BACKGROUND & AIMS: :Poly(N-isopropylacrylamide), PNIPAAm, hydrogels are negatively thermosensitive which means that they have an expanded hydrogel structure at low temperatures and a shrunken structure at high temperatures. Based on this negative thermosensitivity of PNIPAAm, a drug delivery system with PNIPAAm oligomers grafted onto poly(hydroxyethyl methacrylate) PHEMA, a thermally nonresponsive polymer was designed. Poly(hydroxyethyl methacrylate-g-N-isopropylacrylamide), P(HEMA-g-NIPAAm) hydrogels were synthesized to control the release of an imbedded drug. This new grafted system exhibited high diffusivity at temperatures greater than the lower critical solution temperature (LCST) of the PNIPAAm oligomers. Utilizing PNIPAAm's LCST of approximately 34 degrees C, the release rate was controlled by the temperature of the release medium. The LCST of PNIPAAm was tuned by making copolymers with hydrophobic butyl methacrylate (BMA). Theophylline and inulin release profiles were studied using PHEMA, PNIPAAm and P(HEMA-g-NIPAAm) at three temperatures with drug diffusion coefficients determined as a function of temperature and drug type. The molecular weights between crosslinks and mesh sizes of PHEMA hydrogels were calculated using Flory-Rehner and rubber-elasticity theories.

背景与目标： : 聚 (N-异丙基丙烯酰胺)，PNIPAAm，水凝胶是负热敏的，这意味着它们在低温下具有膨胀的水凝胶结构，在高温下具有收缩的结构。基于PNIPAAm的这种负热敏性，设计了一种将PNIPAAm低聚物接枝到聚 (甲基丙烯酸羟乙酯) PHEMA上的药物传递系统，并设计了一种热无响应的聚合物。合成了聚 (甲基丙烯酸羟乙酯-g-N-异丙基丙烯酰胺)，P(HEMA-g-NIPAAm) 水凝胶，以控制嵌入药物的释放。这种新的接枝系统在高于PNIPAAm低聚物的较低临界溶液温度 (LCST) 的温度下表现出高扩散率。利用约34 ℃ 的PNIPAAm的LCST，释放速率由释放介质的温度控制。通过与疏水性甲基丙烯酸丁酯 (BMA) 制备共聚物来调整PNIPAAm的LCST。使用PHEMA，PNIPAAm和P(HEMA-g-NIPAAm) 在三个温度下研究了茶碱和菊粉的释放曲线，并确定了药物扩散系数作为温度和药物类型的函数。使用Flory-Rehner和橡胶弹性理论计算了PHEMA水凝胶的交联和筛孔尺寸之间的分子量。

BACKGROUND & AIMS: UNLABELLED:Abstract Background and Purpose: Topical chemotherapy for urothelial cancer is dependent on adequate contact time of the chemotherapeutic agent with the urothelium. To date, there has not been a reliable method of maintaining this contact for renal or ureteral urothelial carcinoma. We evaluated the safety and feasibility of using a reverse thermosensitive polymer to improve dwell times of mitomycin C (MMC) in the upper tract. MATERIALS AND METHODS:Using a porcine model, four animals were treated ureteroscopically with both upper urinary tracts receiving MMC mixed with iodinated contrast. One additional animal received MMC percutaneously. The treatment side had ureteral outflow blocked with a reverse thermosensitive polymer plug. MMC dwell time was monitored fluoroscopically and intrarenal pressures measured. Two animals were euthanized immediately, and three animals were euthanized 5 days afterward. RESULTS:In control kidneys, drainage occurred at a mean of 5.3±0.58 minutes. Intrarenal pressures stayed fairly stable: 9.7±14.0 cm H20. In treatment kidneys, dwell time was extended to 60 minutes, when the polymer was washed out. Intrarenal pressures in the treatment kidneys peaked at 75.0±14.7 cm H20 and reached steady state at 60 cm H20. Pressures normalized after washout of the polymer with cool saline. Average washout time was 11.8±9.6 minutes. No histopathologic differences were seen between the control and treatment kidneys, or with immediate compared with delayed euthanasia. CONCLUSIONS:A reverse thermosensitive polymer can retain MMC in the upper urinary tract and appears to be safe from our examination of intrarenal pressures and histopathology. This technique may improve the efficacy of topical chemotherapy in the management of upper tract urothelial carcinoma.

背景与目标：

BACKGROUND & AIMS: :The aim of this study was to investigate the physical properties of a chitosan/glycerophosphate (GP) thermosensitive solution which gels at 37 degrees C and evaluate the in vitro release profiles of different model compounds. The gelation rate was dependent on the temperature and on the chitosan deacetylation degree. The solution containing 84%-deacetylated chitosan could be stored 3 months at 4 degrees C without apparent change in viscosity. The in vitro release profiles of the model compounds depended on the presence of GP in the chitosan solution, on their molecular weight and on the presence of lysozyme in the release media. They were not affected by the electrostatic charge of the model compound when present at low concentrations. During the first 4 h, the release was accompanied by a substantial loss of the gel weight which was mainly attributed to the leaching of water and excess GP. Scanning electron micrographs revealed that the solutions yield gels with a highly porous structure after 24 h of exposure to a continuous flow of phosphate buffered saline. These results indicate that the chitosan/GP thermosensitive solutions gel rapidly at body temperature, can remain in the sol state at 4 degrees C and can sustain the delivery of macromolecules.

