中国科技论文统计源期刊 中文核心期刊
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖
, 符馨尹, 裔文静
, FU Xinyin, YI Wenjing
查阅关于肝素-泊洛沙姆407材料的国内外文献,介绍肝素-泊洛沙姆407新材料的合成及临床应用进展。从血管缝合、药物载体应用、血管修复、脊髓细胞及宫腔修复等方面介绍了肝素-泊洛沙姆407新材料的作用和特点。肝素-泊洛沙姆407是目前新兴的具有高亲和性、抗凝生物活性、缓释、定点释放等多种功能为一体的多聚物材料,既有抗凝作用可辅助血管缝合术治疗,又能在多种疾病治疗中起到良好辅助效果。
To discuss the topic of heparin-poloxamer 407 compound in medical progress by consulting relative literature. After that, heparin-poloxamer 407 compound used in vascular anastomosis、combined with growth factor for target therapy,vascular,etal spinal cord cell and uterine cavity repaired and has become a new methods according to the characteristics of it's form. Heparin-poloxamer 407 compound is not only a new form with the characteristics of high-affinity,anticoagulant biological activity,slow and controlled-release, but also can assist surgical operation of vessel anastomosis, and become a good assistant of some kinds of disease.
泊洛沙姆407(poloxamer 407,Pluronic F127) 是由不同比例的聚氧乙烯和聚氧丙烯组成的非离子型表面活性剂,平均相对分子质量约为12 600。泊洛沙姆具有特殊的反向热胶凝作用,即低温时(4~5 ℃)为液体,体温(37 ℃)下转变为凝胶[3]。肝素及低分子肝素是一种敏感的氨基葡聚糖,常与蛋白或其他肽类物质结合,具有缓释及靶向作用。目前文献报道的肝素-泊洛沙姆407材料合成方法的核心为将低分子肝素或普通肝素粉制备成单端胺基肝素后,与泊洛沙姆407在24 h室温条件下经EDC/NHS催化合成具有新结构的物质,并经过滤膜透析3 d,保留相对分子量在14 000内的化合物后冷冻干燥 [4]。化合物粉末经红外光谱和磁共振同时鉴定,可发现该化合物不仅具有肝素和泊洛沙姆407的特征峰,也有因PPO基团上-CH3、-CH,-CH2和PEO基团上-CH2的特征性化学位移产生的新特征吸收峰。经验证,合成后的肝素-泊洛沙姆407材料不仅具备60%低分子肝素的活性,还具有泊洛沙姆的温敏性,即低于体温(37 ℃)为液体,高于体温(40 ℃)转变为凝胶体。同时肝素与泊洛沙姆407的合成也促进了其与多种生物活性物质的亲和力,结合力相较泊洛沙姆407更强。这样的特性使肝素-泊洛沙姆407可广泛应用于医疗中,例如辅助血管缝合、作为多种疾病治疗药物的载体起到靶向及缓释作用。
血管缝合术是各种血管手术的关键步骤。传统的手工缝合技术要求较高,且许多因素如血管再狭窄、血管内膜的增生、血栓的形成以及外来物质的干扰等也给手术的操作带来了挑战,也不适于小血管及微血管的吻合[5]。斯坦福大学医学院的研究者提出应用泊洛沙姆407 凝胶结合医用黏合剂使用,可以解决显微血管吻合术黏合法的瓶颈问题[6]。泊洛沙姆有一种独特性质,在低温下是液体,受热后变成固体,过程是可逆的,将泊洛沙姆407加热到高于体温,使它变成固体,用于撑开血管。温度下降后泊洛沙姆407变成液体,不会阻塞血管,但还是存在必须合用白蛋白来控制胶凝温度、辅以抗凝剂防止栓塞形成等缺陷[7]。然而肝素-泊洛沙姆407既改进泊洛沙姆407凝胶的不足,又能克服传统吻合方法存在的吻合口狭窄和栓塞等问题,是目前研究的热点。王艳等[8]研究显示肝素-泊洛沙姆超声微泡可以增强肝素的溶栓作用,同时减少肝素有效溶栓的剂量,减少不良反应的发生,这提示肝素-泊洛沙姆可能有助于解决血管吻合术中出现的困难。同时 ÖZER等[9]研究也显示,在泊洛沙姆407中加入肝素,该凝胶的温敏现象可在体温时呈固态,在断口处撑开血管,加快了微血管缝合手术时间,1周后,加入了肝素的泊洛沙姆407组血管壁更薄,血流通畅度更高。提示了该种复合物质对无缝合线血管缝合手术益处较大。ZHAO等[4]研制出了肝素-泊洛沙姆407原位凝胶,并将其应用于兔颈静脉血管吻合术中,该凝胶具有与泊洛沙姆407不同的温敏特性,在高于体温时呈现固态,注射在血管断口处可利于撑开血管,同时缝合后撤离热源,凝胶降至体温时呈现液态,不堵塞血管。影像学及病理检查结果显示肝素-泊洛沙姆407辅助缝合术较传统的手工缝合技术更高效,同时还可显著改善兔颈静脉血管缝合处内皮损伤,溶解断口处形成的血栓,促进血管功能的恢复。
