N-琥珀酰壳聚糖纳米粒肿瘤靶向性及抗肿瘤活性评价

目的 评价N-琥珀酰壳聚糖纳米粒(Suc-Chi/NPs)肿瘤靶向性,考察5-氟尿嘧啶-N-琥珀酰壳聚糖纳米粒(5-FU-Suc-Chi/NPs)抗肿瘤活性。方法 建立异硫氰基荧光素(FITC)-Suc-Chi/NPs的体内荧光分析方法,检测Suc-Chi/NPs在Sarcoma 180-荷瘤小鼠体内组织分布数量。采用荧光显微镜观察FICT-Suc-Chi/NPs在组织切片中蓄积量,评价FICT-Suc-Chi/NPs肿瘤靶向性;以Suc-Chi/NPs、5-FU注射液为对照,考察5-FU-Suc-Chi/NPs在Sarcoma 180-荷瘤小鼠体内的瘤体积抑制率及对荷瘤小鼠体重的影响,评价制剂的疗效及不良反应。结果 FICT-Suc-Chi/NPs能够长时间的滞留在血液中,在各组织及血浆中分布的数量次序依次为肾>肿瘤>血液>肝>脾>肺。5-FU-Suc-Chi/NPs与5-FU注射液相比较,能够更有效地抑制Sarcoma 180肿瘤的生长,而且组织毒性较温和。结论 研究表明N-琥珀酰壳聚糖纳米粒具有长循环特性,能够实现实体肿瘤靶向传递;以N-琥珀酰壳聚糖为载体包载抗肿瘤模型药纳米粒具有较高抗肿瘤活性及较低的毒性。     

5-氟尿嘧啶-N-琥珀酰壳聚糖纳米粒体外释药机理探讨

本课题设计以N-琥珀酰壳聚糖（Suc-Chi）[1]作为包载抗肿瘤模型药5-FU的载体制备用于肿瘤靶向传递的纳米粒。在前面的研究中,我们采用乳化溶剂扩散法成功的制备了5-FU-Suc-Chi/NPs[2]。本文在此研究基础上将采用Origin7.5软件对5-FU-Suc-Chi/NPs溶液释药数据进行拟合,从而确定药物释放模型。     

分子参数对5-氟尿嘧啶-N-琥珀酰壳聚糖纳米粒理化性质的影响

目的：考察5-氟尿嘧啶-N-琥珀酰壳聚糖纳米粒（5-FU-Suc-Chi/NPs）理化性质影响因素。方法：采用乳化溶剂挥发法制备5-FU-Suc-Chi/NPs并考察其理化性质的影响因素。结果：5-FU-Suc-Chi/NPs的粒径、Zeta电位、包封率及载药量的大小与N-琥珀酰壳聚糖的取代度（DS）和分子量（Mw）有关。结论：N-琥珀酰壳聚糖的分子参数是影响5-FU-Suc-Chi/NPs理化性质的重要因素。     

5-氟尿嘧啶-N-琥珀酰壳聚糖纳米粒冻干粉针制备

目的:考察5-氟尿嘧啶-N-琥珀酰壳聚糖纳米粒(5-FU-Suc-Chi/NPs)稳定性,制备纳米粒冻干粉针.方法:采用乳化溶剂挥发法制备5-FU-Suc-Chi/NPs;考察纳米粒溶液稳定性;优化纳米粒冻干粉针处方.结果:选定12%的甘露醇为5-FU-Suc-Chi/NPs的支架剂,制备纳米粒冻干粉.结论:5-FU-...     

5-氟尿嘧啶-N-琥珀酰壳聚糖纳米粒在荷瘤小鼠体内组织分布分析方法

目的:建立5-氟尿嘧啶-N-琥珀酰壳聚糖纳米粒(5-FU-Suc-Chi/NPs)在荷瘤小鼠血浆和组织中高效液相色谱(HPLC)分析方法。方法:生物样品经甲醇沉淀蛋白质并提取药物,采用HPLC法测定药物含量。色谱柱:Hypersil ODS C18(4.6mm×200mm,5μm);流动相:水-甲醇(99∶1)以磷酸调pH值6.2;流速:0.8mL.min-1;紫外检测波长:266nm;柱温:室温;进样量:20μL;内标:利巴韦林。结果:该方法线性范围为0.1~10mg.L-1,线性关系良好(r2=0.993 2~0.997 9),方法回收率、日内和日间精密度的RSD均小于15%。结论:该分析方法灵敏性、准确性较高,适用于5-FU-Suc-Chi/NPs荷瘤小鼠肿瘤靶向性及药动学研究。     