背景与目标： : 这项研究的目的是研究在37摄氏度下凝胶的壳聚糖/甘油磷酸 (GP) 热敏溶液的物理性质，并评估不同模型化合物的体外释放曲线。胶凝速率取决于温度和壳聚糖脱乙酰度。含有84%-脱乙酰壳聚糖的溶液可以在4 ℃ 下储存3个月，而粘度没有明显变化。模型化合物的体外释放曲线取决于壳聚糖溶液中GP的存在，其分子量以及释放介质中溶菌酶的存在。当它们以低浓度存在时，它们不受模型化合物的静电荷的影响。在最初的4小时内，释放伴随着凝胶重量的大量损失，这主要归因于水和过量GP的浸出。扫描电子显微照片显示，在连续流动的磷酸盐缓冲盐水中暴露24小时后，溶液会产生具有高度多孔结构的凝胶。这些结果表明，壳聚糖/GP热敏溶液在体温下迅速凝胶，在4 ℃ 下可以保持溶胶状态，并可以维持大分子的递送。

BACKGROUND & AIMS: :In situ forming hydrogels based on thermosensitive polymers have attractive properties for tissue engineering. However, the physical interactions in these hydrogels are not strong enough to yield gels with sufficient stability for many of the proposed applications. In this study, additional covalent cross-links were introduced by photopolymerization to improve the mechanical properties and the stability of thermosensitive hydrogels. Methacrylate groups were coupled to the side chains of triblock copolymers (ABA) with thermosensitive poly( N-(2-hydroxypropyl) methacrylamide lactate) A blocks and a hydrophilic poly(ethylene glycol) B block. These polymers exhibit lower critical solution temperature (LCST) behavior in aqueous solution and the cloud point decreased with increasing amounts of methacrylate groups. These methacrylate groups were photopolymerized above the LCST to render covalent cross-links within the hydrophobic domains. The mechanical properties of photopolymerized hydrogels were substantially improved and their stability was prolonged significantly compared to nonphotopolymerized hydrogels. Whereas non-UV-cured gels disintegrated within 2 days at physiological pH and temperature, the photopolymerized gels degraded in 10 to 25 days depending on the degree of cross-linking. To assess biocompatibility, goat mesenchymal stem cells were seeded on the hydrogel surface or encapsulated within the gel and they remained viable as demonstrated by a LIVE/DEAD cell viability/cytotoxicity assay. Expression of alkaline phosphatase and production of collagen I demonstrated the functionality of the mesenchymal stem cells and their ability to differentiate upon encapsulation. Due to the improved mechanical properties, stability, and adequate cytocompatibility, the photopolymerized thermosensitive hydrogels can be regarded as highly potential materials for applications in tissue engineering.

背景与目标： : 基于热敏聚合物的原位形成水凝胶对组织工程具有吸引力。然而，这些水凝胶中的物理相互作用不够强，不足以产生对于许多建议的应用具有足够稳定性的凝胶。在这项研究中，通过光聚合引入了其他共价交联，以改善热敏水凝胶的机械性能和稳定性。甲基丙烯酸酯基团与具有热敏性聚 (N-(2-羟丙基) 甲基丙烯酰胺乳酸酯) A嵌段和亲水性聚 (乙二醇) B嵌段的三嵌段共聚物 (ABA) 的侧链偶联。这些聚合物在水溶液中表现出较低的临界溶液温度 (LCST) 行为，并且随着甲基丙烯酸酯基团数量的增加，浊点降低。这些甲基丙烯酸酯基团在LCST上方进行光聚合，以在疏水结构域中形成共价交联。与非光聚合水凝胶相比，光聚合水凝胶的机械性能得到了显着改善，并且其稳定性得到了显着延长。尽管非UV固化的凝胶在生理pH和温度下在2天内崩解，但光聚合的凝胶在10至25天内降解，具体取决于交联程度。为了评估生物相容性，将山羊间充质干细胞接种在水凝胶表面或封装在凝胶内，如活/死细胞活力/细胞毒性测定所证明，它们保持活力。碱性磷酸酶的表达和胶原蛋白I的产生证明了间充质干细胞的功能及其在包封后分化的能力。由于改进的机械性能，稳定性和足够的细胞相容性，光聚合的热敏水凝胶可被视为在组织工程中应用的极具潜力的材料。

BACKGROUND & AIMS: :The main purpose of this work was to optimize the rheological properties of docetaxel (DCT)-loaded thermosensitive liquid suppositories for rectal administration. DCT-loaded liquid suppositories were prepared by a cold method and characterized in terms of physicochemical and viscoelastic properties. Major formulation parameters including poloxamer (P407) and Tween 80 were optimized to adjust the thermogelling and mucoadhesive properties for rectal administration. Notably, the gel strength and mucoadhesive force significantly increased with the increase in these variables. Furthermore, DCT incorporation did not alter the viscoelastic behavior, and the mean particle size of nanomicelles in it was approximately 16 nm with a distinct spherical shape. The formulation existed as liquid at room temperature and transformed into gel at physiological temperature through the reverse gelation phenomenon. Thus, DCT-loaded thermosensitive liquid suppositories [DCT/P407/P188/Tween 80 (0.25/11/15/10 %)] with optimal gel properties were easy to prepare and administer rectally, and might enable the gel to stay in the rectum without getting out from rectum.