2.2.1 抗癌药物的靶向作用 肝素-泊洛沙姆407凝胶具有靶向作用,与抗癌药物结合能起到靶向治疗癌症、减小不良反应的作用。CHOI等[10]自组装了肝素-泊洛沙姆407纳米凝胶,并与核糖核酸酶A(ribonuclease A,RNase A) 结合用于抗癌治疗。结果显示RNase A与肝素-泊洛沙姆407凝胶结合力强,具有良好的载药率。同时肝素-泊洛沙姆407纳米凝胶细胞内吞及肝素的细胞核渗透能力显著,可浓集于人宫颈癌细胞质及细胞核内。在细胞毒性方面,肝素-泊洛沙姆407因肝素与泊洛沙姆407发生化学耦联后作用减弱,自身几乎无细胞毒性,而随着纳米凝胶内RNase A浓度的增加,细胞活性逐渐减弱,显示出了细胞毒性。TONG等[11]将顺铂与肝素-泊洛沙姆407纳米凝胶结合,结果显示该凝胶具有较高的载药率(42.5%),同时具有抑制人肺腺癌细胞NCI-H460的作用。另外,该顺铂-肝素-泊洛沙姆407纳米凝胶较之单纯的顺铂具有释放更缓慢及降低细胞毒性的作用。上述研究提示,肝素-泊洛沙姆407是一种安全性高、载药率高、结合能力强的靶向药物载体,可用于癌症靶向治疗。
2.2.2 血管修复作用 药剂学研究领域针对肝素-泊洛沙姆407与生长因子的释放过程及原理进行了探索。 YOON等[12]及CHOI等[13]将碱性成纤维细胞生长因子(b-fibroblast growth factor,bFGF)加入肝素-泊洛沙姆407复合物及肝素-泊洛沙姆/壳聚糖中,发现加入复合物中的生长因子较与加入单纯的泊洛沙姆中的生长因子释放速度更缓慢,且无爆释现象,其原理与肝素中有bFGF的特异结合位点,可形成相互作用有关。其释放生长因子的速度不仅受游离及结合的bFGF浓度影响,还与肝素同泊洛沙姆及壳聚糖的结合有关。带负电荷的肝素与带正点的聚合物间可形成较强的静电力,使bFGF/肝素释放缓慢,而单纯的bFGF与聚合物则结合较弱,释放速度增加。同时bFGF-肝素-泊洛沙姆407凝胶及bFGF-肝素-泊洛沙姆407-壳聚糖凝胶通过体内及体外药效学实验验证,其增殖细胞及毛细血管数量的能力均显著强于bFGF-泊洛沙姆407组,且该凝胶皮下移植进背部后作用可持续15 d,起到长效组织修复的作用。
YANG等[14]将bFGF及血管内皮生长因子(VEGF)165质粒DNA与肝素-泊洛沙姆407结合制成超分子纳米凝胶,并将其注入人内皮祖细胞中,结果显示该凝胶能在体外促进人内皮祖细胞增殖分化成内皮细胞,同时给下肢缺血小鼠模型肌内注射凝胶后,同样促进了小鼠下肢血管的生成。 WU等[15]使用C57BL/6小鼠进行全层皮肤切除处理后分别将与肝素-泊洛沙姆结合的酸性成纤维细胞生长因子(a-fibroblast growth factor,aFGF)和bFGF在伤口上涂抹给药。结果显示肝素-泊洛沙姆结合的aFGF和bFGF均可促进小鼠伤口愈合,并促进血管的生成使组织再上皮化。但是介于aFGF和bFGF表面所带电荷的不同,带正电荷的bFGF与肝素-泊洛沙姆凝胶结合更强,导致其较aFGF更难释放,治疗作用稍差。
2.2.3 脊髓修复靶向作用 肝素-泊洛沙姆407材料目前的研究热点还集中在脊髓损伤的修复中。在现有治疗脊髓损伤的方法中生长因子发挥着重要作用,可显著促进神经的恢复。然而,因为其口服生物利用度低,停留时间短,且通过血脊髓屏障量小等问题也限制了其使用[16]。
将肝素-泊洛沙姆407凝胶与神经生长因子(nerve growth factor,NGF)及胶质源性神经营养因子(glial cell-derived neurotrophic factor,GDNF)结合后,运用体外PC12细胞测定NGF的细胞摄取率和细胞毒性,结果显示在肝素-泊洛沙姆407中,NGF及GDNF具有完整的形态并发挥稳定的生物活性,肝素-泊洛沙姆407增强了NGF及GDNF细胞摄取率,对细胞几乎无毒性[17,18]。为进一步探索其神经元修复作用,将NGF及GDNF-肝素-泊洛沙姆407凝胶在脊髓损伤大鼠中进行损伤部位的原位注射,结果显示,NGF及GDNF-肝素-泊洛沙姆407组较之单纯的NGF及GDNF组和肝素-泊洛沙姆407组更具有神经元功能及形态的修复作用,有效抑制了胶质瘢痕的形成和内质网诱导的细胞凋亡。同时GDNF-肝素-泊洛沙姆407凝胶在体外神经细胞损伤模型中也具有较好的细胞摄取率及细胞突触修复作用,并具有剂量依赖性。以上实验结果提示肝素-泊洛沙姆407作为载体可显著发挥NGF及GDNF的治疗作用。