抗HER2/neu受体拟肽修饰的紫杉醇白蛋白纳米粒的血液毒性和病理学毒性研究（英文）

纳米制剂具备高载药量、靶向性积聚以及表面修饰性质,被广泛应用于临床诊断和治疗,但是相关的毒性研究很少。为了研究白蛋白纳米制剂静脉注射后对正常组织的毒性,我们先通过高压均质法制备稳定、均一的紫杉醇白蛋白纳米粒,通过共价键将靶向肿瘤细胞HER2/neu受体的拟肽AHNP结合于纳米粒表面得到靶向修饰的纳米粒,并考察其理化性质。建立HER2受体过表达的荷瘤裸小鼠模型,静脉注射纳米制剂和紫杉醇传统注射液后取血进行血常规比较分析,发现紫杉醇白蛋白纳米粒和AHNP靶向修饰的紫杉醇白蛋白纳米粒均避免了传统注射液引起的粒细胞减少症和贫血作用。对动物肿瘤和重要组织进行病理切片、H&E染色分析,发现AHNP靶向修饰显著提高紫杉醇白蛋白纳米粒的抗肿瘤效果。紫杉醇白蛋白纳米粒和紫杉醇溶液均引起严重的肝损伤,AHNP靶向修饰能显著降低纳米粒对于肝脏的损伤,但可能增加个别动物的肺部损伤。     

N-(2-羟丙基)甲基丙烯酰胺聚合物-5-氟尿嘧啶接合物的体外释药规律、体内分布及抗肿瘤活性研究

考察本实验室合成的N-(2-羟丙基)甲基丙烯酰胺[N-(2-hydroxypropyl)methacrylamide,HPMA]聚合物-5-氟尿嘧啶(5-flurouracil,5-FU)接合物(P-FU)的体外释药、体内分布及抗肿瘤活性。以小鼠血浆为介质,考察P-FU中5-FU的释放规律;以小鼠H22肝癌实体瘤模型(皮下型)为肿瘤模型,考察接合物在荷瘤小鼠体内的分布情况、药代动力学规律及抑瘤活性。结果表明,37℃时P-FU在小鼠血浆中具有一定的稳定性,半衰期(t1/2)为32.4 h。与5-FU相比,P-FU在荷瘤小鼠体内的循环时间明显延长(血浆中t1/2为原药的166倍),在肿瘤中的沉积量(AUC为5-FU的3.3倍)及滞留时间(t1/2为5-FU的2.3倍)均有明显增加。体内药效学研究表明,P-FU组对荷瘤小鼠的肿瘤生长抑制率(69.09%)显著高于5-FU组(56.49%,P<0.05),瘤块组织病理学观察结果也显示P-FU组小鼠肿瘤组织中细胞凋亡程度大于5-FU组。HPMA聚合物可被用于为5-FU构建一种新型实体瘤高分子给药系统。     

N-琥珀酰壳聚糖纳米粒的制备及体外评价

目的制备N-琥珀酰壳聚糖纳米粒并对其进行体外评价。方法采用乳化溶剂挥发法制备N-琥珀酰壳聚糖纳米粒;以包封率、载药量及粒径为指标,采用正交设计法对处方进行优化;考察其理化特征及体外释药行为。结果纳米粒包封率及载药量分别为62.36%和18.98%,平均粒径及zeta电位分别为(206.6±64.7)nm和(-27.2±0.2)mV;1 h药物释放达到45%,随后药物的释药行为是一个缓释过程。结论作者采用乳化溶剂挥发法成功制得N-琥珀酰壳聚糖纳米粒。该方法制得纳米粒包封率较高,制备工艺简单。     

乙酰半胱氨酸纳米粒的制备及在小鼠体内的分布

以壳聚糖为载体,溶剂扩散法制备乙酰半胱氨酸纳米粒,制得的纳米粒呈大小均匀的球形,平均粒径(163.0±12.8)nm,包封率(81.2+1.2)%,载药量(28.9+0.4)%。用HPLC法测定了小鼠单剂量尾静脉注射乙酰半胱氨酸纳米粒或其注射液后各脏器(心、肝、脾、肺和肾)和血浆中的药物浓度,并以相对摄取量和靶向效率评价纳米粒的靶向性。结果表明,纳米粒明显改变了药物在小鼠体内的生物分布。与注射液组相比,纳米粒组在肝组织中乙酰半胱氨酸浓度明显提高,血浆、心和肾组织中的药物浓度显著降低。     

