聚糖季铵盐/NO加成物的结构和性质进行了详细的讨论;研究了不同分子量和不同位点季铵盐改性壳聚糖对NO释放动力学的影响。结果显示:相对于HTCC来说,O-HTCC的NO负载量较大,释放速率也比较快;而对于同种载体而言,分子量大的季铵盐改性壳聚糖由于改性程度较差,所以与NO的反应能力也较差,同时也不利于NO的释放。
4.叶酸改性壳聚糖、羧甲基壳聚糖和O-HTCC的制备及改性产物负载NO的性能研究。制备了叶酸改性壳聚糖,叶酸改性O-羧甲基壳聚糖,叶酸改性O-HTCC等一系列合成产物,并对其进行了红外和核磁表征;与NO分子反应产生三种新型的亲核NO供体,对产物的结构进行表征,并研究它们的NO释放性能。研究表明:O-HTCC-FA-NO加成产物(摩尔比:O-HTCC/FA=2/1)有较长的NO释放半衰期,t1/2=0.866h;而CS-FA-NO加成产物有相对较短的半衰期,t1/2=0.248h(CS/FA=2/1)和t1/2=0.257h(CS/FA=1/2),但是可以看出,当FA和CS的摩尔比增大时,其合成产物NO加成物的半衰期和负载量都变大,如CS/FA=2/1的最大释放量是36.72nmol/mg,而CS/FA=1/2的最大释放量是84.3nmol/mg。
5.葡萄糖酸改性壳聚糖和改性羧甲基壳聚糖及其负载NO的性能研究。制备了葡萄糖酸改性壳聚糖,葡萄糖酸改性O-羧甲基壳聚糖等一系列合成产物,对其进行红外和核磁表征;与NO分子反应后产生两种新型亲核NO供体,对产物的结构进行表征,并研究了它们的NO释放性能。结果表明:分子量较小的CS生成的SBC-NO供体有较高的负载量;而相同分子量的情况下,CMCS生成的SBCS-NO比CS生成的SBC-NO有更长的释放半衰期。
本文的创新点:
本文主要合成了几种新型的药物载体,并对其性能进行了研究,主要创新点如下:
1.系统的比较了壳聚糖的不同位点季胺化改性产物对清除自由基(羟自由基·OH,超氧阴离子自由基氧O2·-和DPPH.自由基)的能力。研究了不同位点季胺盐改性的壳聚糖,季胺盐改性的不同分子量大小的壳聚糖以及相同位点不同季胺盐改性壳聚糖的抗氧化性差异。阐述了反应位阻和分子缔合以及分子量大小等原因跟清除自由基能力之间的密切关系。
2.以C-6位季胺盐改性壳聚糖为载体,研究了负载BSA药物的性能,同时研究了这些载药纳米粒子的形态和BSA在纳米粒子中晶体结构的变化,并研究了BSA的体外释放性能。
3.以季铵盐改性壳聚糖为载体,首次研究了同时负载阿斯匹林和普罗布考两种药物后的季铵盐改性壳聚糖纳米粒子的形态结构,以及药物在纳米粒子内的存在形态和体外释放性能。这种负载复合药物的纳米载药系统能够满足治疗心血管疾病所需要的药物释放速率和释放周期,具有重要的临床应用价值。
4.首次以季铵盐改性壳聚糖、叶酸改性壳聚糖和葡萄糖酸改性壳聚糖产物作为具有良好生物相容性的新的NO载体,合成出以下新的化合物:季铵盐改性壳聚糖/NO;叶酸改性壳聚糖/NO和葡萄糖酸改性壳聚糖/NO,并对每个产物的化学结构进行详细的表征,同时研究了它们NO的释放性能。
Blood flow through an obstructed coronary artery could be effectively restored by percutaneous transluminal coronary angioplasty (PTCA). Statistically, 30-40% of patients undergoing PTCA require additional surgical intervention because of a combination of factors including elastic recoil, thrombosis, vessel remodeling, local tissue inflammation, and neointima formation. The incidence of elastic recoil had been reduced by the postangioplasty deployment of vascular stents, which reduced the need for follow-up surgery by some 30%. However, even with stent implantation, restenosis was still a significant medical problem after PTCA. In order to improve the cure rate of restenosis after PTCA, new targeting drug carriers were the key to solve the problem, which could meet drug concentration of the treatment and time of drug release at the same time, while reducing toxicity of drugs on normal tissue. In the dissertation, the modified products of chitosan were used as biocompatible and targeting carrier in order to cure restenosis after PTCA. A series of novel chitosan modification were synthesized and characterized, including quaternized chitosan, chitosan modified by folic acid and chitosan modified by gluconic acid. In addition, the release properties of aspirin (ASA), probucol (PRO) and NO loaded in these chitosan modification carriers were investigated. The main content can be classified into five parts as follows:
1. Antioxidative activity of chitosans and novel quaternized chitosans with varying molecular weights. Different types of modified chitosans were prepared and characterized. Chitosan was not only modified by quaternization on the C-2 position, but slso modification happened on C-6 position of chitosan whose functional groups of the NH2 groups were protected in advance. The hydroxyl radical, superoxide anion and DPPH radical scavenging activities of quaternized chitosans with different modification position and different molecular weight were studied, which could also provide a basis for more application.
C-2 quternized chitosan was better than C-6 quternized chitosan in antioxidant capacity, which suggested C-2 hydroxy-antioxidant activity of chitosan played a relatively important role. According to the experimental results, some resistance and molecular reaction of association and other reasons were related to some facts that chitosan with the higher molecular weight had the stronger capacity in the superoxide and hydroxyl radical scavenging activities, on the contrary, chitosan with the lower molecular weight had the stronger capacity in the DPPH radical scavenging. In addition, chitosan with higher molecular weight modified by larger quaternary ammonium salt had the higher antioxidant capacity.
2. O-(2-hydroxy)propyl-3-trimethylammonium chloride chitosan (O-HTCC) was synthesized and characterized, and also BSA loaded O-HTCC nanoparticles was studied. The size and morphology changes of nanoparticles under the different formation conditions were discussed in detail. In vitro release properties of the BSA were studied, at the same time, the changes of BSA crystal in the chitosan and O-HTCC nanoparticles were first characterized.
BSA encapsulation efficiency and BSA loading capacity of O-HTCC nanoparticles were much larger than that of chitosan nanoparticles. When the TPP concentration was 2mg/mL and BSA concentration was 1mg/mL, BSA encapsulation efficiency and BSA loading capacity of O-HTCC nanoparticles reached to 87.5% and 99.5%, respectively. After loaded BSA, the size of BSA loaded chitosan nanoparticles was larger than that of pure chitosan nanoparticles. By contrast, BSA loaded O-HTCC nanoparticles was smaller than that of pure O-HTCC nanoparticles, and also with the BSA concentration increasing, not only the size of BSA loaded chitosan, but the size of BSA loaded O-HTCC nanoparticles became larger. BSA concentration also had a great influence on the BSA burst release in BSA loaded O-HTCC nanoparticles, and with the BSA concentration increasing, BSA encapsulation efficiency and BSA loading capacity increased. The crystal structure of BSA had undergone great change after loaded in the chitosan and O-HTCC nanoparticles, which showed that during the process of cross-linking between cationic macromolecules and TPP, a new crystal structure of BSA occurred.
3. Preparation and characterization of nanoparticles containing aspirin (ASA) and probucol (PRO) based on quant ammonium salt modified and study on quaternized chitosans’NO adducts properties. Only one drug loaded O-HTCC nanoparticles was compared with ASA and PRO combined drugs loaded O-HTCC nanoparticles at the same time, consisted of nanoparticles size and morphology and in vitro release. The results showed that: the presence states of ASA and PRO in the nanoparticles were different, hydrophilicity of the ASA was in the existence of non-state crystal, and lipophilic PRO was in the crystal state. When ASA and PRO were loaded at the same time, both drugs could affect one another in release rate, and speed up the release of their speed. In addition, the quaternary ammonium chitosan salt/NO adducts were synthesized, and the structure and properties of different quaternary ammonium chitosans/NO adducts were discussed in detail, as well as the influence of quaternary ammonium chitosan salt with different molecular weights and different site modification on the release kinetics of NO. These results showed that: Compared with HTCC, O-HTCC had the higher NO loading capacity and also had the higher release rate. As far as quaternized chitosans with the same modification and with the different molecular weight, quaternized chitosan with the higher molecular weight had the poorer NO loading capacity.
4. The study of folic acid modified chitosan, CMCS and O-HTCC and their NO adducts properties. Chitosan, CMCS and O-HTCC modified by folic acid were synthesized and reacted with nitric oxide to form novel nitric oxide donors. The synthesized method was carried out: folic acid was actived by N-Hydroxysuccinimide (NHS) and 1-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDC), then reacted with the amine groups on chitosan, CMCS and O-HTCC. The chemical structures of the products were characterized by FTIR, UV spectrum, and NMR. The results showed that: folic acid modified chitosan, CMCS and O-HTCC at C2 position could be prepared by this method. The maximum NO release and half life of O-HTCC-FA-NO (molar ratio: O-HTCC/FA=2/1), CS-FA-NO (CS/FA=2/1) and CS-FA-NO (CS/FA=1/2) were 52.3nmol/mg (t1/2=0.866h), 36.72nmol/mg (t1/2=0.248h) and 84.3nmol/mg (t1/2=0.257h), respectively. The reasons of these differences were attributed to the different of degree of substitution of folic acid and the obstacle in space of folic acid.
5. Gluconic acid modified chitosan and carboxymethyl chitosan and their NO adducts properties. A series of gluconic acid modified chitosan (SBC) and gluconic acid modified CMCS (SBCS) as new NO adducts were prepared and characterized, as well as NO in vitro release properties were studied. The results showed that: SBC-NO adducts obtained by chitosan modification with the smaller molecular weight had the higher loading capacity, on the contrary, with the same molecular weight, the release half-life of SBCS-NO adducts was much longer than that of SBC-NO adducts.