WANG等[19]将肝素-泊洛沙姆407凝胶与aFGF结合,并对脊髓损伤大鼠进行原位注射,实验结果表明相较于单纯的NGF组和肝素-泊洛沙姆407组,NGF-肝素-泊洛沙姆407凝胶可显著改善血脑脊髓屏障,减少神经细胞凋亡,促进髓鞘及轴突复原,减少因脊髓损伤造成的反应性胶质化现象,抑制炎症细胞扩散及内质网通路破坏,促进运动功能恢复。另外,相比单纯的泊洛沙姆凝胶,肝素的-SH键可增加凝胶与生长因子的结合率,同时具有缓释作用。同时肝素-泊洛沙姆这种温敏性凝胶还可在体温时呈现液态,原位注射时能保护生长因子不被体内的酸、酶等物质破坏及热灭活,同时不影响血管的生理功能。
目前对于治疗脊髓损伤的研究热点开始集中在细胞因子与一种非细胞脊髓骨架结合后,再加入肝素-泊洛沙姆407凝胶中,形成生物复合凝胶,该种凝胶较原先单纯的生长因子-肝素-泊洛沙姆407凝胶释放更为缓慢,更能有效集中于受损脊髓部位,达到长效的治疗效果。XU等[20,21]将细胞因子纤维生长因子-2(fbroblast growth factor-2,FGF-2)及bFGF通过冷处理方式与脊髓非细胞基质或骨架结合后,再加入肝素-泊洛沙姆407形成FGF-2- dscECM-HP和bFGF-ASC-HP新型复合凝胶。该凝胶不仅具有肝素-泊洛沙姆407的温敏特征和原有生长因子-肝素-泊洛沙姆407凝胶的神经元修复及抗氧化还原的作用,同时该种复合基质还为肝素-泊洛沙姆407提供了微小的储存位点,使得生长因子能在体内储存并且能够更持久、集中释放于脊髓损伤部位。肝素-泊洛沙姆407与多种生物基质结合形成的复合基质将是未来研究的热点。
2.2.4 宫腔靶向及缓释治疗作用 17β-雌二醇作为雌激素可有效提高子宫内膜修复作用,恢复子宫腔功能,但该药生物利用度低,选择性低,不仅限制了药物的应用,也增加了血栓及恶性肿瘤发生的风险[22]。ZHANG等[23]将肝素-泊洛沙姆407作为载体与17β-雌二醇结合,不仅克服了17β-雌二醇溶液低生物利用度及低选择性的缺点,同时释放更为缓慢,起到缓释作用。将17β-雌二醇-肝素-泊洛沙姆407注射进入右侧宫腔部位,结果显示该凝胶可显著改善宫腔黏连大鼠的宫腔腺体数量及纤维化面积,通过发挥PI3K/Akt和ERK1/2通路作用达到靶向治疗疾病的效果。
近年来,细胞因子对子宫损伤的修复作用也引起了广泛关注。XU等[24]研究显示,将角化细胞生长因子(keratinocyte growth factor,KGF)加入至肝素-泊洛沙姆407凝胶结合后进行子宫腔内注射,结果显示该凝胶相较于单纯细胞因子溶液更能缓慢集中释放于受损的子宫内膜部位,KGF-肝素-泊洛沙姆407凝胶可通过促进子宫内膜腺管上皮细胞及子宫腔上皮细胞的增殖及自噬作用,促进子宫血管生成和受损子宫修复。两者结合起到了增强药效的作用。另外,该学者研究证实,将带有负电荷的肝素-泊洛沙姆407与带有正电荷的ε-聚赖氨酸(ε-polylysine)结合形成复合凝胶后与KGF结合,该复合凝胶较之单纯的肝素-泊洛沙姆407凝胶具有更好的生物膜附着力,同时因为削弱了肝素-泊洛沙姆407的负电荷对生长因子的结合力,改变生长因子释放速率,导致KGF释放速率加快,能在凝胶黏附时迅速释放药物起到修复子宫内膜的作用[25]。
肝素-泊洛沙姆407是一种新型温敏型高分子材料,研究者在多种实验中探索该材料的用途,其中肝素-泊洛沙姆在血管外科吻合术中的应用成为研究的热点,其温敏特质和对断口处的恢复作用将使之成为外科辅助治疗的新手段。同时,作为药用载体,肝素-泊洛沙姆可与多种生长因子、核糖核酸及激素结合,在维持治疗剂量的同时,具有缓释及靶向作用。现有实验已报道了肝素-泊洛沙姆407材料具有较低的细胞毒性,未来可能对肝素-泊洛沙姆407材料的安全性及其与生长因子结合的制剂用于外科手术,及与其他材料结合形成复合制剂用于靶向治疗疾病作进一步研究。
The authors have declared that no competing interests exist.
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泊洛沙姆在药物制剂领域广泛应用,通常用作基质、增溶剂、稳定剂、乳化剂、吸收促进剂、固体分散体载体等,以控制药物释放,提高药物的稳定性,增加难溶性药物的溶解度,提高药物的生物利用度。
[本文引用:1]