背景与目标： : 这项工作的主要目的是优化用于直肠给药的多西紫杉醇 (DCT) 负载的热敏液体栓剂的流变特性。DCT负载的液体栓剂是通过冷法制备的，并根据理化和粘弹性进行了表征。优化了包括泊洛沙姆 (P407) 和吐温80在内的主要配方参数，以调整直肠给药的热胶凝和粘膜粘附特性。值得注意的是，随着这些变量的增加，凝胶强度和粘膜粘附力显着增加。此外，DCT的掺入不会改变粘弹性行为，并且其中纳米胶粒的平均粒径约为16 nm，具有明显的球形。该制剂在室温下以液体形式存在，并在生理温度下通过反向凝胶现象转化为凝胶。因此，具有最佳凝胶性质的DCT负载的热敏液体栓剂 [DCT/P407/P188/tween80 (0.25/11/15/10%)] 易于制备和直肠施用，并且可能使凝胶能够停留在直肠中而不会从直肠脱出。

BACKGROUND & AIMS: :To characterize the thermal behavior and texture analysis of doxycycline hyclate thermosensitive gels developed for periodontitis treatment containing zinc oxide prepared by using poloxamer (Lutrol(®) F127) as polymeric material and N-methyl pyrrolidone was used as cosolvent. The thermosensitive gel comprising doxycycline hyclate, Lutrol(®) F127, and N-methyl pyrrolidone were characterized for the thermal behavior and texture analysis. The topography of the system after the dissolution test was characterized with scanning electron microscope. Differential scanning calorimetric thermogram exhibited the endothermic peaks in the systems containing high amount of N-methyl pyrrolidone in solvent. The sol-gel transition temperature of the systems decreased as the zinc oxide amount was increased. The addition of doxycycline hyclate, zinc oxide, and N-methyl pyrrolidone affected the syringeability of systems. The addition of zinc oxide into the doxycycline hyclate-Lutrol(®) F127 systems decreased the diameter of inhibition zone against Staphylococcus aureus, Escherichia coli, and Candida albicans since zinc oxide decreased the diffusion and prolonged release of doxycycline hyclate. From scanning electron microscope analysis, the porous surface of 20% w/w Lutrol(®) F127 system was notably different from that of gel comprising doxycycline hyclate which had interconnected pores and smooth surfaces. The number of pores was decreased with increasing zinc oxide and the porous structure was smaller and more compact. Therefore, the addition of zinc oxide could increase the syringeability of doxycycline hyclate-Lutrol(®) F127 system with the temperature dependence. Zinc oxide decreased inhibition zone against test microbes because of prolongation of doxycycline hyclate release and reduced size of continuous cells. Furthermore, zinc oxide also increased the compactness of wall surfaces of Lutrol(®) F127.

背景与目标： : 表征使用泊洛沙姆 (Lutrol (®) F127) 作为聚合物材料，N-甲基吡咯烷酮用作助溶剂。包含盐酸多西环素、Lutrol (®) F127和N-甲基吡咯烷酮被表征用于热行为和质地分析。用扫描电子显微镜表征溶解测试后系统的形貌。差示扫描量热分析图显示了在溶剂中含有大量N-甲基吡咯烷酮的系统中的吸热峰。随着氧化锌量的增加，系统的溶胶-凝胶转变温度降低。盐酸多西环素，氧化锌和N-甲基吡咯烷酮的添加会影响系统的注射器性。氧化锌在盐酸多西环素-Lutrol (®) F127系统减小了对金黄色葡萄球菌，大肠杆菌和白色念珠菌的抑制区直径，因为氧化锌降低了盐酸多西环素的扩散和释放时间。从扫描电子显微镜分析，20% w/w Lutrol的多孔表面 (®) F127系统与包含具有相互连接的孔和光滑表面的多西环素的凝胶明显不同。随着氧化锌的增加，孔的数量减少，多孔结构更小，更致密。因此，添加氧化锌可以增加盐酸多西环素的注射器性 (®) 具有温度依赖性的F127系统。氧化锌减少了对测试微生物的抑制区，这是因为盐酸多西环素释放的延长和连续细胞的尺寸减小。此外，氧化锌还增加了Lutrol壁面的致密性 (®) f127。