引文
[1] Meng C Q. Restenosis Drug DiscoverysA Formidable Task. Curr. Opin. Invest. Drugs, 2001, 2: 1237-1246
[2] Popma J J, Califf R M, Topol E J. Clinical Trial of Restenosis after Coronary Angioplasty. Circulation, 1991, 84: 1426-1436
[3] Beatt K J, Serruys P W, Hugenholtz P G. Restenosis after Coronary Angioplasty: New Standards for Clinical Studies. J. Am. Coll. Cardiol., 1990, 15: 491-498
[4] Currier J W, Faxon D P. Restenosis after Percutaneous Transluminal Coronary Angioplasty: Have We Been Aiming at the Wrong Target?. J. Am. Coll. Cardiol., 1995, 25: 516-520
[5] Serruys P W, de Jaegere P, Kiemeneij F, Macaya C, Rutsch W, Heyndrickx G, Emanuelsson H, Marco J, Legrand V, Materne P, et al. A Comparison of Balloon-Expandable-Stent Implantation with Balloon Angioplasty in Patients with Coronary Artery Disease. N. Engl. J. Med., 1994, 331: 489-495
[6] Fischman D L, Leon M B, Baim D S, Schatz R A, Savage M P, Penn I, Detre K, Veltri L, Ricci D, Nobuyoshi M, et at. A Randomized Comparison of Coronary-Stent Placement and Balloon Angioplasty in the Treatment of Coronary Artery Disease. N. Engl. J. Med., 1994, 331: 496-501
[7] Anggard E. Nitric oxide: mediator, murderer, and medicine. Lancet, 1994, 343: 1199-1206
[8] Moncada S, Higgs E A. Molecular Mechanisms and Therapeutic Strategies Related to Nitric Oxide. FASEB J., 1995, 9: 1319-1329
[9] Janero D R, Ewing J F. Nitric Oxide and Postangioplasty Restenosis: Pathological Correlates and Therapeutic Potential. Free Radical Biol. Med., 2000, 29: 1199-1221
[10] Buergler J M, Tio F O, Schulz D G, Khan M M, Mazur W, French B A, Raizner A E, Ali N M. Use of Nitric-Oxide-Eluting Polymer-Coated Coronary Stents for Prevention of Restenosis in Pigs. Coron. Artery Dis., 2000, 11: 351-357
[11] Shepard A D, Gelfand J A, Callow A D, O’Donnell J E Jr. Complement activation by synthetic vascular prostheses. J. Vasc. Surg., 1984, 1: 829-838
[12] Bruck S D. Interactions of synthetic and natural surfaces with blood in the physiologicalenvironment. J. Biomed. Mater. Res., 1977, 11: 1-21
[13] Kidane A G, Salacinski H, Tiwari A, Bruckdorfer R, Seifalian A M. Anticoagulant and Antiplatelet Agents: Their Clinical and Device Application(s) Together with Usages to Engineer Surfaces. Biomacromolecules, 2004, 5: 798-813
[14] Roohk H V, Pick J, Hill R, Hung E, Bartlett R H. Kinetics of fibrinogen and platelet adherence to biomaterials. Trans. Am. Soc. Artif. Intern. Organs., 1976, 22: 1-8
[15] Sheppeck R A, Bentz M, Dickson C, Hribar S, White J, Janosky J, Berceli S A, Borovetz H S, Johnson P C. Examination of the roles of glycoprotein Ib and glycoprotein IIb/IIIa in platelet deposition on an artificial surface using clinical antiplatelet agents and monoclonal antibody blockade. Blood, 1991, 78: 673-680
[16] Ne`gre-Salvayre A, Vieira O, Escargueil-Blanc I, Salvayre R. Oxidized LDL and 4-Hydroxynonenal Modulate Tyrosine Kinase Receptor Activity. Mol. Aspects Med., 2003, 24: 251-261
[17] De Nigris F, Lerman A, Ignarro L J, Williams-Ignarro S, Sica V, Baker A H, Lerman L O, Geng Y J, Napoli C. Oxidation-Sensitive Mechanisms, Vascular Apoptosis and Atherosclerosis. Trends Mol. Med., 2003, 9: 351-359
[18] Escargueil-Blanc I, Salvayre R, Vacaresse N, Jurgens G, Darblade B, Arnal J F, Parthasarathy S, Ne`gre-Salvayre A. A Midly Oxidised LDL Induces Activation of Platelet-Derived Growth Factor Beta-Receptor Pathway. Circulation, 2001, 104: 1814-1821
[19] Hiltunen M O, Tuomisto T T, Niemi M, Bra¨sen J H, Rissanen T T, To¨ro¨nen P, Vajanto I, Yla-Herttuala S. Changes in Gene Expression in Atherosclerotic Plaques Analyzed Using DNA Array. Atherosclerosis, 2002, 165: 23-32
[20] Diaz M N, Frei B, Vita J A, Keaney J F. Antioxidants and Atherosclerotic Heart Disease. New Eng. J. Med., 1997, 337: 408-416
[21] Noguchi N, Niki E. Phenolic Antioxidants: A Rationale for Design and Evaluation of Novel Antioxidant Drug for Atherosclerosis. Free Radic. Biol. Med., 2000, 28: 1538-1546
[22] Meng C Q. Probucol (Restenosis). Curr. Opin. Cardiovasc. Pulm. Renal Invest. Drugs, 2000, 2: 294-298
[23] Barnhart J W, Wagner E R, Jackson R L. The Synthesis, Metabolism, and Biological Activity of Probucol and Its Analogues. In Antilipidemic Drugs: Medicinal, Chemical, andBiochemical Aspects; Witiak D T, Newman H A I, Feller D R, Eds.; Elsevier Science: Amsterdam, 1991, pp 277-299
[24] Carew T E, Schwenke D C, Steinberg D. Antiatherogenic Effect of Probucol unrelated to its Hypocholesterolemic Effect: Evidence That Antioxidants in vivo Can Selectively Inhibit Low- Density Lipoprotein degradation in Macrophage-rich Fatty Streaks and Slow the Progression of Atherosclerosis in the Watanabe Heritable Hyperlipidemic Rabbit. Proc. Natl. Acad. Sci. U.S.A., 1987, 84: 7725-7729
[25] Tardif J C, Cote G, Lesperance J, Bourassa M, Lambert J, Doucet S, Bilodeau L, Nattel S, De Guise P. Probucol and Multivitamins in the Prevention of Restenosis after Coronary Angioplasty., Multivitamins and Probucol Study Group. New Engl. J. Med., 1997, 337: 365-372
[26]王大新,壳多糖支架对兔颈动脉球囊损伤后再狭窄的作用及其机制的实验研究,博士论文,第二军医大学,2001
[27]许玉林,崔英英,侯建新,冠心病介入治疗现状与发展,社区医学杂志,2003, 1(2): 8-10
[28] Garas S M, Huber P, Scott N A. Overview of therapies for prevention of restenosis after coronary interventions, .Pharmacol. Ther., 2001, 92(2-3): 165-178
[29]陈修、陈维州,心血管药理学(第三版),人民卫生出版社,2002.8
[30] Ignarro L J. Nitric oxide, A novel signal transduction. mechanism for transcellular communication. Hypertension, 1990, 16: 477-483
[31] Motley D, Maragos C M, Zhang X, Boignon M, Wink D A, Keerfer L K. Mechanism of Vascular Relaxation Induced by the Nitric Oxide (NO)/Nucleophile Complexes, a New Class of NO-Based Vasodilators. Journal of Cardiovascular Pharmacology, 1993, 21: 670-676
[32] Moncada S, Palmer R M J, Higgs E A. Nitric oxide: physiology, pathology and pharmacology. Pharmaco. Rev., 1991, 43: 109-142
[33] Diodati J G, Quyyumi A A, Hussain N, Keefer L K. Complexes of nitric oxide with nucleophiles as agents for the controlled biological release of nitric oxide: antiplatelet effect. Thromb Haemost., 1993, 70: 654-658
[34] Schmidt H H H W, Walter U. NO at work. Cell, 1994, 78: 919-925
[35] Bredt D S, Snyder S H. Nitric oxide: A physiologic messenger molecule. Annual Review of Biochemistry, 1994, 63: 175-195
[36] Laskove J A, Frishman W H, Bronx M D. Ninric oxide donors in the treatment of cardiovascular and pulmonary diseases. American Heart Journal, 1995, 129(3): 604-613
[37] Furchgott R F. Endothelium-derived relaxing factor: discovery, early studies, and identifcation asnitric oxide (Nobel lecture). Angew. Chem. Int. Edit., 1999, 38: 1870-1880
[38] Murad F. Discovery of some of the biological effects of nitric oxide and its role in cell signaling (Nobel lecture). Angew. Chem. Int. Edit., 1999, 38: 1856-1868
[39] Ignarro L J. Nitric oxide: a unique endogenous signaling molecule in vascular biology (Nobel lecture). Angew. Chem. Int. Edit., 1999, 38: 1882-1892
[40] Umans J G, Levi R. Nitric oxide in the regulation of blood flow and arterial pressure. Annu. Rev. Physiol., 1995, 57: 771-790
[41] Lloyd-Jones D M, Bloch K D. The vascular biology of nitric oxide and its role in atherogenesis. Annu. Rev. Med., 1996, 47: 365-375
[42] Koshland D E Jr. The molecule of the year. Science, 1992, 258: 1861
[43] Mittal C K, Murad F. Activation of guanylate cyclase by superoxide dismutase and hydroxyl radical: a physiological regulator of guanosine 3′,5′-monophosphate formation. Proc. Natl. Acad. Sci. USA., 1977, 74: 4360-4364
[44] Craven P, DeRubertis F R. Restoration of the responsiveness of purified guanylate cyclase to nitrosoguanidine, nitric oxide, and related activators by heme and hemeproteins. J. Biol. Chem., 1978, 253: 8433-8443
[45] Ignarro L J, Adams J B, Horwitz P M, Wood K S. Activation of soluble guanylate cyclase by NO-hemoproteins involves NO-heme exchange: Comparison of heme-containing and heme-deficient enzyme forms. Journal of Biological Chemistry, 1986, 261: 4997-5002
[46] Doyle M P, Hoekstra J. Oxidation of nitrogen oxides by bound dioxygen in hemoproteins. J. Inorg. Biochem., 1981, 14: 351-358
[47] Olson J S. Numerical analysis of kinetic ligand binding data. Methods in Enzymology, 1981, 76, 652-667
[48]杨君,秦永文,一氧化氮与PTCA术后再狭窄的防治,国外医学内科学分册,2002,29 (8):349-351
[49] Sato J, Nair K, Hiddinga J, Eberhardt N L, Fitzpatrick L A, Katusic Z S, O’Brien T. eNOS gene transfer to vascular smooth muscle cells inhibits cell proliferation via upregulation ofp27 and p21 and not apoptosis. Cardiovasc. Res., 2000, 47(4): 697-706
[50] Niebauer J, Schwarzacher S P, Hayase M, Wang B, Kernoff R S, Cooke J P, Yeung A C. Local L-Arginine Delivery After Balloon Angioplasty Reduces Monocyte Binding and Induces Apoptosis Circulation. 1999, 100(17): 1830-1835
[51] Provost P, Tremblay J, Merhi Y. The Antiadhesive and Antithrombotic Effects of the Nitric Oxide Donor SIN-1 Are Combined With a Decreased Vasoconstriction in a Porcine Model of Balloon Angioplasty. Arterioscler Thromb. Vasc. Biol., 1997, 17(9): 1806-1812
[52] Tsao P S, Wang B, Buitrago R, Shyy JY-J, Cooke J P. Nitric Oxide Regulates Monocyte Chemotactic Protein-1. Circulation, 1997, 96: 934-940
[53]赵红卫,一氧化氮与免疫调节,上海免疫学杂志,1996, 16(6): 373-375
[54]穆莉,华维一,彭司勋,一氧化氮用于心脑血管药物研究进展,中国医科大学学报,1996, 27(12): 764-768
[55] Hrabie J A, Keefer L K. Chemistry of the Nitric Oxide-Releasing Diazeniumdiolate (“Nitrosohydroxylamine”) Functional Group and Its Oxygen-Substituted Derivatives. Chem. Rev., 2002, 102: 1135-1154
[56]陈鲁生,周武,姜云生,壳聚糖粘均分子量的测定[J],化学通报,1996, 4: 57-58
[57]蒋挺大编著,壳聚糖,蒋挺大编著,化学工业出版社,2001年3月第1版
[58]王真,陈西广,郎刚华,甲壳素及其衍生物生物生理活性研究进展,海洋科学[J],2000,24(9): 30-32
[59] Denuziere A, Ferrier D, Damour O, Domard A. Chitosan-chondroitin sulfate and chitosan-hyaluronate polyelectrolyte complexes: biological properties. Biomaterials, 1998, 19(14): 1275-1285
[60] Gaserod O, Smidstod O, Skjak-Braek G. Microcapsules of alginate-chitosan I: A quantitative study of the interaction between alginate and chitosan. Biomaterials, 1998, 19(20): 1815-1825