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本文对泊洛沙姆407(商品名为普朗尼克F127)进行了流变学性质的考察。通过剪切速率触变性实验、温度敏感性实验和多次升温后表观黏度复原性实验得到了泊洛沙姆407各项流变学参数。结果表明,随着泊洛沙姆407水溶液浓度的提高,其由牛顿流体转变为假塑性流体,触变性和胶凝温度均逐渐降低(15.25%泊洛沙姆407可在体温下形成凝胶)。本文为泊洛沙姆407作为凝胶剂基质的应用提供了可参考的流变学数据。
[本文引用:1]
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Despite progress in the design of advanced surgical techniques, stenosis recurs in a large percentage of vascular anastomosis. In this study, a novel heparin-poloxamer (HP) hydrogel was designed and its effects for improving the quality and safety of vascular anastomosis were studied. HP copolymer was synthesized and its structure was confirmed by Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance spectroscopy (1H-NMR). Hydrogels containing HP were prepared and their important characteristics related to the application in vascular anastomosis including gelation temperature, rheological behaviour and micromorphology were measured. Vascular anastomosis were performed on the right common carotid arteries of rabbits, and the in vivo efficiency and safety of HP hydrogel to achieve vascular anastomosis was verified and compared with Poloxamer 407 hydrogel and the conventional hand-sewn method using Doppler ultrasound, CT angiograms, scanning electron microscopy (SEM) and histological technique. Our results showed that HP copolymer displayed special gel-sol-gel phase transition behavior with increasing temperature from 5 to 60 C. HP hydrogel prepared from 18 wt% HP solution had a porous sponge-like structure, with gelation temperature at approximately 38 C and maximum elastic modulus at 10,000 Pa. In animal studies, imaging and histological examination of rabbit common jugular artery confirmed that HP hydrogel group had similar equivalent patency, flow and burst strength as Poloxamer 407 group. Moreover, HP hydrogel was superior to poloxamer 407 hydrogel and hand-sewn method for restoring the functions and epithelial structure of the broken vessel junctions after operation. By combining the advantages of heparin and poloxamer 407, HP hydrogel holds high promise for improving vascular anastomosis quality and safety.