BACKGROUND & AIMS: :The objective of this investigation was to develop a thermosensitive vaginal gel containing raltegravir+efavirenz loaded PLGA nanoparticles (RAL+EFV-NPs) for pre-exposure prophylaxis of HIV. RAL+EFV-NPs were fabricated using a modified emulsion-solvent evaporation method and characterized for size and zeta potential. The average size and surface charge of RAL+EFV-NP were 81.8±6.4 nm and -23.18±7.18 mV respectively. The average encapsulation efficiency of raltegravir and efavirenz was 55.5% and 98.2% respectively. Thermosensitive vaginal gel containing RAL+EFV-NPs was successfully prepared using a combination of Pluronic F127 (20% w/v) and Pluronic F68 (1% w/v). Incorporation RAL+EFV-NPs in the gel did not result in nanoparticle aggregation and RAL+EFV-NPs containing gel showed thermogelation at 32.5°C. The RAL+EFV-NPs were evaluated for inhibition of HIV-1(NL4-3) using TZM-bl indicator cells. The EC(90) of RAL+EFV-NPs was lower than raltegravir+efavirenz (RAL+EFV) solution but did not reach significance. Compared to control HeLa cells without any treatment, RAL+EFV-NPs or blank gel were not cytotoxic for 14 days in vitro. The intracellular levels of efavirenz in RAL+EFV-NPs treated HeLa cells were above the EC(90) for 14 days whereas raltegravir intracellular concentrations were eliminated within 6 days. Transwell experiments of NPs-in-gel demonstrated rapid transfer of fluorescent nanoparticles from the gel and uptake in HeLa cells within 30 min. These data demonstrate the potential of antiretroviral NP-embedded vagina gels for long-term vaginal pre-exposure prophylaxis of heterosexual HIV-1 transmission.

背景与目标： : 这项研究的目的是开发一种热敏性阴道凝胶，该凝胶包含雷特格拉韦依非韦伦负载的PLGA纳米颗粒 (RAL efv-nps)，用于预防HIV暴露前。使用改进的乳液-溶剂蒸发方法制备RAL efv-nps，并对尺寸和zeta电位进行了表征。RAL + EFV-NP的平均尺寸和表面电荷分别为81.8 ± 6.4 nm和-23.18 ± 7.18 mV。raltegravir和efavirenz的平均包封效率分别为55.5% 和98.2%。使用Pluronic F127 (20% w/v) 和Pluronic F68 (1% w/v) 的组合成功地制备了含有RAL + EFV-NPs的热敏阴道凝胶。在凝胶中掺入RAL + efv-nps不会导致纳米颗粒聚集，并且含RAL + efv-nps的凝胶在32.5 °C下显示出热凝胶化。使用TZM-bl指示剂细胞评估RAL + EFV-NPs对HIV-1(NL4-3) 的抑制作用。RAL + EFV-NPs的EC(90) 低于雷替格拉韦 + 依非韦伦 (RAL + EFV) 溶液，但没有达到显著性。与未经任何处理的对照HeLa细胞相比，RAL + EFV-NPs或空白凝胶在体外14天内无细胞毒性。RAL + EFV-NPs处理的HeLa细胞中依非韦仑的细胞内水平在14天内高于EC(90)，而raltegravir细胞内浓度在6天内被消除。凝胶中NPs的Transwell实验表明，荧光纳米颗粒在30分钟内从凝胶中快速转移并在HeLa细胞中吸收。这些数据证明了抗逆转录病毒NP包埋的阴道凝胶对长期阴道暴露前预防异性HIV-1传播的潜力。

BACKGROUND & AIMS: :Thermosensitive injectable chitosan hydrogels can be formed by neutralization of acidic chitosan solutions with sodium betaglycerophosphate (Na-β-GP) coupled with increasing temperature to body temperature. Such hydrogels have been considered for applications in bone regeneration. In this study, chitosan hydrogels were enriched with glycerol and the enzyme alkaline phosphatase (ALP) with a view to improving their suitability as materials for bone tissue engineering. Mineral formation was confirmed by infrared spectroscopy (FTIR) and increases in the mass fraction of the hydrogel not consisting of water. Incorporation of ALP in hydrogels followed by incubation in a solution containing calcium ions and glycerophosphate, a substrate for ALP, led to formation of calcium phosphate within the hydrogel. MG-63 osteoblast-like cells were cultivated in eluates from hydrogels containing ALP and without ALP at different dilutions and directly on the hydrogel samples. Hydrogels containing ALP exhibited superior cytocompatibility to ALP-free hydrogels. These results pave the way for the use of glycerol- and ALP-enriched hydrogels in bone regeneration.