[61] Roy K, Mao H Q, Huang S K, Leong K W. Oral gene delivery with chitosan-DNA nanoparticles generates immunologic protection in a murine model of peanut allergy. Nature Medicine, 1999, 5(4): 387-391
[62] Parkpoom T, Amorn S, Achariya S, Ashim K M. Chitosan as nasal adsorption enhancers of peptides: comparison between free amine chitosans and soluble salts. Int J Pharm, 2000,197(1-2): 53-67
[63] Kate A F, Luessen H L. Chitosan for enhanced intestinal permeability: prospects for derivatives soluble in neutral and basic environment. Eur. J Pharm. Sci., 1999, 7(2): 145-151
[64] Dodne V, Amin Khan M, Merwin J R. Effect of chitosan on epithelval permeability and structure. Int J Pharrn, 1999, 182(1): 21-32
[65] Madihally S V, Matthew H. Porous chitosan scaffolds for tissue engineering. Biomaterials, 1999, 20(12): 1133-1142
[66] Park S, You J, Park H, Haam S, Kim W. A novel pH-sensitive membrance from chitosan TEOS IPN: preparation and its drug permeation characteristics. Biomaterials , 2001, 22(4): 323-330
[67]庄昭霞,林志勇,曹金芳,壳聚糖-羧甲基壳聚糖膜的生物相容性研究,上海口腔医学, 2003, 12(5): 362-365
[68]卢凤琦,曹宗顺,庄昭霞,壳聚糖膜的降解与生物相容性研究.生物医学工程学杂志,1998, 15(2)
[69]王大新,周斌,壳多糖对兔主动脉平滑肌细胞和内皮细胞增殖的影响.第二军医大学学报,1999, 20(12): 962-964
[70] Lueben H L, Rental C O, Kotae A F, et al. Mucoadhesivepolymers in peroral peptide drug delivery IV: Polycarbophil and chitosan are potent enhancers of peptide transport acrvsuntestinal mucosue in vitro. J Contr. Rel., 1997, 45: 15-24
[71] Awie F K, Hentih L L, Bas J D, et al. Comparison of the effect of different chitosan salts and N-trimethyl chitosan chloride on the permeability of intestinal epithelial cells (Caco-2). J Contr. Rel., 1998, 51: 35-43
[72] Janes K A, Fresneau M P, Marazuela A, et al. Chitosan nanoparticles as delivery systems for doxorubicin. J Contr. Rel., 2001, 73(2-3): 255-267
[73] Calvo P, Remunan-lopez C, Vila-Jato J L, et al. Novel hydrophilic chitosan/polyethylene oxide nanoparticles as proteins carriers. J Appl. Polym. Sci, 1997, 63: 125-132
[74] Fernandez-Urrusuno R, Calvo P, Remunan-Lopez C, et al. Enhancement of nasal absorption of insulin using chitosan nanoparticles. Pharm. Res., 1999, 16(10): 1576-1581
[75] Mooren F C, Berthold A, Domschke W, et al. Inflence of chitosan microspheres on the transport of prednisolone sodium phosphate across HT-29 cell monolayers. Pharm. Res.,1998, 15(1): 58-65
[76] Mitra S, Gaur U, Ghosh P C, et al. Tumour targeted delivery of encapsulated dextran-doxorubicin conjugate using chitosan nanoparticles as carrier. J Contr. Rel., 2001, 74(1-3): 317-323
[77] De Campos A.M., Sanchez A, Alonso M J. Chitosan nanoparticles: a new vehicle for the improvement of the delivery of drugs to the ocular surface, Application to cyclosporin A. Int. J Pharm., 2001, 224(1-2): 159-168
[78] Musaarelli R., Biochemical significance at exogenous chitins and chitosans in animals and patients. Biomaterials, 1993, 20: 7-16
[79] Musaarelli R, Baldaseane V, Coni F. Biological activity of chitosan: Ultrastructural study. Biomaterials, 1998, 9: 247-252
[80] Ohya Y, Shireteni M, Kobayashi H, et al. Release behavior of 5-fiuorouracil from chitosan-gel nanospheres immobilizing 5-fluorouracil costed with polysaccharides and their cell specific cytotoxicity. J Biomedical Mater. Res. 1989, 61: 203-211
[81] Tanima B, Susmita M, Singh K, et al. Preparation, characterization and biodistribution of ultrafine chitosan nanoparticles. Int. J Pharm., 2002, 243(1-2): 93-102
[82] Watske H J, Dieschbourg C. Novel silica-biopolymer nanocomposites: the silica sol-ge1 process in biopolymer organogels. Adv. Coll. Interfac. Sci., 1994, 50: 1-14
[83] Ko J A, Park H J, Hwang, Park J B, et al. Preparation and characterization of chitosan microparticles intendend for controlled drug delivery, Int. J Pharm., 2002, 249(1-2): 165-174
[84] Alonso M I, Calvo P, Remunan C, et al. Application of nanoparticles based on hydrophilic polymers as pharmaceutical forms. EP0860166, Aug, 1998
[85] Bodmeier R, Chen H G, Paeratakul O. A novel approach to the delivery of micro- or nanoparticles. Pharm. Res., 1989, 6(5): 413-417
[86]刘晨光,刘成圣,孟祥红,壳聚糖作为药物缓释材料的研究进展,高技术通讯,2003(3): 98-103
[87] Mi F L, Shyu S S, Chen C T, et al. Adsorption of indomethacin onto chemically modified chitosan beads. Polymer, 2002, 43(3): 757-765
[88] Mi F L, Shyu S S, Chen C T, et al. Porous chitosan microphere for controlling the antigan release of Newcastle disease vaccine: preparation of antigen-adsorbed microsphere and invitro release. Biomaterials, 1999, 20(17): 1603-1612
[89] Berthold A, Cremer K, Kreuter J. Preparation and characterization of chitosan microspheres as drug carrier for prednisolon sodium phosphate as model for anti-inflammatory drugs. J Control Release, 1996, 39: 17-25
[90] Tian X X, Groves M J. Formulation and biological activity of antineoplastic proteoglycans derived from Mycobacterium vaccine in chitosan nanoparticles. J Pharm Pharmacol., 1999, 51: 151-157
[91] Cui Z, Mumper R J. Chitosan-based nanoparticles for topical genetic imminization. J Contro Release, 2001, 75(3): 409-419
[92] El-Shabouri M H. Positively charged nanoparticles for improving the oral bioavailability of cyclosporin-A. Int. J of Pharm., 2002, 249(1-2): 101-108
[93] Hu Y, Jiang X, Ding Y, et al. Synthesis and characterization of chitosan-poly(acrylic acid) nanoparticles. Biomaterials, 2002, 23: 3193-3201
[94] Mumper R J, Wang J, Claspell J M, et al. Novel polymeric condensing carriers for gene delivery[C]. Proc. Intl. Symp. Control Rel. Bioact. Mater., 1995, 22: 178-179
[95] Mao H Q, Roy K, Walsh S M, et al. DNA-chitosan nanospheres for gene delivery[C]. Proc. Intl. Symp. Control Rel. Bioact. Mater., 1996, 23: 401-402.
[96] Ohya Y, Cai R, Nishizawa H, et al. Preparation of PEG-grafted chitosan nanoparticle for peptide drug carrier. Proc. Intl. Symp. Control Rel. Bioact. Mater., 1999, 26: 655-656
[97] Lee K Y, Kwon I C, Kim Y H, et al. Preparation of chitosan self-aggregates as a gene delivery system. J Control Rel., 1998, 51: 213-220
[98] Lee K Y, Kwon I C, Kim Y H, et al. Structural investigation of chitosan self-aggregate prepared for gene delivery[C]. Proc. Intl. Symp. Control Rel. Bioact. Mater., 1998, 25: 340-341
[99] Uhrich K E, Cannizzaro S M, Langer R S, Shakesheff K M. Polymeric systems for controlled drug release. Chem. ReV., 1999, 99: 3181-3198.
[100] Kost J, Langer R. Responsive polymeric delivery systems. AdV. Drug Deliv. ReV., 2001, 46: 125-148
[101] Batrakova E V, Vinogradov S V, Robinson S M, Niehoff M L, Banks W A, Kabanov A V. Polypeptide Point Modification with Fatty Acids and Pluronic Block Copolymers forEnhanced Brain Delivery. Bioconjugate Chem., 2005, 16 (4): 793-802
[102] Bronich T K, Keifer P A, Shlyakhtenko L S, Kabanov A V. Polymer micelle with cross-linked ionic core. J. Am. Chem. Soc., 2005, 127: 8236-8237
[103] Jung T, Kamm W, Breitenbach A, Kaiserling E, Xiao J X, Kissel T. Biodegradable nanoparticles for oral delivery of peptides: is there a role for polymers to affect mucosal uptake?. Eur. J. Pharm. Biopharm., 2000, 50: 147-160
[104] Kohane D S, Anderson D G, Yu C, Langer R. pH Triggered release of macromolecules from spraydried polymethacrylate microparticles. Pharm. Res., 2003, 20: 1533-1538
[105] Cai T, Hu Z B, Ponder B, St. John J, Moro D. Synthesis and study of and controlled release from nanoparticles and their networks based on functionalized hydroxypropylcellulose. Macromolecules, 2003, 36(17): 6559-6564
[106] Pillai O, Panchagnula R. Polymers in drug delivery. Curr. Opin. Chem. Biol. 2001, 5(4): 447-451
[107] Na K, Lee K H, Bae Y H. pH-Sensitivity and pH-dependent interior structural change of selfassembled hydrogel nanoparticles of pullulan acetate/oligosulfonamide conjugate. J. Control. Release, 2004, 97: 513-525
[108] Zhang H, Oh M, Allen C, Kumacheva E. Monodisperse Chitosan Nanoparticles for Mucosal Drug Delivery. Biomacromolecules, 2004, 5(6): 2461-2468
[109] Freiberg S, Zhu X X. Polymer microspheres for controlled drug release. Int. J. Pharm., 2004, 282: 1-18
[110] Hobbs S K, Monsky W L, Yuan F, Roberts W G, Griffith L, Torchilin V P, Jain R K. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc. Natl. Acad. Sci. USA., 1998, 95: 4607-4612
[111] Lin M Z, Teitell M A, Schiller G J. The evolution of antibodies into versatile tumor-targeting agents. Clin. Cancer Res., 2005, 11: 129-138
[112] Zhang H, Mardyani S, Chan W C W, Kumacheva E. Design of Biocompatible Chitosan Microgels for Targeted pH-Mediated Intracellular Release of Cancer Therapeutics. Biomacromolecules, 2006, 7: 1568-1572
[113] Killisch I, Steinlein P, Romisch K, Hollinshead R, Beug H, Griffiths G. Characterization of early and late endocytic compartments of the transferrin cycle. Transferrin receptor antibodyblocks erythroid differentiation by trapping the receptor in the early endosome. J. Cell Sci., 1992, 103, 211-232
[114] Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy:mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res., 1986, 46: 6387-6392
[115] Papahadjopoulos D, Allen T M, Gabizon A, et al. Sterically stabilized liposomes: improvements in pharmacokinetics and antitumor therapeutic efficacy. Proc. Natl. Acad. Sci. U.S.A., 1991, 88: 11460-11464
[116] Fabrizio M, Francüois L. Active targeting with particulate drug carriers in tumor therapy: fundamentals and recent progress. Drug Discovery Today, 2004, 9(5): 219-228
[117] Cemazar M, Pavlin D, Kranjc S, Grosel A, Mesojednik S, Sersa G. Sequence and time dependence of transfection efficiency of electrically-assisted gene delivery to tumors in mice. Curr. Drug Deliv., 2006, 3: 77-81
[118] Davidson B L, Breakefield X O. Viral vectors for gene delivery to the nervous system. Nat. ReV. Neurosci., 2003, 4(5): 353-364
[119] Ramachandran S, Quist A P, Kumar S, Lal R. Cisplatin Nanoliposomes for Cancer Therapy: AFM and Fluorescence Imaging of Cisplatin Encapsulation, Stability, Cellular Uptake, and Toxicity. Langmuir, 2006, 22: 8156-8162