骆驼蓬生物碱壳聚糖纳米粒在小鼠体内的组织分布

目的:研究骆驼蓬生物碱壳聚糖纳米粒在小鼠体内的组织分布情况。方法:采用离子交联法制备骆驼蓬生物碱壳聚糖纳米粒。80只KM小鼠随机均分为溶液(骆驼蓬生物碱壳聚糖溶液,10 mg/kg)组与纳米粒(骆驼蓬生物碱壳聚糖纳米粒,10 mg/kg)组,尾静脉注射给药,于给药0.083、0.17、0.5、1、1.5、2、4、8 h时取样,以高效液相色谱法测定小鼠不同时间脑、心、肝、脾、肺、肾的药物质量浓度,并计算制剂的靶向性参数。结果:制备的骆驼蓬生物碱壳聚糖纳米粒粒度分布范围为63²31 nm,纳米粒外观形态饱满、表面光滑、分散性良好,无粘连现象。小鼠脑的相对摄取率为2.46,脑组织峰浓度比值为2.38;靶向效应最大值为2.845,靶向效应最小值为1.337。结论:骆驼蓬生物碱壳聚糖纳米粒在小鼠体内具有较明显脑靶向性。     

Nanoparticles of 5-fluorouracil (5-FU) loaded N-succinyl-chitosan (Suc-Chi) for cancer chemotherapy: preparation, characterization--in-vitro drug release and anti-tumour activity

N-Succinyl-chitosan has favourable properties as a drug carrier, such as biocompatibility, low toxicity and long-term retention in the body. It is a good candidate for cancer chemotherapy as a polymeric drug carrier. This study describes the preparation and characterization of 5-fluorouracil-loaded N-succinyl-chitosan nanoparticles (5-FU-Suc-Chi/NP) by an emulsification solvent diffusion method. The influence of the initial 5-FU concentration on the nanoparticle characteristics and release behaviour in phosphate-buffered saline solution (PBS) was evaluated. The Suc-Chi nanoparticles had a particle diameter (Z-average) in the range 202 approximately 273 nm and a negative zeta-potential (approx. -27 to -18 mV). The formulation with an initial 5-FU concentration of 1000 microg mL-1 provided the highest loading capacity (19%) and the highest extent of release (61% at 24 h). The 5-FU-Suc-Chi/NP showed good anti-tumour activity against Sarcoma 180 solid tumour and mild toxicity. According to the data obtained, this Suc-Chi-based nanotechnology opens new and interesting perspectives for cancer chemotherapy.     

Characterization and anti-tumor activity of pollen polysaccharide

The polysaccharide LBPP was extracted and isolated from the pollen of Brassica napus L., and the anti-tumor activity was evaluated on Sarcoma 180-bearing mice and B16 melanoma-bearing mice through transplantable animal tumor. Mice were treated with three doses of the polysaccharide LBPP (50, 100 and 200 mg/kg body weight) for 10 days. Tumor weight, relative spleen and thymus weight, lymphocyte proliferation, natural killer cell activity, delayed type hypersensitivity (DTH), phagocytic function of monocyte, serum hemolysis antibody and peripheral blood of tumor-bearing mice were studied. At the doses of 100 and 200 mg/kg, a significant decrease (P<0.01) in tumor formation, a significant increase (P<0.05) in relative spleen and thymus weight, natural killer cell activity, phagocytic function of monocyte, lymphocyte proliferation, and serum hemolysis antibody, and a significant improvement of peripheral blood abnormality (P<0.05) and anemia (P<0.01) were observed. Results of these studies demonstrated that the polysaccharide LBPP had anti-tumor activity, which was mediated by immunomodulation and leukogenic and antianemic actions.     

Modulation of 5-fluorouracil metabolism by thymidine. In vivo and in vitro studies on RNA-directed effects in rat liver and hepatoma

The effects of thymidine (TdR) co-administration on the cytotoxicity and incorporation of 5-fluorouracil (5-FU) into RNA of various tissues was studied in rats bearing an ascites hepatoma (AH 130). The role of pyrimidine degradation in determining the modulating effects of TdR on the formation of FU-RNA was studied in hepatocytes and AH 130 cells in vitro. TdR (500 mg/kg) potentiated the antitumour effect of 5-FU (150 mg/kg) and also increased host toxicity as judged by changes in body weight. TdR given alone did not significantly affect tumour growth and body weight gain. Examination of the effect of TdR on the incorporation of 5-FU into RNA revealed a differential modulation of RNA-directed toxicity in different tissues. Incorporation of 5-FU into RNA in tumour and bone marrow was increased 2- and 4-fold, respectively. In spleen and kidney the incorporation increased by approximately 50%, but the values did not reach statistical significance. In contrast, the incorporation into RNA of liver and intestinal mucosa was decreased to ca 35% of the control. TdR at concentrations of 40 microM-40 mM progressively inhibited the degradation of 5-FU and decreased the incorporation of 5-FU into RNA of hepatocytes in vitro. In AH 130 cells in vitro TdR did not significantly influence the metabolism of 5-FU and the incorporation into RNA. These results demonstrate that the enhanced incorporation of 5-FU into tumour RNA in vivo after pretreatment with TdR is related not to local effects on the tumour cells but rather to an increased bioavailability of the drug. Although co-administration of TdR did not selectively enhance the antitumour effect of 5-FU, a differential toxicity in host tissues was indicated by the modulated incorporation of 5-FU into RNA.     