背景与目标： : 热敏性可注射壳聚糖水凝胶可以通过用 β 甘油磷酸钠 (Na-β-GP) 中和酸性壳聚糖溶液并增加温度至体温来形成。这种水凝胶已被考虑用于骨再生。在这项研究中，壳聚糖水凝胶富含甘油和碱性磷酸酶 (ALP)，以提高其作为骨组织工程材料的适用性。通过红外光谱 (FTIR) 确认了矿物的形成，并且不包含水的水凝胶的质量分数增加。将ALP掺入水凝胶中，然后在含有钙离子和甘油磷酸 (ALP的底物) 的溶液中孵育，导致在水凝胶中形成磷酸钙。MG-63成骨细胞样细胞在洗脱液中培养，从含有ALP和不含ALP的水凝胶在不同稀释度下，并直接在水凝胶样品上培养。含有ALP的水凝胶显示出优于无ALP水凝胶的细胞相容性。这些结果为在骨再生中使用富含甘油和ALP的水凝胶铺平了道路。

BACKGROUND & AIMS: BACKGROUND:Gene delivery to target cells is crucially important to establish gene therapy and regenerative medicine. Although various virus-based and synthetic molecule-based gene vectors have been developed to date, selective transfection in a site or a cell level is still challenging. For this study, both light-responsive and temperature-responsive synthetic gene vectors were designed for spatiotemporal control of a transfection system. METHODS:11-Mercaptoundecanoic acid-coated gold nanorods were mixed with polyamidoamine dendron-bearing lipids of two types having amino-terminus or ethoxydiethylene glycol-terminus to obtain hybrid vectors. Hybrid vectors were mixed further with pDNA. Then we investigated their physicochemical properties and transfection efficacy with or without near infrared laser irradiation. RESULTS:Hybrid vectors formed complexes with pDNA and exhibited enhanced photothermal property under near infrared laser irradiation compared with parent gold nanorods. Transfection efficacy of complexes was promoted considerably by brief laser irradiation soon after complex application to the cells. Analysis of intracellular distribution revealed that laser irradiation promoted the adsorption of complexes to the cells and cytosolic release of pDNA, which is derived from the change in surface hydrophobicity of complexes through dehydration of temperature-responsive groups. CONCLUSIONS:Hybrid vector is promising as a light-activatable transfection system.

背景与目标：

BACKGROUND & AIMS: :Most erythroleukemic cell lines established in vitro coexpress erythrocytic and megakaryocytic markers that often are associated with expression of Spi-1 and/or Fli-1 transcription factors known as transactivators of megakaryocyte-specific promoters. In the present study, we examined the possibility of establishing new cell lines keeping strictly erythroid-specific properties in vitro through the targeted and conditional immortalization of erythrocytic progenitors. For that purpose, we established several lines of transgenic mice displaying erythroid-specific expression of a thermosensitive SV40 T antigen. As expected, these transgenic mice developed splenomegaly due to the massive amplification of Ter 119 positive erythroid nucleated cells expressing T antigen. Despite this drastic effect in vivo, the in vitro immortalization of erythropoietin-dependent erythroid progenitors unexpectedly occurred at low frequency, and all four cell lines established expressed both erythrocytic (globins) and megakaryocytic markers (glycoprotein IIb, platelet factor 4) as well as Spi-1 and Fli-1 transcripts at permissive temperature. Switching the cells to the nonpermissive temperature led to a marked increase in globin gene expression and concomitant decrease in expression of Spi-1, Fli-1, and megakaryocytic genes in an erythropoietin-dependent manner. Interestingly, enhanced expression of Spi-1 and Fli-1 genes already was detected in the Ter 119 positive cell population of transgenic mice spleen in vivo. However, like normal Ter 119 erythroid cells, these Ter 119 positive cells from transgenic mice still expressed high levels of beta-globin and very low or undetectable glycoprotein IIb and platelet factor 4 megakaryocytic transcripts. Taken together, these data indicate that the unexpected expression of megakaryocytic genes is a specific property of immortalized cells that cannot be explained only by enhanced expression of Spi-1 and/or Fli-1 genes.

背景与目标： : 体外建立的大多数红白血病细胞系共表达红细胞和巨核细胞标记，这些标记通常与被称为巨核细胞特异性启动子的反式激活因子的Spi-1和/或Fli-1转录因子的表达相关。在本研究中，我们研究了通过红细胞祖细胞的靶向和条件永生化在体外建立严格保持红细胞特异性特性的新细胞系的可能性。为此，我们建立了几行显示热敏SV40 T抗原的红细胞特异性表达的转基因小鼠。如预期的那样，这些转基因小鼠由于表达T抗原的Ter 119阳性红系有核细胞的大量扩增而出现脾肿大。尽管在体内产生了这种巨大的作用，但促红细胞生成素依赖性红系祖细胞的体外永生化意外地以低频率发生，并且所建立的所有四种细胞系均表达红细胞 (球蛋白) 和巨核细胞标记物 (糖蛋白IIb，血小板因子4) 以及Spi-1和Fli-1转录本在允许的温度下。将细胞切换到非允许温度导致珠蛋白基因表达显着增加，并以促红细胞生成素依赖性方式伴随着Spi-1，Fli-1和巨核细胞基因的表达降低。有趣的是，在体内转基因小鼠脾脏的Ter 119阳性细胞群中已经检测到Spi-1和Fli-1基因的增强表达。然而，像正常的Ter 119红系细胞一样，这些来自转基因小鼠的Ter 119阳性细胞仍表达高水平的 β-珠蛋白和非常低或不可检测的糖蛋白IIb和血小板因子4巨核细胞转录物。综上所述，这些数据表明巨核细胞基因的意外表达是永生化细胞的特定特性，不能仅通过Spi-1和/或Fli-1基因的增强表达来解释。