[120] Huth U S, Schubert R, Peschka-Suss R. Investigating the uptake and intracellular fate of pH-sensitive liposomes by flow cytometry and spectral bio-imaging. J. Control. Rel., 2006, 110: 490-504
[121] Torchilin V P. Structure and design of polymeric surfactant-based drug delivery. systems. J. Control. Rel., 2001, 73: 137-172
[122] Leamon C P, Low P S. Delivery of macromolecules into living cells:a method that exploits folate receptor endocytosis. Proc. Natl. Acad. Sci. U.S.A., 1991, 88(13): 5572-5576
[123] Jang J S, Kim S Y, Lee S B, Kim K O, Han J S, Lee Y M. Poly(ethylene glycol)/poly(e-caprolacton) diblock copolymeric nanoparticles for Non-viral gene delivery: the role of charge group and molecular weight in particle formation, cytotoxicity and transfect. J. Control. Rel., 2006, 113(2): 173-182
[124] Park E K, Kim S Y, Lee S B, Lee Y M. Folate-conjugated methoxy poly(ethyleneglycol)/poly( -caprolactone) amphiphilic block copolymeric micelles for tumor-targeted drug delivery. J. Controlled Release, 2005, 109(1-3): 158-168
[125] Park E K, Lee S B, Lee Y M. Preparation and characterization of methoxy poly (ethylene glycol)/poly (ε-caprolactone) amphiphilic block copolymeric nanospheres for tumor-specific folate-mediated targeting of anticancer drugs. Biomaterials, 2005, 26(9): 1053-1061
[126] Gonzalez-Guerrico A, Meshki J, Xiao L, Benavides F, Conti C J, Kazanietz M G. Molecular mechanisms of protein kinase C-induced apoptosis in prostate cancer cells. J Biochem. Mol. Biol., 2005, 38: 639-645
[127] Qu X, Khutoryanskiy V, Stewart A, Rahman S, Papahadjopoulos-Sternberg B, Dufes C, McCarthy D, Wilson C G. Lyons R, Carter K, Schazlein A, Uchegbu I. Carbohydrate-Based Micelle Clusters Which Enhance Hydrophobic Drug Bioavailability by Up to 1 Order of Magnitude. Biomacromolecules, 2006, 7(12): 3452-3459
[128] Feng H, Dong C-M. Preparation, characterization, and self-assembled properties of biodegradable chitosan-poly(L-lactide) hybrid amphiphiles. Biomacromolecules, 2006, 7(11): 3069-3075
[129] Jiang G B, Quan D, Liao K, Wang H. Novel Polymer Micelles Prepared from Chitosan Grafted Hydrophobic Palmitoyl Groups for Drug Delivery, Mol. Pharm., 2006, 3(2): 152-160
[130] Kim Y H, Gihm S H, Park C R, et al. Structural characteristics of size-controlled self-aggregates of deoxycholic acid-modified chitosan and their application as a DNA delivery carrier. Bioconjug. Chem., 2001, 12(6): 932-938
[131] Felgner J H, Kumar R, Sridhar C N, Wheeler C J, Tsai Y J, Border R, Ramsey P, Martin M, Felgner P L. Enhanced Gene Delivery and Mechanism Studies with a Novel Series of Cationic Lipid Formulation. J. Biol. Chem., 1994, 269: 2550-2561
[132] Antonella M, Roberta C, Claudia B, Ludovica G, Maria R G. Cellular uptake and cytotoxicity of solid lipid nanospheres incorporation doxorubicin or paclitaxel. Int. J. Pharm. 2000, 210: 61-67
[133] Hu F Q, Ren G F, Yuan H, Du Y Z, Zeng S. Shell cross-linked stearic acid grafted chitosan oligosaccharide self-aggregated micelles for controlled release of paclitaxel. Colloids. Surf.B., 2006, 50: 97-103
[134] Hu F Q, Zhao M D, Yuan H, You J, Du Y Z, Zeng S. A novel chitosan oligosaccharide-stearic acid micelles for gene delivery: properties and in vitro transfection studies. Int. J. Pharm. 2006, 315: 158-166
[135] Schiff P, Fant J, Horwitz S B. Taxol increases the rate and extent of microtubule assembly in vitro and stabilizes microtubules in vitro and in cells. Nature, 1979, 277: 665-667
[136] Schiff P, Horwitz S B. Proc. Taxol stabilizes microtubes in mouse fibroblast cells. Natl. Acad. Sci. U.S.A., 1980, 77: 1561-1565
[137] Rowinsky E K, Donehower R C, Jones R J, Tucker R W. Microtubule changes and cytotoxicity in leukemic cell lines treated with taxol. Cancer Res., 1988 , 48(14): 4093–4100
[138]赵文恩,韩雅珊,乔旭光等,类胡萝卜素对H2O2-NaOCL体系生成的·O2淬灭作用,生物物理学报, 1997, 13(1): 137-142
[139]周惠萍,王叔如,浒苔多糖的降血脂及其对SOD活力和LPO含量的影响,生物化学杂志, 1995, 2: 161-164
[140] Park P J, Je J Y, Kim S K. Free radical scavenging activities of differently deacetylated chitosans using an ESR spectrometer. Carbohydr. Polym., 2004, 55: 17-22
[141] Xie W M, Xu P X, L iu Q. Antioxidant activity of water-soluble chitosan derivatives. Bioorg. Med. Chem. Lett., 2001, 11(13): 1699-1701
[142]陈瑗,周玫,自由基与衰老[M],第一版,北京:人民卫生出版社,2004
[143] Zhang Q, Zhai J J, Zhang Y R, et al. Antioxdative and antitumor properties of metal (II) solid complexes with 8-acetyl-4-methyl umbelliferone. Transition Metal Chemistry, 2000, 25(1): 93-98
[144]宋俊峰,邵勇,过玮,黄体酮清除超氧离子作用机理及反作用机理及反应动力学,Chin. Sci. Bull., 2000, 45(14): 1505-1510
[145]胡道道,史启祯,唐宗薰.甲壳素/壳聚糖的配位化学和配合物应用的研究进展,无机化学学报,2000, 16(3): 385~393
[146] Halliwell B, Gutteridge J M C. Role of free radicals and metal ions in human disease: an overview. Methods Enzymol., 1990, 186: 1-85
[147] Guo Z Y, Xing R E, Liu S, Yu H H, Wang P B, Li C P, Li P C. The synthesis and antioxidantactivity of the Schiff bases of chitosan and carboxymethyl chitosan. Bioorg. Med. Chem. Lett. 2005, 15(20): 4600-4603
[148] Guo Z Y, Liu H Y, Chen X L, Jia X, Lia P C. Hydroxyl radicals scavenging activity of N-substituted chitosan and quaternized chitosan. Bioorganic & Medicinal Chemistry Letters, 2006, 16: 6348-6350
[149] Jeon Y J, Kim S K. Potential immuno-stimulating effect of antitumoral fraction of chitosan oligosaccharides. J. Chitin Chitosan, 2001, 6: 163-167
[150] Sudharshan N R, Hoover D G, Knorr D. Anti bacterial Action of Chitosan. Food Biotechnol, 1992, 6: 257-272
[151] Maezaki Y, Tsuji K, Nakagawa Y, Kawai Y, Akimoto M, Tsugita T, Takekawa W, Terada A, Hara H, Mitsuoka T. Hypo cholesterolemic Effect of Chitosan in Adult Males. Biosci. Biotechnol. Biochem, 1993, 57: 1439-1444
[152] Kumaran A, karunakaran R J. Antioxidant and free radical scavenging activity of an aqueous extract of Coleus aromaticus. Food Chemistry, 2006, 97(1): 109-114
[153]金鸣,蔡压欣,邻二氮菲- Fe2+氧化法检测H2O Fe2+产生的羟自由基,生物化学与生物物理进展,1996, 23(6): 553- 555
[154]高秀蕊,石双群,宁秀芹,某些药物对酪氨酸酶的抑制和对O-2自由基的清除,生物化学与生物物理进展,1992, 19(1): 70-72
[155]张歧,王睿,易美华,芦荟小分子提取物对超氧阴离子自由基的清除作用,自由基生命科学进展(第8集),北京:原子能出版社, 2001, 54-55
[156] Yazdani P M, Lagos A, Campos N, Retuert J. Int J Polym M ater, 1992, 18: 25
[157] Yang D Z, Liu X F, Li Z, et al. On the Factors Influencing the Antibacterial Activity of Chitosan. Chinese J. Appl. Chem., 2000, 17 (6) : 598-602
[158] Xu Y M, Du Y M, Huang, R H, Gao L P. Preparation and modification O,N-(2-hydroxyl-propyl-3-trimethy ammonium chitosan chloride nanoparticles as a protein carrier. Biomaterials, 2003, 24(27): 5015-5022
[159] Loubaki E, Ourevitch M, Sicsic S. Chemical modification of chitosan by glycidyl trimethylammonium chloride. characterization of modified chitosan by 13C- and 1H-NMR spectroscopy. Eur. Polym. J., 1991, 27(3): 311-317
[160] Liu C G, Desai K G H, Chen X G, Park H J. Linolenic acid-modified chitosan for formationof self-Assembled nanoparticles. J. Agric. Food. Chem., 2005, 53: 437-441
[161] Kittur F S, Harish Prashanth K V, Udaya Sankar K, Tharanathan R N. Characterization of chitin, chitosan and their carboxymethyl derivatives by differential scanning calorimetry. Carbohydrate Polymer, 2002, 49: 185-193
[162] Qi L F, Xu Z R, Jiang X, Hu C H, Zou X F. Preparation and antibacterial activity of chitosan nanoparticles. Carbohydrate Research, 2004, 339(16): 2693-2700
[163] Gao Q W, Shao Z Z, Sun Y Y, Lin H, Yu T Y. Complex formation of silk fibroin with poly(acrylic acid). Poym. J., 2000, 32: 269–274
[164]宋存先,杨菁,心血管内局部定位药物缓释体系的实验研究,中国心血管杂志,1998, 3: 70-73
[165]王浩,多肽与蛋白质类药物给药系统的研究现状,中国医药工业杂志,1994, 25: 421-426
[166] Haider M, Megeed Z, Ghandehari H. Genetically engineered polymers, status and prospects for controlled release. Journal of Comtrolled Release, 2004, 95: 1-26
[167] Zhao Z P, Wang Z, Ye N, Wang S C. A novel N,O-carboxymethyl amphoteric chitosan/poly(ethersulfone) composite MF meembrane and its chaged characteristics. Desalination, 2002, 144: 35-39
[168] Yin L C, Fei L K, Cui F Y, Tang C, Yin C H. Superporous hydrogels containing poly(acrylic acid-co-acrylamide)/O-carboxymethyl chitosan interpenetrating polymer nerworks. Biomaterials, 2007, 28: 1258-1266
[169] Cho J Y, Grant J, Piquette-Miller M, Allen C. Synthesis and Physicochemical and Dynamic Mechanical Properties of a Water-Soluble Chitosan Derivative as a Biomaterial. Biomacromolecules, 2006, 7: 2845-2855
[170] Brzezinska A, W inska P, B alinska M. Cellular aspects of folate and antifolate membrane transport. Acta Biochim Pol, 2000, 47: 735-749
[171] Konda S D, Aref M, Brechbiel M, et al. Development of a tumor-targeting MR contrast agent using the high-affinity folate receptor: work in p rogress. Invest Radiol, 2000, 35: 50-57
[172] Konda S D, Wang S, Brechbiel M, et al. Biodistribution of a 153Gd2 folate dendrimer, generation=4, in mice with folate-receptor positive and negative ovarian tumor xengrafts. Invest Radiol, 2002, 37: 199-204
[173] Doucette M M, Stevens V L. Folate recep tor function is regulated in response to different cellular growth rates in cultured mammalian cells. J. Nutr., 2001, 131: 2819-2825
[174] Nishimura S I, Kohgo O, Kurita K, Kuzuhara H. Chemospecific manipulations of a rigid polysaccharide: syntheses of novel chitosan derivatives with excellent solubility in common organic solvents by regioselective chemical modifications. Macromolecules, 1991, 24: 4745-4748
[175] Sorlier P, Denuzie`re A, Viton C, Domard A. Relation between the degree of acetylation and the electrostatic properties of chitin and chitosan. Biomacromolecules, 2001, 2: 765-772
[176] Sashiwa H, Shigemasa Y. Chemical modification of chitin and chitosan 2:preparation and water soluble property of N-acylated or N-alkylated partially deacetylated chitins. Carbohydr. Polym., 1999, 39: 127-138
[177] Yang T, Chou C, Li C. Preparation, water solubility and rheological property of the N-alkylated mono or disaccharide chitosan derivatives. Food Res. Int., 2002, 35(8): 707-713
[178] Muzzarelli R A A, Tanfani F, Emanuelli M, Mariotti S. N-(carboxymethylidene) chitosans and N-(carboxymethyl)chitosans: novel chelating polyampholytes obtained from chitosan glyoxylate. Carbohydr. Res., 1982, 107: 199-214