[本文引用:2]
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Background In recent years, several methods and new techniques have been studied and proposed for establishment of sutureless vascular anastomoses, streaming use of sutureless vascular surgery in the future. Presentation of the hypothesis The new vascular connector (NVC) is a hypothetical design of a vascular device, proposed for creation and maintenance of sutureless vascular anastomosis. Implication of NVC would introduce a new device and technique in establishment of sutureless vascular anastomosis in which surgical approach is minimized and so post-operation disorders. It would eliminate need for suture; shorten clampage and operation time, consequently reducing stress for both, the surgeon and the patient. It enables the creation of vascular anastomosis fast, simple, safe, reliable, with satisfactory patency and stability of anastomosis. Testing the hypothesis Efficacy of NVC needs to be evaluated in further studies, in order to be confirmed for clinical use. The effectiveness of NVC should be verified firstly in vitro and in vivo tests; and by animal experiments. The likelihood of its negative influence in thrombogenicity should be well evaluated. Implications of the hypothesis Implication of the new vascular connector (NVC) would be of interest to both patients and the surgeon due to the following main achievements: 1) enables the creation of vascular anastomosis fast and simple, 2) significant shortening of clampage time of blood vessels and operation time-this assumption would be followed by reduced risk of operative and post-operative complications and length of hospital stay or admission to Intensive care unit, 3) safe and reliable, 4) compatible with any blood vessel and standard vascular graft, 5) using the NVC we will reduce in minimum need for replaced blood volume, 6) reduces the cost of treatment. It is anticipated that the NVC would provide shorter operation time and least operative and post-operative complications in creation of sutureless vascular anastomosis.
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| [6] |
Vascular anastomosis is the cornerstone of vascular, cardiovascular and transplant surgery. Most anastomoses are performed with sutures, which are technically challenging and can lead to failure from intimal hyperplasia and foreign body reaction. Numerous alternatives to sutures have been proposed, but none has proven superior, particularly in small or atherosclerotic vessels. We have developed a new method of sutureless and atraumatic vascular anastomosis that uses US Food and Drug Administration (FDA)-approved thermoreversible tri-block polymers to temporarily maintain an open lumen for precise approximation with commercially available glues. We performed end-to-end anastomoses five times more rapidly than we performed hand-sewn controls, and vessels that were too small (<1.0 mm) to sew were successfully reconstructed with this sutureless approach. Imaging of reconstructed rat aorta confirmed equivalent patency, flow and burst strength, and histological analysis demonstrated decreased inflammation and fibrosis at up to 2 years after the procedure. This new technology has potential for improving efficiency and outcomes in the surgical treatment of cardiovascular disease.
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| [7] |
注射用原位凝胶制剂是近年来缓释型注射剂领域的研究新热点。其中,以泊洛沙姆407为基质的原位凝胶研究较为成熟。综述介绍了泊洛沙姆407的性质、安全性及其用于制备注射用温敏型原位凝胶的研究进展,为相关的制剂研发提供一定的依据。
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| [8] |
目的:探讨治疗性超声(US) 介导结合肝素-泊洛沙姆(HP)的微泡(MB)对自制体外血栓的溶解作用及机制。方法:对兔耳缘静脉进行取血,制备体外血栓,通过考察不同栓龄、超声声强 (净强度2~8 W/cm2)、作用时间和材料浓度下的栓溶率来确定各组的溶栓效应,并对其机制进行探讨。实验分组为:1US组;2US+MB组;3HP组;4US+HP 组;5US+MB+HP组。结果:US+MB+HP组超声所需时间最短,溶栓效果最好,而其余各组对于体外血栓也有一定溶解作用。结论:新合成的材料HP 与超声微泡联合应用后溶栓效果明显提高,其在临床治疗血栓性疾病中具有较好的应用潜力。
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| [9] |
Anastomosis with tissue adhesives is an alternative method for conventional anastomosis. However, this technique has several technical challenges. It requires using suture to prevent leakage into lumen and precise application on to all surfaces of the anastomosis site. In order to solve these problems poloxamer 407 (P 407) was used as a stent previously. In this study, we made heparinized P 407 (h-P 407) as a new formula. We aimed to use h-P 407 as a stent in sutureless anastomosis successfully in the rat abdominal aorta model. Sixty Sprague- Dawley rats were used. In the first group, end-to-end anastomoses were performed with suture, in the second and third groups; sutureless anastomoses were performed with 2-octyl cyanoacrylate. As an intraluminal stent, poloxamer 407 (P 407) was used in the second group heparinized poloxamer 407 (h-P 407) was used in the third group. Anastomosis time is measured. Lumen width, intimal hyperplasia and foreign body reaction were assessed histologically. Velocity flow rates and vessel diameters were measured radiological. Burst strength was measured. The results were evaluated statistically. Sutureless anastomosis was more rapid than conventional anastomosis. Lumen width was narrower in the suture group. nflammation and foreign body reaction was more severe in the suture group. There was no radiologic and biomechanical difference in all groups. We found intimal hyperplasia was less in h-P 407 than in P 407. Heparinized P407 can be used as an intraluminal stent for sutureless microvascular anastomosis with tissue adhesives successfully.