BACKGROUND & AIMS: :Thermosensitive liposomes (TSL) in combination with regional hyperthermia represent a powerful tool for tumor specific drug delivery. The objective of this study was to investigate the influence of vesicle size on the biophysical properties of TSL. TSL were composed of DPPC/DSPC/1,2-dipalmitoyl-sn-glycero-3-phosphoglyceroglycerol (DPPG(2)) 50:20:30 (mol/mol) (DPPG(2)-TSL) and DPPC/P-Lyso-PC/DSPE-PEG2000 90:10:4 (mol/mol) (PEG/Lyso-TSL) with encapsulated fluorescent dye carboxyfluorescein, anticancer drug doxorubicin or magnetic resonance contrast agent gadodiamide. Extrusion was performed with polycarbonate filters of distinct pore size to obtain TSL with different diameters (50 to 200nm). Phase transition temperature (T(m)) of the bilayer forming phospholipids was not influenced by vesicle size in the tested range. However, vesicle size had a major impact on in vitro content release properties of TSL in the investigated temperature range between 30 and 45°C. Generally, vesicle size was inversely related to content release properties with increased content release rates for decreased vesicle sizes. Size dependency of content release properties varied between all tested formulations and DPPG(2)-TSL were generally less affected by size changes in the range of 100 to 150nm as compared to PEG/Lyso-TSL. Independent from gadodiamide release, vesicle size influenced the signal intensity of DPPG(2)-TSL also at temperatures below T(m) due to improved water exchange for smaller vesicles. Liposomes around 100nm in size are routinely used in vivo, hence a quality control for TSL preparations is required prior to use. Even small changes in size or a wider size distribution might affect stability and release properties and thus yield in decreased efficacy or unwanted side effects of drug loaded TSL during in vivo applications.

背景与目标： : 热敏脂质体 (TSL) 与局部热疗相结合是肿瘤特异性药物递送的强大工具。这项研究的目的是研究囊泡大小对TSL生物物理性质的影响。TSL由DPPC/DSPC/1，2-dipalmitoyl-sn-glycero-3-phosphoglyceroglycerol (DPPG(2)) 50:20:30 (mol/mol) (DPPG(2)-TSL) 和DPPC/P-lyso-pc/DSPE-PEG2000 90:10组成: 4 (mol/mol) (PEG/lyso-tsl) 用包封荧光染料羧基荧光素、抗癌药物阿霉素或磁共振对比剂加多二胺。用不同孔径的聚碳酸酯过滤器进行挤出，以获得不同直径 (50至200nm) 的TSL。在测试范围内，形成双层的磷脂的相变温度 (T(m)) 不受囊泡大小的影响。然而，在30至45 °C的研究温度范围内，囊泡大小对TSL的体外含量释放特性有重大影响。通常，囊泡大小与内容物释放特性成反比，随着囊泡大小减小，内容物释放速率增加。在所有测试的制剂之间变化的内容物释放性质的尺寸依赖性，与PEG/lyso-tsl相比，DPPG(2)-TSL通常受100至150nm范围内的尺寸变化的影响较小。与gadodiamide的释放无关，囊泡的大小在低于T(m) 的温度下也影响了DPPG(2)-TSL的信号强度，这是因为较小的囊泡的水交换得到了改善。体内常规使用大小约100nm的脂质体，因此在使用前需要对TSL制剂进行质量控制。即使尺寸的微小变化或较宽的尺寸分布也可能影响稳定性和释放特性，从而在体内应用过程中降低了载药TSL的功效或不想要的副作用。

BACKGROUND & AIMS: :The prognosis of peritoneal carcinomatosis is regarded as poor because safe, effective therapeutic modalities are lacking. Intraperitoneal chemotherapy is one treatment option, involving the delivery of a high concentration of chemotherapeutic drugs into the abdominal cavity, but the severe side effects associated with such treatment are a major obstacle in clinical application. We evaluated the anti-cancer effects of intraperitoneal delivery of a thermosensitive polymeric hydrogel containing chemotherapeutics in an animal model of carcinomatosis. The progress of peritoneal carcinomatosis, introduced by injecting a luciferase-transfected human gastric cancer cell line (HSC44Luc) into the peritoneal cavity of nude mice, was quantitatively evaluated by in vivo bioluminescence imaging. Three days after intraperitoneal (IP) injection of HSC44Luc cells, treatment solutions were injected into the peritoneal cavity. Mice were categorized into four groups depending on treatment method; these were (1) a control PBS group (n = 5), (2) a hydrogel-only group (n = 5), (3) a paclitaxel solution (30 mg/kg) group (n = 3), and (4) a hydrogel-with-paclitaxel (15 mg/kg) group (n = 5). Quantitative photon counting was performed weekly in each animal. Mice were sacrificed on the 5th or 28th day after treatment, for pathologic evaluation. In vivo bioluminescence imaging showed that photon counts in the hydrogel-with-paclitaxel and paclitaxel solution groups were significantly lower than in the PBS group over the entire experimental period. Although neither group of responding mice showed any peritoneal nodules on the 28th day after treatment, only the paclitaxel solution group exhibited dilated edematous changes in the intestine; these side effects were absent in animals treated with hydrogel-with-paclitaxel group. In conclusion, a thermosensitive hydrogel containing paclitaxel may be a safe and effective treatment option for peritoneal carcinomatosis.