Pharmacological and toxicological studies on new Rh(I) organometallic complexes.

New rhodium(I) complexes, belonging to the general structure [Rh(CO)2 (L)], where dithiocarbamate and xanthate derivatives, were synthesized and assayed as cytostatic and antitumour agents in vitro against KB cells and in vivo against P388 leukaemia, Ehrlich ascites carcinoma, Sarcoma 180 ascites and ADJ/PC6A solid tumour. Assays against five trypanosoma strains were also performed. Among the new compounds the [Rh(CO)2 (DPA-dtc)] appeared to be active in all biological systems without showing evident nephrotoxicity.     

Characterization and antitumor activity of pollen polysaccharide

The polysaccharide LBPP was extracted and isolated from the pollen of brassica napus L., and the antitumor activity was evaluated on Sarcoma 180-bearing mice and B16 melanoma-bearing mice through transplantable animal tumor. Mice were treated with three doses of the polysaccharide LBPP (50, 100 and 200 mg/kg body weight) for 10 days. Tumor weight, relative spleen and thymus weight, lymphocyte proliferation, natural killer cell activity, delayed type hypersensitivity (DTH), phagocytic function of monocyte, serum hemolysis antibody and peripheral blood of tumor-bearing mice were studied. At the doses of 100 and 200 mg/kg, a significant decrease (P<0.01) in tumor formation, a significant increase (P<0.05) in relative spleen and thymus weight, natural killer cell activity, phagocytic function of monocyte, lymphocyte proliferation, and serum hemolysis antibody, and a significant improvement of peripheral blood abnormality (P<0.05) and anemia (P<0.01) were observed. Results of these studies demonstrated that the polysaccharide LBPP had anti-tumor activity, which was mediated by immunomodulation and leukogenic and antianemic actions.     

枸杞多糖联合氟尿嘧啶对荷瘤小鼠免疫功能影响的实验研究

目的探讨枸杞多糖单独应用及与氟尿嘧啶联合应用于荷S180小鼠的抗肿瘤机制。方法小鼠右前侧腋窝接种S180肿瘤细胞,制造荷瘤小鼠模型。实验分为生理盐水组、氟尿嘧啶组、枸杞多糖高、中、低剂量组以及枸杞多糖加氟尿嘧啶组。实验结束后,检测各干预组脾指数、瘤重、肿瘤抑制率,MTT法检测淋巴细胞增殖反应、LDH检测NK细胞毒作用及中性红实验评估巨噬细胞吞噬能力,Griess法检测NO浓度,ELISA法测定TNF-α水平。结果枸杞多糖抑制荷S180小鼠肿瘤生长,刺激脾细胞增殖反应,提高NK细胞细胞毒效应以及巨噬细胞吞噬能力,刺激巨噬细胞NO分泌量,提高血清TNF-α水平。与氟尿嘧啶联合应用降低了氟尿嘧啶导致的免疫系统损伤。结论枸杞多糖可能是化疗药物的有效辅助药物。     

硫酸壳聚糖体内抗肿瘤作用的实验研究

目的：研究硫酸壳聚糖的体内抗肿瘤作用。方法：用高、低（200、100mg/kg）两个剂量的硫酸壳聚糖分别腹腔注射治疗肉瘤180（S180）小鼠和艾氏腹水癌（EAC）小鼠10d,然后测定其抑瘤率、重要器官的内脏指数和生命延长率,同时设生理盐水组（空白对照组）和氟尿嘧啶组（阳性对照组）进行比较。结果：硫酸壳聚糖高、低剂量组和氟尿嘧啶组的抑瘤率分别为38.67%、30.19%和43.27%,3组的生命延长率分别为65.38%、69.23%和54.93%。和生理盐水组、氟尿嘧啶组相比,硫酸壳聚糖高、低剂量组的S180小鼠的胸腺指数均有明显增加（P〈0.05）。结论：硫酸壳聚糖能有效抑制S180小鼠肿瘤的生长和延长EAC小鼠的生存时间,其作用机制可能与其提高机体的免疫力有关。