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| [10] |
A novel self-assembled nanogel was prepared for the intracellular delivery of ribonuclease A (RNase A) and the anti-cancer efficacy of RNase A delivery was investigated. The physical properties of self-assembled heparin-Pluronic (HP) nanogels incorporating RNase A (HPR nanogels) were characterized by dynamic light scattering (DLS), ξ-potential, and transmission electron microscopy (TEM). RNase A showed a strong affinity for the HP nanogel, resulting in a high loading efficiency (> 78%) and significantly decreased hydrodynamic size (from 89 to ~ 29). HPR nanogels were efficiently internalized into HeLa cells and localized in the cytosol as well as the nucleus. In the mechanism study of cellular uptake, treating with methoxy β-cyclodextrin (Mβ-CD) decreased the uptake efficiency of HP nanogel, indicating that internalization occurs via caveolae/lipid-raft mediated endocytosis. Localization in the nucleus most likely occurred because the conjugated heparin facilitated nucleus penetration. The cytotoxicity of HPR nanogels was significantly increased when the RNase A concentration was increased, which resulted from the degradation of single stranded RNAs in the cytosol and the nucleus due to the intracellular localization of the HPR nanogels. These results demonstrate that self-assembled HP nanogels are a remarkable vehicle for intracellular protein delivery and hold promise for use as cancer chemotherapeutics.
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| [11] |
In recent decades, platinum compounds have been many contributions in medicine. Development of new drugs from the active platinum compounds as well as nanocarriers for targeted delivery and reducing side effects of the drugs has paid much attention. In the study, nanocomplexes were prepared from aquated species of cisplatin and pluronic-conjugated heparin which distributed in the range of 80090009100 nm by Transmission Electron Microscopy and 134 nm by Dynamic light scattering (DLS). Formation of the complex was confirmed by FTIR and DLS. The nanocomplexes exhibited high drug-loading capacity (approximately 42.5% wt/wt at 37 00°C and 37.5% wt/wt at 25 00°C). In vitro, drug-loaded nanogels showed much slower release profiles of cisplatin CDDP in pH 7.4 (physiological pH) compared with pH 5.5 condition at 37 00°C. Moreover, the cytotoxicity assay results also indicated that Hep-F127 was cytocompatible; meanwhile, CDDP-loaded nanocomplex was able to reduce the cytotoxic ability of free CDDP (IC50 = 5.68 00± 0.73 0204g/ml), which still maintain a significantly antiproliferative activity on NCI-H460 lung cancer cell. The in vitro preliminarily obtained results indicate that the nanocomplex is a candidate for CDDP delivery which can be studied further in cancer therapy.
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| [12] |
Photo-crosslinkable and biodegradable Pluronic/heparin composite hydrogels were fabricated for local and sustained delivery of basic fibroblast growth factor (bFGF) to induce angiogenesis. Terminally di-acrylated Pluronic F127 and vinyl group conjugated heparin were used as a mixed macromer precursor solution to prepare a photo-crosslinkable hydrogel. An aqueous solution containing the two macromers with different weight ratios was photo-crosslinked in the presence of bFGF to produce in situ formed bFGF loaded Pluronic/heparin hydrogels. Swelling, mass erosion, bFGF release characteristics of Pluronic/heparin hydrogels were thoroughly examined by varying the weight ratio of the two macromers. The incorporation of heparin in the composite hydrogel enabled the controlled release of bFGF over a one month period in a near zero order manner. The prolonged release of bFGF could be attributed to the specific interaction between bFGF and heparin in the hydrogel matrices. The released bFGF fraction from the degradable hydrogels also showed sufficient proliferation activity of human umbilical vein endothelial cell (HUVEC). When the Pluronic/heparin hydrogels were implanted in vivo, a significant extent of neo-vascularization was observed. 2007 Wiley Periodicals, Inc. J Biomed Mater Res 2007
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| [13] |