[179] Murata, J.; Ohya, Y.; Ouchi, T. Possibility of Application of Quaternary Chitosan Having Pendant Galactose Residues as Gene Delivery Tool. Carbohydr. Polym., 1996, 29(1): 69-74
[180]张庆云,张利平,胡迎庆等,壳聚糖在靶向制剂中的应用进展,天津药学,2004, 16(2): 56-59
[181] Ko J A, Park H J, Hwang Y S, Park J B. Chitosan microparticle preparation for controlled drug release by response surface methology. J. Microencapsulation., 2003, 20: 791-797
[182] Lee D W, Park S J, Park J B, Park H J. Preparation and release characteristics of polymer-coated and blended alginate microsphere. J. Microencapsulation., 2003, 20: 179-192
[183] Hejazi R, Amiji M. Chitosan-based delivery systems: Physicochenical properties and pharmaceutical applications. In Polymer Biomaterials, 2nd ed; Dumitriu, S., Ed.; Marcel Dekker: New York, 2002, pp 213-238
[184]薛松,有机结构分析,中国科学技术大学出版社,2005, 296-303
[185] Sieval A B, Thanou M, KotzéA F, Verhoef J C, Brussee J, Junginger H E. Preparation andNMR characterization of highly substituted IV-trimethyl chitosan chloride. Carbohydrate Polymers, 1998, 36 : 157-165
[186] Spinelli V A, Laranjeira M C M, Fávere V T. Preparation and characterization of quaternary chitosansalt: adsorption equilibrium of chromium(VI) ion. Reactive & Functional Polymers, 2004, 61: 347-352
[187]高群,新型亲核NO供体的合成及性能研究,上海交通大学博士论文,2006
[188] Li Q, Lunn E T, Grandmaison E W, Goosen M F A. In Applications and properties of chitosan; Goosen, M. F. A., Ed.; Technomic Publishing Co., Inc.: Lancaster, 1997, pp 3
[189] Hirano S. Chitin and chitosan as novel biotechnological materials. Polym. Int., 1999, 48: 732-734
[190] Ravi Kumar M N V. A review of chitin and chitosan applications. React. Funct. Polym., 2000, 46: 1-27
[191] Molinaro G, Leroux J, Damas J, Adam A. Biocompatibility of Thermosensitive Chitosan-based Hydrogels: An In vivo Experimental Approach to Injectable Biomaterials. Biomaterials, 2002, 23(13): 2717-2722
[192] Kubota N, Tatsumoto N, Sano T, Toya K. A simple preparation of half N-acetylated chitosan highly soluble in water and aqueous organic solvents. Carbohydr. Res. 2000, 324, 268-274
[193] Onishi H, Machida Y. Biodegradation and distribution of water-soluble chitosan in mice. Biomaterials, 1999, 20(2): 175-182
[194] Cho Y W, Cho Y N, Chung S H, Yoo G, Ko S W. Water-soluble chitin as a wound healing accelerator. Biomaterials, 1999, 20: 2139-2145
[195] Park J H, Cho Y W, Chung H, Kwon I C, Jeong S Y. Synthesis and Characterization of Sugar-Bearing Chitosan Derivatives: Aqueous Solubility and Biodegradability. Biomacromolecules, 2003, 4: 1087-1091
[196] Dufes C, Scha¨tzlein A G, Tetley L, Gray A I, Watson D G, Olivier J, Couet W, Uchegbu I F. Polymeric Vesicles Bearing Targeting Ligands. Pharm. Res. 2000, 17(10), 1250-1258
[197] Yasugi, K.; Nakamura, T.; Nagasaki, Y.; Kato, M.; Kataoka, K. Sugar-installed polymer micelles: synthesis and micellization of poly(ethylene glycol)-poly(D, L-lactide) block copolymers having sugar groups at PEG chain end. Macromolecules, 1999, 32: 8024-8032
[198] Nagasaki Y, Yasugi K, Yamamoto Y, Harada A, Kataoka K. Sugar-installed block copolymermicelles:their preparation and specific interaction with lectin molecules. Biomacromolecules, 2001, 2: 1067-1070
[199] Dwek, R. A. Glycobiology-Toward Understanding the Function of Sugars. Chem. ReV. 1996, 96: 683-720
[200] Lis H, Sharon N. Lectins: carbohydrate-specific proteins that mediate cellular recognition. Chem. ReV., 1998, 98: 637-674
[201] Lee Y C. In Carbohydrate Recognition in Cellular Function; Bock, G., Harnette, S., Eds.; Ciba Foundation Symposium 145; Wiley: Chichester, England, 1989, pp 80
[202] Rauvala H, Carter W G, Hakomori S I. Studies on cell adhesion and recognition. I. Extent and specificity of cell adhesion triggered by carbohydrate-reactive proteins (glycosidases and lectins) and by fibronectin. J. Cell Biol., 1981, 88 (1): 127-137
[203] Roseman, S. Reflections on glycobiology. J. Biol. Chem., 2001, 276(45): 41527-41542
[204] Tomohiro O, Kenichi N, Norimasa I, Noriko N, Hideyuki S, Ryusuke K, Tokifumi M, Akio M, Shin-Ichiro N. Specific Cell Behavior of Human Fibroblast onto Carbohydrate Surface Detected by Glycoblotting Films. Biomacromolecules, 2006, 7: 2949-2955
[205] Baek M-G, Roy R. Design and Synthesis of Water-Soluble Glycopolymers Bearing Breast Tumor Marker and Enhanced Lipophilicity for Solid-Phase Assays. Biomacromolecules, 2000, 1: 768-770
[2] Popma J J, Califf R M, Topol E J. Clinical Trial of Restenosis after Coronary Angioplasty. Circulation, 1991, 84: 1426-1436
[3] Beatt K J, Serruys P W, Hugenholtz P G. Restenosis after Coronary Angioplasty: New Standards for Clinical Studies. J. Am. Coll. Cardiol., 1990, 15: 491-498
[4] Currier J W, Faxon D P. Restenosis after Percutaneous Transluminal Coronary Angioplasty: Have We Been Aiming at the Wrong Target?. J. Am. Coll. Cardiol., 1995, 25: 516-520
[5] Serruys P W, de Jaegere P, Kiemeneij F, Macaya C, Rutsch W, Heyndrickx G, Emanuelsson H, Marco J, Legrand V, Materne P, et al. A Comparison of Balloon-Expandable-Stent Implantation with Balloon Angioplasty in Patients with Coronary Artery Disease. N. Engl. J. Med., 1994, 331: 489-495
[6] Fischman D L, Leon M B, Baim D S, Schatz R A, Savage M P, Penn I, Detre K, Veltri L, Ricci D, Nobuyoshi M, et at. A Randomized Comparison of Coronary-Stent Placement and Balloon Angioplasty in the Treatment of Coronary Artery Disease. N. Engl. J. Med., 1994, 331: 496-501
[7] Anggard E. Nitric oxide: mediator, murderer, and medicine. Lancet, 1994, 343: 1199-1206
[8] Moncada S, Higgs E A. Molecular Mechanisms and Therapeutic Strategies Related to Nitric Oxide. FASEB J., 1995, 9: 1319-1329
[9] Janero D R, Ewing J F. Nitric Oxide and Postangioplasty Restenosis: Pathological Correlates and Therapeutic Potential. Free Radical Biol. Med., 2000, 29: 1199-1221
[10] Buergler J M, Tio F O, Schulz D G, Khan M M, Mazur W, French B A, Raizner A E, Ali N M. Use of Nitric-Oxide-Eluting Polymer-Coated Coronary Stents for Prevention of Restenosis in Pigs. Coron. Artery Dis., 2000, 11: 351-357
[11] Shepard A D, Gelfand J A, Callow A D, O’Donnell J E Jr. Complement activation by synthetic vascular prostheses. J. Vasc. Surg., 1984, 1: 829-838
[12] Bruck S D. Interactions of synthetic and natural surfaces with blood in the physiologicalenvironment. J. Biomed. Mater. Res., 1977, 11: 1-21
[13] Kidane A G, Salacinski H, Tiwari A, Bruckdorfer R, Seifalian A M. Anticoagulant and Antiplatelet Agents: Their Clinical and Device Application(s) Together with Usages to Engineer Surfaces. Biomacromolecules, 2004, 5: 798-813
[14] Roohk H V, Pick J, Hill R, Hung E, Bartlett R H. Kinetics of fibrinogen and platelet adherence to biomaterials. Trans. Am. Soc. Artif. Intern. Organs., 1976, 22: 1-8
[15] Sheppeck R A, Bentz M, Dickson C, Hribar S, White J, Janosky J, Berceli S A, Borovetz H S, Johnson P C. Examination of the roles of glycoprotein Ib and glycoprotein IIb/IIIa in platelet deposition on an artificial surface using clinical antiplatelet agents and monoclonal antibody blockade. Blood, 1991, 78: 673-680
[16] Ne`gre-Salvayre A, Vieira O, Escargueil-Blanc I, Salvayre R. Oxidized LDL and 4-Hydroxynonenal Modulate Tyrosine Kinase Receptor Activity. Mol. Aspects Med., 2003, 24: 251-261
[17] De Nigris F, Lerman A, Ignarro L J, Williams-Ignarro S, Sica V, Baker A H, Lerman L O, Geng Y J, Napoli C. Oxidation-Sensitive Mechanisms, Vascular Apoptosis and Atherosclerosis. Trends Mol. Med., 2003, 9: 351-359
[18] Escargueil-Blanc I, Salvayre R, Vacaresse N, Jurgens G, Darblade B, Arnal J F, Parthasarathy S, Ne`gre-Salvayre A. A Midly Oxidised LDL Induces Activation of Platelet-Derived Growth Factor Beta-Receptor Pathway. Circulation, 2001, 104: 1814-1821
[19] Hiltunen M O, Tuomisto T T, Niemi M, Bra¨sen J H, Rissanen T T, To¨ro¨nen P, Vajanto I, Yla-Herttuala S. Changes in Gene Expression in Atherosclerotic Plaques Analyzed Using DNA Array. Atherosclerosis, 2002, 165: 23-32
[20] Diaz M N, Frei B, Vita J A, Keaney J F. Antioxidants and Atherosclerotic Heart Disease. New Eng. J. Med., 1997, 337: 408-416
[21] Noguchi N, Niki E. Phenolic Antioxidants: A Rationale for Design and Evaluation of Novel Antioxidant Drug for Atherosclerosis. Free Radic. Biol. Med., 2000, 28: 1538-1546
[22] Meng C Q. Probucol (Restenosis). Curr. Opin. Cardiovasc. Pulm. Renal Invest. Drugs, 2000, 2: 294-298
[23] Barnhart J W, Wagner E R, Jackson R L. The Synthesis, Metabolism, and Biological Activity of Probucol and Its Analogues. In Antilipidemic Drugs: Medicinal, Chemical, andBiochemical Aspects; Witiak D T, Newman H A I, Feller D R, Eds.; Elsevier Science: Amsterdam, 1991, pp 277-299
[24] Carew T E, Schwenke D C, Steinberg D. Antiatherogenic Effect of Probucol unrelated to its Hypocholesterolemic Effect: Evidence That Antioxidants in vivo Can Selectively Inhibit Low- Density Lipoprotein degradation in Macrophage-rich Fatty Streaks and Slow the Progression of Atherosclerosis in the Watanabe Heritable Hyperlipidemic Rabbit. Proc. Natl. Acad. Sci. U.S.A., 1987, 84: 7725-7729
[25] Tardif J C, Cote G, Lesperance J, Bourassa M, Lambert J, Doucet S, Bilodeau L, Nattel S, De Guise P. Probucol and Multivitamins in the Prevention of Restenosis after Coronary Angioplasty., Multivitamins and Probucol Study Group. New Engl. J. Med., 1997, 337: 365-372
[26]王大新,壳多糖支架对兔颈动脉球囊损伤后再狭窄的作用及其机制的实验研究,博士论文,第二军医大学,2001
[27]许玉林,崔英英,侯建新,冠心病介入治疗现状与发展,社区医学杂志,2003, 1(2): 8-10
[28] Garas S M, Huber P, Scott N A. Overview of therapies for prevention of restenosis after coronary interventions, .Pharmacol. Ther., 2001, 92(2-3): 165-178
[29]陈修、陈维州,心血管药理学(第三版),人民卫生出版社,2002.8
[30] Ignarro L J. Nitric oxide, A novel signal transduction. mechanism for transcellular communication. Hypertension, 1990, 16: 477-483
[31] Motley D, Maragos C M, Zhang X, Boignon M, Wink D A, Keerfer L K. Mechanism of Vascular Relaxation Induced by the Nitric Oxide (NO)/Nucleophile Complexes, a New Class of NO-Based Vasodilators. Journal of Cardiovascular Pharmacology, 1993, 21: 670-676