背景与目标： : 由于缺乏安全，有效的治疗方式，因此认为腹膜癌的预后较差。腹腔化疗是一种治疗方法，包括将高浓度的化疗药物送入腹腔，但与此类治疗相关的严重副作用是临床应用的主要障碍。我们评估了在癌变动物模型中腹膜内递送含有化学疗法的热敏聚合物水凝胶的抗癌作用。通过体内生物发光成像定量评估了通过将荧光素酶转染的人胃癌细胞系 (HSC44Luc) 注射到裸鼠腹膜腔中引入的腹膜癌的进展。腹腔内 (IP) 注射HSC44Luc细胞后三天，将治疗溶液注入腹膜腔。根据治疗方法将小鼠分为四组; 分别是 (1) PBS对照组 (n   =   5)，(2) 仅水凝胶组 (n   =   5)，(3) 紫杉醇溶液 (30 mg/kg) 组 (n   =   3)，(4) 紫杉醇水凝胶 (15 mg/kg) 组 (n   =   5)。每周对每只动物进行定量光子计数。在治疗后第5天或第28天处死小鼠，以进行病理评估。体内生物发光成像显示，在整个实验期间，紫杉醇水凝胶和紫杉醇溶液组的光子计数显着低于PBS组。尽管两组应答小鼠在治疗后第28天均未显示任何腹膜结节，但只有紫杉醇溶液组在肠道中表现出扩张的水肿变化; 在用紫杉醇水凝胶组治疗的动物中没有这些副作用。总之，含有紫杉醇的热敏水凝胶可能是治疗腹膜癌的安全有效的选择。

BACKGROUND & AIMS: :Epilepsy is a disorder characterized by seizures and convulsions. The basis of epilepsy is an increase in neuronal excitability that, in some cases, may be caused by functional defects in neuronal voltage gated sodium channels (NaVs). The C121W mutation of the β1 subunit, in particular, gives rise to the thermosensitive generalized epilepsy with febrile seizures plus (GEFS+) phenotype. Lacosamide is used to treat epileptic seizures and is distinct from other anti-seizure drugs by targeting NaV slow-inactivation. We studied the effects of a physiologically relevant concentration of lacosamide on the biophysical properties of NaV1.2 channels associated with either WT-β1 or the mutant C121W-β1 subunit. Biophysical parameters were measured at both normal (22°C) and elevated (34°C) temperatures to elicit the differential temperature-sensitivity of C121W. Lacosamide was more effective in NaV1.2 associated with the WT-β1 than with C121W-β1 at either temperature. There is also a more potent effect by lacosamide on slow inactivation at elevated temperatures. Our data suggest a modulatory role is imparted by the β1 subunit in the interaction between the drug and the channel.

背景与目标： : 癫痫是一种以癫痫发作和抽搐为特征的疾病。癫痫的基础是神经元兴奋性的增加，在某些情况下，可能是由神经元电压门控钠通道 (NaVs) 的功能缺陷引起的。特别是 β1亚基的C121W突变会引起具有高热惊厥加 (GEFS) 表型的热敏性全身性癫痫。Lacosamide用于治疗癫痫发作，并通过靶向NaV慢灭活与其他抗癫痫药物不同。我们研究了生理相关浓度的lacosamide对与WT-β1或突变C121W-β1亚基相关的NaV1.2通道的生物物理特性的影响。在正常 (22 °C) 和高 (34 °C) 温度下均测量了生物物理参数，以引起C121W的不同温度敏感性。在任一温度下，Lacosamide在与WT-β1相关的NaV1.2中比与C121W-β1更有效。lacosamide在高温下对缓慢失活也有更有效的作用。我们的数据表明，β1亚基在药物与通道之间的相互作用中具有调节作用。