In order to act as a cell reservoir, a hydrogel has to have a suitable mechanical strength and should also enhance proliferation of cells. We have developed a hydrogel composed of chitosan and Pluronic containing a complex of basic fibroblast growth factor (bFGF) and heparin for cell encapsulation, and its ability as a scaffold for cells was evaluated. The hydrogel was composed of glycidyl methacrylated chitooligosaccharide (COS) and diacrylated Pluronic F127 (Pluronic) in various blend ratios. A mixture of COS and Pluronic was homogeneously mixed with cells, bFGF and heparin; then, the hydrogel precursor was photo-irradiated. With increasing amount of COS, the chemically cross-linked COS/Pluronic hydrogel showed an approx. 2-fold increase of its elastic modulus and a lower mass erosion rate than the hydrogel composed of only Pluronic after 28 days. The amount of bFGF was increased according to the presence of heparin within the hydrogel, but the amount of released bFGF was decreased by increasing the content of COS. The hydrogel containing bFGF with heparin showed higher proliferation of cells compared to the hydrogel without heparin at 20% COS. However, when the blend ratio of COS was 50%, the hydrogel showed less proliferation of cells than those with 20% COS. Therefore, the chemically cross-linked COS/Pluronic hydrogel be useful for a protein-delivery system and tissue-engineering scaffold. (C) Koninklijke Brill NV, Leiden, 2012
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| [14] |
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Wound therapy remains a clinical challenge. Incorporation of growth factors (GFs) into heparin-functionalized polymer hydrogel is considered as a promising strategy to improve wound healing efficiency. However, different GFs incorporation into the same heparin-based hydrogels often lead to different wound healing effects, and the underlying GF-induced wound healing mechanisms still remain elusive. Herein, we developed a thermos-sensitive heparin-poloxamer (HP) hydrogel to load and deliver different GFs (aFGF and bFGF) for wound healing in vivo. The resulting GFs-based hydrogels with and without HP hydrogels were systematically evaluated and compared for their wound healing efficiency by extensive in vivo tests, including wound closure rate, granulation formation, re-epithelization, cell proliferation, collagen, and angiogenesis expressions. While all GFs-based dressings with and without HP hydrogels exhibited better wound healing efficacy than controls, both HP-aFGF and HP-bFGF hydrogels demonstrated thei...
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| [16] |
[Display omitted]
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| [17] |
Spinal cord injury (SCI) is a devastating condition that can lead to sudden loss of sensory and autonomic function. Current treatment includes decompression surgery, injury stabilization, secondary complications prevention and rehabilitation. However, neurological recovery is limited. Nerve growth factor (NGF) has potential in SCI therapy, but limited by the poor physicochemical stability and low ability to cross the blood spinal cord barrier. Hydrogels have good affinity and compatibility to biological tissue. In this study, we developed a novel heparin-poloxamer (HP) thermo-sensitive hydrogel to enhance the spinal cord regeneration of NGF. From SCI rat experiment, HP hydrogel combined with orthotopic injection technique showed best neuroprotective effects among experimental groups. This novel combined technique will provide an effective strategy for SCI regeneration.
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| [18] |
Abstract Traumatic spinal cord injury (SCI) results in paraplegia or quadriplegia, and currently, therapeutic interventions for axonal regeneration after SCI are not clinically available. Animal studies have revealed that glial cell-derived neurotrophic factor (GDNF) plays multiple beneficial roles in neuroprotection, glial scarring remodelling, axon regeneration and remyelination in SCI. However, the poor physicochemical stability of GDNF, as well as its limited ability to cross the blood-spinal cord barrier, hampers the development of GDNF as an effective therapeutic intervention in clinical practice. In this study, a novel temperature-sensitive heparin-poloxamer (HP) hydrogel with high GDNF-binding affinity was developed. HP hydrogels showed a supporting scaffold for GDNF when it was injected into the lesion epicentre after SCI. GDNF-HP by orthotopic injection on lesioned spinal cord promoted the beneficial effects of GDNF on neural stem cell proliferation, reactive astrogliosis inhibition, axonal regeneration or plasticity, neuroprotection against cell apoptosis, and body functional recovery. Most interestingly, GDNF demonstrated a bidirectional regulation of autophagy, which inhibited cell apoptosis at different stages of SCI. Furthermore, the HP hydrogel promoted the inhibition of autophagy-induced apoptosis by GDNF in SCI. This article is protected by copyright. All rights reserved. 2017 Wiley Periodicals, Inc.