[32] Moncada S, Palmer R M J, Higgs E A. Nitric oxide: physiology, pathology and pharmacology. Pharmaco. Rev., 1991, 43: 109-142
[33] Diodati J G, Quyyumi A A, Hussain N, Keefer L K. Complexes of nitric oxide with nucleophiles as agents for the controlled biological release of nitric oxide: antiplatelet effect. Thromb Haemost., 1993, 70: 654-658
[34] Schmidt H H H W, Walter U. NO at work. Cell, 1994, 78: 919-925
[35] Bredt D S, Snyder S H. Nitric oxide: A physiologic messenger molecule. Annual Review of Biochemistry, 1994, 63: 175-195
[36] Laskove J A, Frishman W H, Bronx M D. Ninric oxide donors in the treatment of cardiovascular and pulmonary diseases. American Heart Journal, 1995, 129(3): 604-613
[37] Furchgott R F. Endothelium-derived relaxing factor: discovery, early studies, and identifcation asnitric oxide (Nobel lecture). Angew. Chem. Int. Edit., 1999, 38: 1870-1880
[38] Murad F. Discovery of some of the biological effects of nitric oxide and its role in cell signaling (Nobel lecture). Angew. Chem. Int. Edit., 1999, 38: 1856-1868
[39] Ignarro L J. Nitric oxide: a unique endogenous signaling molecule in vascular biology (Nobel lecture). Angew. Chem. Int. Edit., 1999, 38: 1882-1892
[40] Umans J G, Levi R. Nitric oxide in the regulation of blood flow and arterial pressure. Annu. Rev. Physiol., 1995, 57: 771-790
[41] Lloyd-Jones D M, Bloch K D. The vascular biology of nitric oxide and its role in atherogenesis. Annu. Rev. Med., 1996, 47: 365-375
[42] Koshland D E Jr. The molecule of the year. Science, 1992, 258: 1861
[43] Mittal C K, Murad F. Activation of guanylate cyclase by superoxide dismutase and hydroxyl radical: a physiological regulator of guanosine 3′,5′-monophosphate formation. Proc. Natl. Acad. Sci. USA., 1977, 74: 4360-4364
[44] Craven P, DeRubertis F R. Restoration of the responsiveness of purified guanylate cyclase to nitrosoguanidine, nitric oxide, and related activators by heme and hemeproteins. J. Biol. Chem., 1978, 253: 8433-8443
[45] Ignarro L J, Adams J B, Horwitz P M, Wood K S. Activation of soluble guanylate cyclase by NO-hemoproteins involves NO-heme exchange: Comparison of heme-containing and heme-deficient enzyme forms. Journal of Biological Chemistry, 1986, 261: 4997-5002
[46] Doyle M P, Hoekstra J. Oxidation of nitrogen oxides by bound dioxygen in hemoproteins. J. Inorg. Biochem., 1981, 14: 351-358
[47] Olson J S. Numerical analysis of kinetic ligand binding data. Methods in Enzymology, 1981, 76, 652-667
[48]杨君,秦永文,一氧化氮与PTCA术后再狭窄的防治,国外医学内科学分册,2002,29 (8):349-351
[49] Sato J, Nair K, Hiddinga J, Eberhardt N L, Fitzpatrick L A, Katusic Z S, O’Brien T. eNOS gene transfer to vascular smooth muscle cells inhibits cell proliferation via upregulation ofp27 and p21 and not apoptosis. Cardiovasc. Res., 2000, 47(4): 697-706
[50] Niebauer J, Schwarzacher S P, Hayase M, Wang B, Kernoff R S, Cooke J P, Yeung A C. Local L-Arginine Delivery After Balloon Angioplasty Reduces Monocyte Binding and Induces Apoptosis Circulation. 1999, 100(17): 1830-1835
[51] Provost P, Tremblay J, Merhi Y. The Antiadhesive and Antithrombotic Effects of the Nitric Oxide Donor SIN-1 Are Combined With a Decreased Vasoconstriction in a Porcine Model of Balloon Angioplasty. Arterioscler Thromb. Vasc. Biol., 1997, 17(9): 1806-1812
[52] Tsao P S, Wang B, Buitrago R, Shyy JY-J, Cooke J P. Nitric Oxide Regulates Monocyte Chemotactic Protein-1. Circulation, 1997, 96: 934-940
[53]赵红卫,一氧化氮与免疫调节,上海免疫学杂志,1996, 16(6): 373-375
[54]穆莉,华维一,彭司勋,一氧化氮用于心脑血管药物研究进展,中国医科大学学报,1996, 27(12): 764-768
[55] Hrabie J A, Keefer L K. Chemistry of the Nitric Oxide-Releasing Diazeniumdiolate (“Nitrosohydroxylamine”) Functional Group and Its Oxygen-Substituted Derivatives. Chem. Rev., 2002, 102: 1135-1154
[56]陈鲁生,周武,姜云生,壳聚糖粘均分子量的测定[J],化学通报,1996, 4: 57-58
[57]蒋挺大编著,壳聚糖,蒋挺大编著,化学工业出版社,2001年3月第1版
[58]王真,陈西广,郎刚华,甲壳素及其衍生物生物生理活性研究进展,海洋科学[J],2000,24(9): 30-32
[59] Denuziere A, Ferrier D, Damour O, Domard A. Chitosan-chondroitin sulfate and chitosan-hyaluronate polyelectrolyte complexes: biological properties. Biomaterials, 1998, 19(14): 1275-1285
[60] Gaserod O, Smidstod O, Skjak-Braek G. Microcapsules of alginate-chitosan I: A quantitative study of the interaction between alginate and chitosan. Biomaterials, 1998, 19(20): 1815-1825
[61] Roy K, Mao H Q, Huang S K, Leong K W. Oral gene delivery with chitosan-DNA nanoparticles generates immunologic protection in a murine model of peanut allergy. Nature Medicine, 1999, 5(4): 387-391
[62] Parkpoom T, Amorn S, Achariya S, Ashim K M. Chitosan as nasal adsorption enhancers of peptides: comparison between free amine chitosans and soluble salts. Int J Pharm, 2000,197(1-2): 53-67
[63] Kate A F, Luessen H L. Chitosan for enhanced intestinal permeability: prospects for derivatives soluble in neutral and basic environment. Eur. J Pharm. Sci., 1999, 7(2): 145-151
[64] Dodne V, Amin Khan M, Merwin J R. Effect of chitosan on epithelval permeability and structure. Int J Pharrn, 1999, 182(1): 21-32
[65] Madihally S V, Matthew H. Porous chitosan scaffolds for tissue engineering. Biomaterials, 1999, 20(12): 1133-1142
[66] Park S, You J, Park H, Haam S, Kim W. A novel pH-sensitive membrance from chitosan TEOS IPN: preparation and its drug permeation characteristics. Biomaterials , 2001, 22(4): 323-330
[67]庄昭霞,林志勇,曹金芳,壳聚糖-羧甲基壳聚糖膜的生物相容性研究,上海口腔医学, 2003, 12(5): 362-365
[68]卢凤琦,曹宗顺,庄昭霞,壳聚糖膜的降解与生物相容性研究.生物医学工程学杂志,1998, 15(2)
[69]王大新,周斌,壳多糖对兔主动脉平滑肌细胞和内皮细胞增殖的影响.第二军医大学学报,1999, 20(12): 962-964
[70] Lueben H L, Rental C O, Kotae A F, et al. Mucoadhesivepolymers in peroral peptide drug delivery IV: Polycarbophil and chitosan are potent enhancers of peptide transport acrvsuntestinal mucosue in vitro. J Contr. Rel., 1997, 45: 15-24
[71] Awie F K, Hentih L L, Bas J D, et al. Comparison of the effect of different chitosan salts and N-trimethyl chitosan chloride on the permeability of intestinal epithelial cells (Caco-2). J Contr. Rel., 1998, 51: 35-43
[72] Janes K A, Fresneau M P, Marazuela A, et al. Chitosan nanoparticles as delivery systems for doxorubicin. J Contr. Rel., 2001, 73(2-3): 255-267
[73] Calvo P, Remunan-lopez C, Vila-Jato J L, et al. Novel hydrophilic chitosan/polyethylene oxide nanoparticles as proteins carriers. J Appl. Polym. Sci, 1997, 63: 125-132
[74] Fernandez-Urrusuno R, Calvo P, Remunan-Lopez C, et al. Enhancement of nasal absorption of insulin using chitosan nanoparticles. Pharm. Res., 1999, 16(10): 1576-1581
[75] Mooren F C, Berthold A, Domschke W, et al. Inflence of chitosan microspheres on the transport of prednisolone sodium phosphate across HT-29 cell monolayers. Pharm. Res.,1998, 15(1): 58-65
[76] Mitra S, Gaur U, Ghosh P C, et al. Tumour targeted delivery of encapsulated dextran-doxorubicin conjugate using chitosan nanoparticles as carrier. J Contr. Rel., 2001, 74(1-3): 317-323
[77] De Campos A.M., Sanchez A, Alonso M J. Chitosan nanoparticles: a new vehicle for the improvement of the delivery of drugs to the ocular surface, Application to cyclosporin A. Int. J Pharm., 2001, 224(1-2): 159-168
[78] Musaarelli R., Biochemical significance at exogenous chitins and chitosans in animals and patients. Biomaterials, 1993, 20: 7-16
[79] Musaarelli R, Baldaseane V, Coni F. Biological activity of chitosan: Ultrastructural study. Biomaterials, 1998, 9: 247-252
[80] Ohya Y, Shireteni M, Kobayashi H, et al. Release behavior of 5-fiuorouracil from chitosan-gel nanospheres immobilizing 5-fluorouracil costed with polysaccharides and their cell specific cytotoxicity. J Biomedical Mater. Res. 1989, 61: 203-211
[81] Tanima B, Susmita M, Singh K, et al. Preparation, characterization and biodistribution of ultrafine chitosan nanoparticles. Int. J Pharm., 2002, 243(1-2): 93-102
[82] Watske H J, Dieschbourg C. Novel silica-biopolymer nanocomposites: the silica sol-ge1 process in biopolymer organogels. Adv. Coll. Interfac. Sci., 1994, 50: 1-14
[83] Ko J A, Park H J, Hwang, Park J B, et al. Preparation and characterization of chitosan microparticles intendend for controlled drug delivery, Int. J Pharm., 2002, 249(1-2): 165-174
[84] Alonso M I, Calvo P, Remunan C, et al. Application of nanoparticles based on hydrophilic polymers as pharmaceutical forms. EP0860166, Aug, 1998
[85] Bodmeier R, Chen H G, Paeratakul O. A novel approach to the delivery of micro- or nanoparticles. Pharm. Res., 1989, 6(5): 413-417
[86]刘晨光,刘成圣,孟祥红,壳聚糖作为药物缓释材料的研究进展,高技术通讯,2003(3): 98-103
[87] Mi F L, Shyu S S, Chen C T, et al. Adsorption of indomethacin onto chemically modified chitosan beads. Polymer, 2002, 43(3): 757-765
[88] Mi F L, Shyu S S, Chen C T, et al. Porous chitosan microphere for controlling the antigan release of Newcastle disease vaccine: preparation of antigen-adsorbed microsphere and invitro release. Biomaterials, 1999, 20(17): 1603-1612
[89] Berthold A, Cremer K, Kreuter J. Preparation and characterization of chitosan microspheres as drug carrier for prednisolon sodium phosphate as model for anti-inflammatory drugs. J Control Release, 1996, 39: 17-25
[90] Tian X X, Groves M J. Formulation and biological activity of antineoplastic proteoglycans derived from Mycobacterium vaccine in chitosan nanoparticles. J Pharm Pharmacol., 1999, 51: 151-157
[91] Cui Z, Mumper R J. Chitosan-based nanoparticles for topical genetic imminization. J Contro Release, 2001, 75(3): 409-419
[92] El-Shabouri M H. Positively charged nanoparticles for improving the oral bioavailability of cyclosporin-A. Int. J of Pharm., 2002, 249(1-2): 101-108
[93] Hu Y, Jiang X, Ding Y, et al. Synthesis and characterization of chitosan-poly(acrylic acid) nanoparticles. Biomaterials, 2002, 23: 3193-3201
[94] Mumper R J, Wang J, Claspell J M, et al. Novel polymeric condensing carriers for gene delivery[C]. Proc. Intl. Symp. Control Rel. Bioact. Mater., 1995, 22: 178-179
[95] Mao H Q, Roy K, Walsh S M, et al. DNA-chitosan nanospheres for gene delivery[C]. Proc. Intl. Symp. Control Rel. Bioact. Mater., 1996, 23: 401-402.