BACKGROUND & AIMS: :Recently, more and more alternative therapeutic methods have been used for the treatment of benign prostatic hyperplasia (BPH). We will report on therapeutic results with a new thermosensitive stent system (Memotherm). This wire mesh stent has been designed especially for urological purposes. It is made of Nitinol, a thermoreactive material, and gains its maximum expansion force al body temperature. Due to the properties of the material the stent is flexible and can adapt to the anatomical conditions of the prostatic part of the urethra. Because of individual variations in the length of the prostatic part of the urethra, the system is available in lengths from 2 to 8 cm. The knitted structure for the first time allows atraumatic removal. Between April, 1992, and September, 1993, we treated a total of 54 BPH patients with the stent system. Mean patient age was 76.1 +/- 7.6 years (61-98). Mean prostatic volume was 51.9 +/- 25 ml (20-150), and the length of the applicated stents was 32.3 +/- 9.5 mm (20-70). Patient selection for stent treatment was carried out with regard to the preoperative risk status of this patient group. Fourteen (26%) of the patients treated were able to micturate before operation; in 40 (74%) urinary drainage was accomplished by means of an indwelling catheter. Following stent application, 53 out of 54 patients were able to micturate. With the first group (preoperative voiding ability), maximum flow had increased from 4.5 ml/s to a mean of 15.8 ml/s, while residual urine volume had decreased from 194.4 ml to 11.8 ml and the AUA 6 Symptoms Score had improved from 24 points to 3.5 points 6 months after stent application. All differences were statistically significant (P < 0.02). With the second group (no preoperative voiding ability), the AUA 6 Symptoms Score had improved from 25 points to 3.9 points (P < 0.02) 6 months after the operation, at which time the mean maximum flow rate was 14.8 ml/s and residual urine volume 14.8 ml. There was no statistically significant difference between the patients who were able and those who were unable to micturate before operation. One case of epididymitis was the only major complication observed after stent placement. Frequent urgency symptoms (30 out of 54 patients; 55.5%) subsided after a mean period of 1 week. The Memotherm stent offers an interesting therapeutic alternative for BPH risk patients.

背景与目标： : 最近，越来越多的替代治疗方法已用于治疗良性前列腺增生 (BPH)。我们将报告新的热敏支架系统 (Memotherm) 的治疗结果。这种金属丝网支架是专门为泌尿外科目的设计的。它由镍钛诺 (一种热活性材料) 制成，并获得最大的膨胀力和体温。由于材料的特性，支架是柔性的，可以适应尿道前列腺部分的解剖条件。由于尿道的前列腺部分的长度的个体变化，该系统的长度为2至8厘米。针织结构首次允许无损伤去除。在1992年4月和1993年9月之间，我们总共用支架系统治疗了54例BPH患者。患者平均年龄为76.1 +/- 7.6岁 (61-98岁)。平均前列腺体积为51.9 +/-25毫升 (20-150)，应用支架的长度为32.3 +/-9.5毫米 (20-70)。根据该患者组的术前风险状况进行了支架治疗的患者选择。接受治疗的患者中有14名 (26% 名) 能够在手术前进行排尿; 在40名 (74% 名) 中，通过留置导管完成了尿液引流。支架应用后，54例患者中有53例能够排尿。对于第一组 (术前排尿能力)，最大流量从4.5毫升/s增加到平均15.8毫升/s，而残余尿量从194.4毫升减少到11.8毫升，AUA 6症状评分从24分提高到3.5分。支架应用6个月后。所有差异均有统计学意义 (P <0.02)。第二组 (无术前排尿能力)，术后6个月AUA 6症状评分从25分提高到3.9分 (P <0.02)，平均最大流量为14.8毫升/s，残余尿量14.8毫升。能够与术前无法排尿的患者之间没有统计学上的显着差异。1例附睾炎是支架置入后唯一观察到的主要并发症。平均1周后，频繁的紧急症状 (54例患者中有30例; 55.5% 例) 消退。Memotherm支架为BPH风险患者提供了一种有趣的治疗选择。

BACKGROUND & AIMS: By selecting variants of Chinese hamster cells that were resistant to 6-thioguanine at 39 degrees C, but which would continue to grow in HAT medium at 33 degrees C, we have isolated cell lines with thermosensitive phenotypes. These clones form colonies in HAT medium and incorporate 14-C-hypoxanthine much more efficiently at 33 degrees C than at 39 degrees C. The specific activity of hypoxanthine-guanine phosphoribo-syltransferase is at least 10 times higher in variant cells grown at 33 degrees C than in those grown in 39 degrees C, and the enzymes from the variant clones are inactivated in vitro at 39 degrees C 7-9 times more rapidly than is the enzyme from wild-type cells. The results are consistent with the conclusion that the selected clones have missense mutations in the structural gene for the enzyme.

背景与目标： 通过选择在39 ℃ 对6-硫鸟嘌呤具有抗性但在33 ℃ 的HAT培养基中继续生长的中国仓鼠细胞的变体，我们分离了具有热敏表型的细胞系。这些克隆在HAT培养基中形成菌落，并在33摄氏度下比在39摄氏度下更有效地掺入14-C-次黄嘌呤。在33 ℃ 下生长的变异细胞中，次黄嘌呤-鸟嘌呤磷酸核苷-syltranase的比活性比在39 ℃ 下生长的变异细胞高至少10倍，并且来自变体克隆的酶在39 ℃ 下在体外失活的速度比来自野生型细胞的酶快7-9倍。结果与所选克隆在该酶的结构基因中存在错义突变的结论一致。