目的 构建尺寸可变纳米递送系统PAMAM/DOX-pep并进行表征,检测其理化性质并评价其体外抗肿瘤效果与靶向性。方法 将阿霉素（DOX）物理包埋在阳离子聚合物PAMAM的疏水空腔内,以4-（N-马来酰亚胺基甲基）环己烷羧酸N-羟基琥珀酰亚胺酯（SMCC）作为交联剂,采用金属基质蛋白酶（MMP-2）敏感的多肽pep（CPLGVRGC）串联小粒径纳米颗粒形成大尺寸纳米递送系统（PAMAM/DOX-pep）,对各纳米颗粒的粒径、电位、理化性质以及对小鼠乳腺癌细胞（4T1）的抑制作用、细胞摄取效果和核靶向作用进行检测。结果 PAMAM/DOX粒径约为10 nm,载药率为23%,多肽pep交联后形成的PAMAM/DOX-pep粒径约为200 nm,可在低pH下缓释DOX,7天内体外保持稳定且溶血率低、安全无毒,其与MMP-2共孵育后细胞摄取量与核靶向性显著增加。结论 尺寸可变纳米颗粒有助于克服尺寸所引发的递送障碍,将药物靶向递送至乳腺癌细胞核内并发挥作用,为纳米递送系统的设计提供了新策略。

Objective To construct and characterize the size-variable nano-delivery system PAMAM/DOX-pep,examine its physicochemical properties and evaluate its antitumor and targeting effects in vitro. Methods Small particle size PAMAM/DOX was obtained by physically encapsulating DOX within the hydrophobic cavity of the cationic polymer PAMAM. The large size nano-delivery system(PAMAM/DOX-pep)was formed by tandem linking small size nanoparticles by MMP-2 sensitive peptide pep(CPLGVRGC)using SMCC as a cross-linker. The particle size,potential,physical and chemical properties,inhibitory effect,cell uptake and nuclear targeting effect of each nanoparticle on mouse breast cancer cells(4T1)were detected. Results The particle size of PAMAM/DOX was about 10 nm,and the drug loading rate was 23%. PAMAMAM/DOX-pep,formed after cross-linking of peptide,had a particle size of about 200 nm,which could release DOX slowly at low pH,and remained stable,safe and non-toxic in vitro for 7 days with low hemolysis rate,and its cellular uptake amount and nuclear targeting rate increased significantly after co-incubation with MMP. Conclusions Size-variable nanoparticles overcome size-induced delivery barriers to target and deliver drugs to the 4T1 nucleus,providing a new strategy for the design of nano delivery systems.

目的 制备以牛血清白蛋白为模型药物的壳聚糖纳米制剂(BAS/CS NPs)及其体内外性质的研究,并通过加入羧化壳聚糖(WCS)来改善聚阳离子制备的纳米粒(CS NPs)的安全性。方法 利用油包水乳化-冻干法制备而得的CS NPs,通过激光粒度分析仪测定纳米粒粒径和电荷,用BCA法测定纳米粒包封率和载药量,并用Caco-2 cells单层膜模型评价BAS/CS NPs的细胞摄取情况和跨膜转运,以Franz扩散池法考察吸收考察BAS/CS NPs的离体各个小肠段黏膜的渗透性能,采用荧光分光光度计测定累积渗透量。结果 所制备的BAS/CS NPs平均粒径 在100～500 nm之间,电荷(-42.32±2.56)mV,包封率为88.37±6.82(%),载药量7.48±0.50(%),细胞毒性和细胞摄取实验表明羧化壳聚糖的BAS/CS NPs能降低细胞的毒性,并发现在十二指肠纳米粒具有促进BSA吸收作用(P<0.05)。结论 BAS/CS NPs是通过打开细胞紧密连接的方式增加BSA在小肠内的吸收。WCS降低BAS/CS NPs的细胞毒性,增强了兔小肠的BSA运输。作用要优于广泛研究的聚阳离子纳米粒体系,为口服蛋白类药物的传递提供了新的渠道。

目的 探讨二甲双胍和胰高糖素样多肽-1对2型糖尿病患者并发骨折恢复的影响。方法 选取2016年5月—2017年4月我院骨科收治的2型糖尿病并发骨折患者120例,按随机原则分为5组,每组24例,单药低剂量二甲双胍组(A1)、单药高剂量二甲双胍组(A2)、单药GLP-1组(B)、低剂量二甲双胍联合GLP-1组(C1)和高剂量二甲双胍联合GLP-1组(C2)。二甲双胍低剂量用药量为0.5 g/次,每日2次口服,高剂量用药量为0.5 g/次,每日4次口服。皮下注射利拉鲁肽每日1次,起始量为每日0.6 mg,1周增加为每日1.2 mg,再1周后增加为每日1.8 mg。血糖控制在理想水平后按照标准的手术方法和规程行相应的手术治疗。同时给予饮食控制及其它对症治疗。分别在1、3、6个月时检测其股骨颈骨密度值(BMD)和Harris系统评分。结果 随着治疗时间延长,A1组、C1组、C2组BMD值和Harris系统评分均增高, 在术后3月和6月时,C1组骨密度值和Harris评分高于A1组(P<0.05), C1组骨密度值和Harris评分高于C2组(P<0.05)。结论 胰高糖素样多肽-1可促进2型糖尿病患者骨折愈合、功能恢复,且与低剂量二甲双胍联用促进骨折愈合效果优于与高剂量二甲双胍联用。

Objective To investigate the effects of metformin and glucagon like polypeptide -1 on fracture recovery in patients with type 2 diabetes mellitus(DM). Methods We selected 120 patients with type 2 diabetes mellitus from May 2016 to April 2017 in department of orthopedicsin in our hospital and randomly divided them into 5 groups, 24 cases in each group,includingthe low dose of metformin monotherapy group (A1), the high dose of metformin monotherapy group (A2), single drug GLP-1 group (B), and GLP-1 group low dose of metformin combination (C1) and high dose of metformin combination with GLP-1 group (C2). The low dose of metformin was 0.5 g / time, 2 times a day for oral administration. The high dose was 0.5 g / time, 4 times a day. Subcutaneous injection of liraglutide was once daily, starting at a daily dose of 0.6 mg, 1.2 mg daily after 1 week and 1.8 mg daily after another week. After an ideal level of blood glucose control, corresponding surgical procedures should be performed according to standard surgical methods and procedures. Diet control and other symptomatic treatments were also given. The femoral neck bone mineral density (BMD) and the Harris system score were examined at the first, third, and sixth month respectively. Results With the prolongation of treatment time, the BMD value and Harris system score in the A1 group, C1 group, C2 group were increased. After surgery in March and June, the BMD and Harris score of C1 group were higher than that of A1 group (P<0.05). The bone mineral density and Harris score of C1 group was significantly higher than that of group C2 (P<0.05). Conclusion Glucagon like peptide -1 may promote the fracture recovery and functional recovery in patients with type 2 diabetes mellitus, and with combination of low dose metformin is more effective than that with high dose metformin.