[96] Ohya Y, Cai R, Nishizawa H, et al. Preparation of PEG-grafted chitosan nanoparticle for peptide drug carrier. Proc. Intl. Symp. Control Rel. Bioact. Mater., 1999, 26: 655-656
[97] Lee K Y, Kwon I C, Kim Y H, et al. Preparation of chitosan self-aggregates as a gene delivery system. J Control Rel., 1998, 51: 213-220
[98] Lee K Y, Kwon I C, Kim Y H, et al. Structural investigation of chitosan self-aggregate prepared for gene delivery[C]. Proc. Intl. Symp. Control Rel. Bioact. Mater., 1998, 25: 340-341
[99] Uhrich K E, Cannizzaro S M, Langer R S, Shakesheff K M. Polymeric systems for controlled drug release. Chem. ReV., 1999, 99: 3181-3198.
[100] Kost J, Langer R. Responsive polymeric delivery systems. AdV. Drug Deliv. ReV., 2001, 46: 125-148
[101] Batrakova E V, Vinogradov S V, Robinson S M, Niehoff M L, Banks W A, Kabanov A V. Polypeptide Point Modification with Fatty Acids and Pluronic Block Copolymers forEnhanced Brain Delivery. Bioconjugate Chem., 2005, 16 (4): 793-802
[102] Bronich T K, Keifer P A, Shlyakhtenko L S, Kabanov A V. Polymer micelle with cross-linked ionic core. J. Am. Chem. Soc., 2005, 127: 8236-8237
[103] Jung T, Kamm W, Breitenbach A, Kaiserling E, Xiao J X, Kissel T. Biodegradable nanoparticles for oral delivery of peptides: is there a role for polymers to affect mucosal uptake?. Eur. J. Pharm. Biopharm., 2000, 50: 147-160
[104] Kohane D S, Anderson D G, Yu C, Langer R. pH Triggered release of macromolecules from spraydried polymethacrylate microparticles. Pharm. Res., 2003, 20: 1533-1538
[105] Cai T, Hu Z B, Ponder B, St. John J, Moro D. Synthesis and study of and controlled release from nanoparticles and their networks based on functionalized hydroxypropylcellulose. Macromolecules, 2003, 36(17): 6559-6564
[106] Pillai O, Panchagnula R. Polymers in drug delivery. Curr. Opin. Chem. Biol. 2001, 5(4): 447-451
[107] Na K, Lee K H, Bae Y H. pH-Sensitivity and pH-dependent interior structural change of selfassembled hydrogel nanoparticles of pullulan acetate/oligosulfonamide conjugate. J. Control. Release, 2004, 97: 513-525
[108] Zhang H, Oh M, Allen C, Kumacheva E. Monodisperse Chitosan Nanoparticles for Mucosal Drug Delivery. Biomacromolecules, 2004, 5(6): 2461-2468
[109] Freiberg S, Zhu X X. Polymer microspheres for controlled drug release. Int. J. Pharm., 2004, 282: 1-18
[110] Hobbs S K, Monsky W L, Yuan F, Roberts W G, Griffith L, Torchilin V P, Jain R K. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc. Natl. Acad. Sci. USA., 1998, 95: 4607-4612
[111] Lin M Z, Teitell M A, Schiller G J. The evolution of antibodies into versatile tumor-targeting agents. Clin. Cancer Res., 2005, 11: 129-138
[112] Zhang H, Mardyani S, Chan W C W, Kumacheva E. Design of Biocompatible Chitosan Microgels for Targeted pH-Mediated Intracellular Release of Cancer Therapeutics. Biomacromolecules, 2006, 7: 1568-1572
[113] Killisch I, Steinlein P, Romisch K, Hollinshead R, Beug H, Griffiths G. Characterization of early and late endocytic compartments of the transferrin cycle. Transferrin receptor antibodyblocks erythroid differentiation by trapping the receptor in the early endosome. J. Cell Sci., 1992, 103, 211-232
[114] Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy:mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res., 1986, 46: 6387-6392
[115] Papahadjopoulos D, Allen T M, Gabizon A, et al. Sterically stabilized liposomes: improvements in pharmacokinetics and antitumor therapeutic efficacy. Proc. Natl. Acad. Sci. U.S.A., 1991, 88: 11460-11464
[116] Fabrizio M, Francüois L. Active targeting with particulate drug carriers in tumor therapy: fundamentals and recent progress. Drug Discovery Today, 2004, 9(5): 219-228
[117] Cemazar M, Pavlin D, Kranjc S, Grosel A, Mesojednik S, Sersa G. Sequence and time dependence of transfection efficiency of electrically-assisted gene delivery to tumors in mice. Curr. Drug Deliv., 2006, 3: 77-81
[118] Davidson B L, Breakefield X O. Viral vectors for gene delivery to the nervous system. Nat. ReV. Neurosci., 2003, 4(5): 353-364
[119] Ramachandran S, Quist A P, Kumar S, Lal R. Cisplatin Nanoliposomes for Cancer Therapy: AFM and Fluorescence Imaging of Cisplatin Encapsulation, Stability, Cellular Uptake, and Toxicity. Langmuir, 2006, 22: 8156-8162
[120] Huth U S, Schubert R, Peschka-Suss R. Investigating the uptake and intracellular fate of pH-sensitive liposomes by flow cytometry and spectral bio-imaging. J. Control. Rel., 2006, 110: 490-504
[121] Torchilin V P. Structure and design of polymeric surfactant-based drug delivery. systems. J. Control. Rel., 2001, 73: 137-172
[122] Leamon C P, Low P S. Delivery of macromolecules into living cells:a method that exploits folate receptor endocytosis. Proc. Natl. Acad. Sci. U.S.A., 1991, 88(13): 5572-5576
[123] Jang J S, Kim S Y, Lee S B, Kim K O, Han J S, Lee Y M. Poly(ethylene glycol)/poly(e-caprolacton) diblock copolymeric nanoparticles for Non-viral gene delivery: the role of charge group and molecular weight in particle formation, cytotoxicity and transfect. J. Control. Rel., 2006, 113(2): 173-182
[124] Park E K, Kim S Y, Lee S B, Lee Y M. Folate-conjugated methoxy poly(ethyleneglycol)/poly( -caprolactone) amphiphilic block copolymeric micelles for tumor-targeted drug delivery. J. Controlled Release, 2005, 109(1-3): 158-168
[125] Park E K, Lee S B, Lee Y M. Preparation and characterization of methoxy poly (ethylene glycol)/poly (ε-caprolactone) amphiphilic block copolymeric nanospheres for tumor-specific folate-mediated targeting of anticancer drugs. Biomaterials, 2005, 26(9): 1053-1061
[126] Gonzalez-Guerrico A, Meshki J, Xiao L, Benavides F, Conti C J, Kazanietz M G. Molecular mechanisms of protein kinase C-induced apoptosis in prostate cancer cells. J Biochem. Mol. Biol., 2005, 38: 639-645
[127] Qu X, Khutoryanskiy V, Stewart A, Rahman S, Papahadjopoulos-Sternberg B, Dufes C, McCarthy D, Wilson C G. Lyons R, Carter K, Schazlein A, Uchegbu I. Carbohydrate-Based Micelle Clusters Which Enhance Hydrophobic Drug Bioavailability by Up to 1 Order of Magnitude. Biomacromolecules, 2006, 7(12): 3452-3459
[128] Feng H, Dong C-M. Preparation, characterization, and self-assembled properties of biodegradable chitosan-poly(L-lactide) hybrid amphiphiles. Biomacromolecules, 2006, 7(11): 3069-3075
[129] Jiang G B, Quan D, Liao K, Wang H. Novel Polymer Micelles Prepared from Chitosan Grafted Hydrophobic Palmitoyl Groups for Drug Delivery, Mol. Pharm., 2006, 3(2): 152-160
[130] Kim Y H, Gihm S H, Park C R, et al. Structural characteristics of size-controlled self-aggregates of deoxycholic acid-modified chitosan and their application as a DNA delivery carrier. Bioconjug. Chem., 2001, 12(6): 932-938
[131] Felgner J H, Kumar R, Sridhar C N, Wheeler C J, Tsai Y J, Border R, Ramsey P, Martin M, Felgner P L. Enhanced Gene Delivery and Mechanism Studies with a Novel Series of Cationic Lipid Formulation. J. Biol. Chem., 1994, 269: 2550-2561
[132] Antonella M, Roberta C, Claudia B, Ludovica G, Maria R G. Cellular uptake and cytotoxicity of solid lipid nanospheres incorporation doxorubicin or paclitaxel. Int. J. Pharm. 2000, 210: 61-67
[133] Hu F Q, Ren G F, Yuan H, Du Y Z, Zeng S. Shell cross-linked stearic acid grafted chitosan oligosaccharide self-aggregated micelles for controlled release of paclitaxel. Colloids. Surf.B., 2006, 50: 97-103
[134] Hu F Q, Zhao M D, Yuan H, You J, Du Y Z, Zeng S. A novel chitosan oligosaccharide-stearic acid micelles for gene delivery: properties and in vitro transfection studies. Int. J. Pharm. 2006, 315: 158-166
[135] Schiff P, Fant J, Horwitz S B. Taxol increases the rate and extent of microtubule assembly in vitro and stabilizes microtubules in vitro and in cells. Nature, 1979, 277: 665-667
[136] Schiff P, Horwitz S B. Proc. Taxol stabilizes microtubes in mouse fibroblast cells. Natl. Acad. Sci. U.S.A., 1980, 77: 1561-1565
[137] Rowinsky E K, Donehower R C, Jones R J, Tucker R W. Microtubule changes and cytotoxicity in leukemic cell lines treated with taxol. Cancer Res., 1988 , 48(14): 4093–4100
[138]赵文恩,韩雅珊,乔旭光等,类胡萝卜素对H2O2-NaOCL体系生成的·O2淬灭作用,生物物理学报, 1997, 13(1): 137-142
[139]周惠萍,王叔如,浒苔多糖的降血脂及其对SOD活力和LPO含量的影响,生物化学杂志, 1995, 2: 161-164
[140] Park P J, Je J Y, Kim S K. Free radical scavenging activities of differently deacetylated chitosans using an ESR spectrometer. Carbohydr. Polym., 2004, 55: 17-22
[141] Xie W M, Xu P X, L iu Q. Antioxidant activity of water-soluble chitosan derivatives. Bioorg. Med. Chem. Lett., 2001, 11(13): 1699-1701
[142]陈瑗,周玫,自由基与衰老[M],第一版,北京:人民卫生出版社,2004
[143] Zhang Q, Zhai J J, Zhang Y R, et al. Antioxdative and antitumor properties of metal (II) solid complexes with 8-acetyl-4-methyl umbelliferone. Transition Metal Chemistry, 2000, 25(1): 93-98
[144]宋俊峰,邵勇,过玮,黄体酮清除超氧离子作用机理及反作用机理及反应动力学,Chin. Sci. Bull., 2000, 45(14): 1505-1510
[145]胡道道,史启祯,唐宗薰.甲壳素/壳聚糖的配位化学和配合物应用的研究进展,无机化学学报,2000, 16(3): 385~393
[146] Halliwell B, Gutteridge J M C. Role of free radicals and metal ions in human disease: an overview. Methods Enzymol., 1990, 186: 1-85
[147] Guo Z Y, Xing R E, Liu S, Yu H H, Wang P B, Li C P, Li P C. The synthesis and antioxidantactivity of the Schiff bases of chitosan and carboxymethyl chitosan. Bioorg. Med. Chem. Lett. 2005, 15(20): 4600-4603
[148] Guo Z Y, Liu H Y, Chen X L, Jia X, Lia P C. Hydroxyl radicals scavenging activity of N-substituted chitosan and quaternized chitosan. Bioorganic & Medicinal Chemistry Letters, 2006, 16: 6348-6350