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Abstract Acidic fibroblast growth factor (aFGF) exerts a protective effect on spinal cord injury (SCI) but is limited by the lack of physicochemical stability andthe ability to cross the blood spinal cord barrier (BSCB). As promising biomaterials, hydrogels contain substantial amounts of water and a 3D porous structureand are commonly used to load and deliver growth factors. Heparin can not only enhance growth factor loading onto hydrogels but also can stabilize the structure and control the release behavior. Herein, a novel aFGF-loaded thermosensitive heparin-poloxamer (aFGF-HP) hydrogel was developed and applied to provide protection and regeneration after SCI. To assess the effects of the aFGF-HP hydrogel, BSCB restoration, neuron and axonal rehabilitation, glial scar inhibition, inflammatory response suppression and motor recovery were studied both in vivo and in vitro. The aFGF-HP hydrogels exhibited sustained release of aFGF and protected the bioactivity of aFGF in vitro. Compared to groups i.v. administered either drug-free HP hydrogel or aFGF alone, the aFGF-HP hydrogel group revealed prominent and attenuated disruption of the BSCB, reduced neuronal apoptosis, reactive astrogliosis and increased neuron and axonal rehabilitation both in vivo and in vitro. This work provides an effective approach to enhance recovery after SCI and provide a successful strategy for SCI protection.
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DOI:10.2147/IJN
URL
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| [21] |
Because of the short half-life, either systemic or local administration of bFGF shows significant drawbacks to spinal injury.
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Abstract OBJECTIVE: The aim of this study was to investigate the association between hormone therapy (HT) use and the development of bone fractures. METHODS: Using terms related to HT and fractures, we searched PubMed, Embase, and the Cochrane library for randomized controlled trials on HT and the associated risk of fractures published before August 2014. Two evaluators independently selected studies on the basis of predetermined selection criteria, and 28 studies were included in the meta-analysis. Summary estimates were obtained using fixed- or random-effects models as appropriate. RESULTS: A total of 28 studies included 33,426 participants and 2,516 fractures cases. The overall relative risk of HT was 0.74 (95% confidence interval [CI] 0.69-0.80) for total fractures, 0.72 (95% CI 0.53-0.98) for hip fractures, and 0.63 (95% CI 0.44-0.91) for vertebral fractures. In subgroup analyses, women of an age less than 60 years had lower risk of total fractures compared with women of an age more than 60 years (P = 0.003). Estradiol led to greater decrease in the risk of total fractures compared with conjugated equine estrogens (P = .01). There is greater reduction in total fracture risk in trials of follow-up less than 36 months than that of follow-up more than 36 months (P = 0.003). No increase in the incidence of total cancer events but an increase in the incidence of thrombus was found to be associated with HT. CONCLUSIONS: HT is associated with a reduced risk of total, hip, and vertebral fractures, with a possible attenuation of this protection effect after it is stopped or when it is begun after 60 years. However, there may be an increase in the incidence of thrombus formation associated with HT.
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DOI:10.2147/IJN
URL
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Abstract Endometrial injury usually results in intrauterine adhesion (IUA), which is an important cause of infertility and recurrent miscarriage in reproductive women. There is still lack of an effective therapeutic strategy to prevent occurrence of IUA. Keratinocyte growth factor (KGF) is a potent repair factor for epithelial tissues. Here, a temperature-sensitive heparin-modified poloxamer (HP) hydrogel with affinity to KGF (KGF-HP) was used as a support matrix to prevent IUA and deliver KGF. The rheology of KGF-HP hydrogel was carefully characterized. The cold KGF-HP solution was rapidly transited to hydrogel with suitable storage modulus (G) and loss modulus (G) for the applications of uterus cavity at temperature of 33 C. In vitro release demonstrated that KGF was released from HP hydrogels in sustained release manner for a long time. In vivo bioluminescence imaging showed that KGF-HP hydrogel was able to prolong the retention of the encapsulated KGF in injured uterus of rat model. Moreover, the morphology and function of the injured uterus were significantly recovered after administration of KGF-HP hydrogel, which were evaluated by two-dimensional ultrasound imaging and receptive fertility. Not only proliferation of endometrial glandular epithelial cells and luminal epithelial cells but also angiogenesis of injured uterus were observed by Ki67 and CD31 staining after 7 d of treatment with KGF-HP hydrogel. Finally, a close relatively relationship between autophagy and proliferation of endometrial epithelial cells (EEC) and angiogenesis was firstly confirmed by detecting expression of LC3-II and P62 after KGF treatment. Overall, KGF-HP may be used as a promising candidate for IUA treatment.
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