[149] Jeon Y J, Kim S K. Potential immuno-stimulating effect of antitumoral fraction of chitosan oligosaccharides. J. Chitin Chitosan, 2001, 6: 163-167
[150] Sudharshan N R, Hoover D G, Knorr D. Anti bacterial Action of Chitosan. Food Biotechnol, 1992, 6: 257-272
[151] Maezaki Y, Tsuji K, Nakagawa Y, Kawai Y, Akimoto M, Tsugita T, Takekawa W, Terada A, Hara H, Mitsuoka T. Hypo cholesterolemic Effect of Chitosan in Adult Males. Biosci. Biotechnol. Biochem, 1993, 57: 1439-1444
[152] Kumaran A, karunakaran R J. Antioxidant and free radical scavenging activity of an aqueous extract of Coleus aromaticus. Food Chemistry, 2006, 97(1): 109-114
[153]金鸣,蔡压欣,邻二氮菲- Fe2+氧化法检测H2O Fe2+产生的羟自由基,生物化学与生物物理进展,1996, 23(6): 553- 555
[154]高秀蕊,石双群,宁秀芹,某些药物对酪氨酸酶的抑制和对O-2自由基的清除,生物化学与生物物理进展,1992, 19(1): 70-72
[155]张歧,王睿,易美华,芦荟小分子提取物对超氧阴离子自由基的清除作用,自由基生命科学进展(第8集),北京:原子能出版社, 2001, 54-55
[156] Yazdani P M, Lagos A, Campos N, Retuert J. Int J Polym M ater, 1992, 18: 25
[157] Yang D Z, Liu X F, Li Z, et al. On the Factors Influencing the Antibacterial Activity of Chitosan. Chinese J. Appl. Chem., 2000, 17 (6) : 598-602
[158] Xu Y M, Du Y M, Huang, R H, Gao L P. Preparation and modification O,N-(2-hydroxyl-propyl-3-trimethy ammonium chitosan chloride nanoparticles as a protein carrier. Biomaterials, 2003, 24(27): 5015-5022
[159] Loubaki E, Ourevitch M, Sicsic S. Chemical modification of chitosan by glycidyl trimethylammonium chloride. characterization of modified chitosan by 13C- and 1H-NMR spectroscopy. Eur. Polym. J., 1991, 27(3): 311-317
[160] Liu C G, Desai K G H, Chen X G, Park H J. Linolenic acid-modified chitosan for formationof self-Assembled nanoparticles. J. Agric. Food. Chem., 2005, 53: 437-441
[161] Kittur F S, Harish Prashanth K V, Udaya Sankar K, Tharanathan R N. Characterization of chitin, chitosan and their carboxymethyl derivatives by differential scanning calorimetry. Carbohydrate Polymer, 2002, 49: 185-193
[162] Qi L F, Xu Z R, Jiang X, Hu C H, Zou X F. Preparation and antibacterial activity of chitosan nanoparticles. Carbohydrate Research, 2004, 339(16): 2693-2700
[163] Gao Q W, Shao Z Z, Sun Y Y, Lin H, Yu T Y. Complex formation of silk fibroin with poly(acrylic acid). Poym. J., 2000, 32: 269–274
[164]宋存先,杨菁,心血管内局部定位药物缓释体系的实验研究,中国心血管杂志,1998, 3: 70-73
[165]王浩,多肽与蛋白质类药物给药系统的研究现状,中国医药工业杂志,1994, 25: 421-426
[166] Haider M, Megeed Z, Ghandehari H. Genetically engineered polymers, status and prospects for controlled release. Journal of Comtrolled Release, 2004, 95: 1-26
[167] Zhao Z P, Wang Z, Ye N, Wang S C. A novel N,O-carboxymethyl amphoteric chitosan/poly(ethersulfone) composite MF meembrane and its chaged characteristics. Desalination, 2002, 144: 35-39
[168] Yin L C, Fei L K, Cui F Y, Tang C, Yin C H. Superporous hydrogels containing poly(acrylic acid-co-acrylamide)/O-carboxymethyl chitosan interpenetrating polymer nerworks. Biomaterials, 2007, 28: 1258-1266
[169] Cho J Y, Grant J, Piquette-Miller M, Allen C. Synthesis and Physicochemical and Dynamic Mechanical Properties of a Water-Soluble Chitosan Derivative as a Biomaterial. Biomacromolecules, 2006, 7: 2845-2855
[170] Brzezinska A, W inska P, B alinska M. Cellular aspects of folate and antifolate membrane transport. Acta Biochim Pol, 2000, 47: 735-749
[171] Konda S D, Aref M, Brechbiel M, et al. Development of a tumor-targeting MR contrast agent using the high-affinity folate receptor: work in p rogress. Invest Radiol, 2000, 35: 50-57
[172] Konda S D, Wang S, Brechbiel M, et al. Biodistribution of a 153Gd2 folate dendrimer, generation=4, in mice with folate-receptor positive and negative ovarian tumor xengrafts. Invest Radiol, 2002, 37: 199-204
[173] Doucette M M, Stevens V L. Folate recep tor function is regulated in response to different cellular growth rates in cultured mammalian cells. J. Nutr., 2001, 131: 2819-2825
[174] Nishimura S I, Kohgo O, Kurita K, Kuzuhara H. Chemospecific manipulations of a rigid polysaccharide: syntheses of novel chitosan derivatives with excellent solubility in common organic solvents by regioselective chemical modifications. Macromolecules, 1991, 24: 4745-4748
[175] Sorlier P, Denuzie`re A, Viton C, Domard A. Relation between the degree of acetylation and the electrostatic properties of chitin and chitosan. Biomacromolecules, 2001, 2: 765-772
[176] Sashiwa H, Shigemasa Y. Chemical modification of chitin and chitosan 2:preparation and water soluble property of N-acylated or N-alkylated partially deacetylated chitins. Carbohydr. Polym., 1999, 39: 127-138
[177] Yang T, Chou C, Li C. Preparation, water solubility and rheological property of the N-alkylated mono or disaccharide chitosan derivatives. Food Res. Int., 2002, 35(8): 707-713
[178] Muzzarelli R A A, Tanfani F, Emanuelli M, Mariotti S. N-(carboxymethylidene) chitosans and N-(carboxymethyl)chitosans: novel chelating polyampholytes obtained from chitosan glyoxylate. Carbohydr. Res., 1982, 107: 199-214
[179] Murata, J.; Ohya, Y.; Ouchi, T. Possibility of Application of Quaternary Chitosan Having Pendant Galactose Residues as Gene Delivery Tool. Carbohydr. Polym., 1996, 29(1): 69-74
[180]张庆云,张利平,胡迎庆等,壳聚糖在靶向制剂中的应用进展,天津药学,2004, 16(2): 56-59
[181] Ko J A, Park H J, Hwang Y S, Park J B. Chitosan microparticle preparation for controlled drug release by response surface methology. J. Microencapsulation., 2003, 20: 791-797
[182] Lee D W, Park S J, Park J B, Park H J. Preparation and release characteristics of polymer-coated and blended alginate microsphere. J. Microencapsulation., 2003, 20: 179-192
[183] Hejazi R, Amiji M. Chitosan-based delivery systems: Physicochenical properties and pharmaceutical applications. In Polymer Biomaterials, 2nd ed; Dumitriu, S., Ed.; Marcel Dekker: New York, 2002, pp 213-238
[184]薛松,有机结构分析,中国科学技术大学出版社,2005, 296-303
[185] Sieval A B, Thanou M, KotzéA F, Verhoef J C, Brussee J, Junginger H E. Preparation andNMR characterization of highly substituted IV-trimethyl chitosan chloride. Carbohydrate Polymers, 1998, 36 : 157-165
[186] Spinelli V A, Laranjeira M C M, Fávere V T. Preparation and characterization of quaternary chitosansalt: adsorption equilibrium of chromium(VI) ion. Reactive & Functional Polymers, 2004, 61: 347-352
[187]高群,新型亲核NO供体的合成及性能研究,上海交通大学博士论文,2006
[188] Li Q, Lunn E T, Grandmaison E W, Goosen M F A. In Applications and properties of chitosan; Goosen, M. F. A., Ed.; Technomic Publishing Co., Inc.: Lancaster, 1997, pp 3
[189] Hirano S. Chitin and chitosan as novel biotechnological materials. Polym. Int., 1999, 48: 732-734
[190] Ravi Kumar M N V. A review of chitin and chitosan applications. React. Funct. Polym., 2000, 46: 1-27
[191] Molinaro G, Leroux J, Damas J, Adam A. Biocompatibility of Thermosensitive Chitosan-based Hydrogels: An In vivo Experimental Approach to Injectable Biomaterials. Biomaterials, 2002, 23(13): 2717-2722
[192] Kubota N, Tatsumoto N, Sano T, Toya K. A simple preparation of half N-acetylated chitosan highly soluble in water and aqueous organic solvents. Carbohydr. Res. 2000, 324, 268-274
[193] Onishi H, Machida Y. Biodegradation and distribution of water-soluble chitosan in mice. Biomaterials, 1999, 20(2): 175-182
[194] Cho Y W, Cho Y N, Chung S H, Yoo G, Ko S W. Water-soluble chitin as a wound healing accelerator. Biomaterials, 1999, 20: 2139-2145
[195] Park J H, Cho Y W, Chung H, Kwon I C, Jeong S Y. Synthesis and Characterization of Sugar-Bearing Chitosan Derivatives: Aqueous Solubility and Biodegradability. Biomacromolecules, 2003, 4: 1087-1091
[196] Dufes C, Scha¨tzlein A G, Tetley L, Gray A I, Watson D G, Olivier J, Couet W, Uchegbu I F. Polymeric Vesicles Bearing Targeting Ligands. Pharm. Res. 2000, 17(10), 1250-1258
[197] Yasugi, K.; Nakamura, T.; Nagasaki, Y.; Kato, M.; Kataoka, K. Sugar-installed polymer micelles: synthesis and micellization of poly(ethylene glycol)-poly(D, L-lactide) block copolymers having sugar groups at PEG chain end. Macromolecules, 1999, 32: 8024-8032
[198] Nagasaki Y, Yasugi K, Yamamoto Y, Harada A, Kataoka K. Sugar-installed block copolymermicelles:their preparation and specific interaction with lectin molecules. Biomacromolecules, 2001, 2: 1067-1070
[199] Dwek, R. A. Glycobiology-Toward Understanding the Function of Sugars. Chem. ReV. 1996, 96: 683-720
[200] Lis H, Sharon N. Lectins: carbohydrate-specific proteins that mediate cellular recognition. Chem. ReV., 1998, 98: 637-674
[201] Lee Y C. In Carbohydrate Recognition in Cellular Function; Bock, G., Harnette, S., Eds.; Ciba Foundation Symposium 145; Wiley: Chichester, England, 1989, pp 80
[202] Rauvala H, Carter W G, Hakomori S I. Studies on cell adhesion and recognition. I. Extent and specificity of cell adhesion triggered by carbohydrate-reactive proteins (glycosidases and lectins) and by fibronectin. J. Cell Biol., 1981, 88 (1): 127-137
[203] Roseman, S. Reflections on glycobiology. J. Biol. Chem., 2001, 276(45): 41527-41542
[204] Tomohiro O, Kenichi N, Norimasa I, Noriko N, Hideyuki S, Ryusuke K, Tokifumi M, Akio M, Shin-Ichiro N. Specific Cell Behavior of Human Fibroblast onto Carbohydrate Surface Detected by Glycoblotting Films. Biomacromolecules, 2006, 7: 2949-2955
[205] Baek M-G, Roy R. Design and Synthesis of Water-Soluble Glycopolymers Bearing Breast Tumor Marker and Enhanced Lipophilicity for Solid-Phase Assays. Biomacromolecules, 2000, 1: 768-770
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