搜索:  
浙大王立教授和俞豪杰副教授团队 ACS AMI:用于模拟一日三餐血糖控制的葡萄糖响应纳米粒子及其微针贴
2023-07-08  来源:高分子科技

  糖尿病是一种以高血糖为主要特征的慢性疾病,型或严重的型糖尿病患者往往需要皮下注射胰岛素来维持血糖稳定。由于过量的胰岛素可能导致低血糖,甚至危及生命,因此每日通常需要分2~4次注射,给糖尿病患者的日常生活带来巨大不便。因此,设计具有葡萄糖响应性能的胰岛素递送体系,根据血糖浓度智能地控制胰岛素释放速率,对减少给药次数、方便患者生活具有重要意义。


  近日,浙江大学王立教授和俞豪杰副教授团队通过分子对接技术对配体与胰岛素的相互作用域进行可视化分析,发现胰岛素含有疏水氨基酸残基并带有负电荷,可以与疏水并带有正电荷的配体发生疏水相互作用和静电吸引作用。由此设计了一种葡萄糖响应苯硼酸基负载胰岛素纳米粒子,制备了相应的微针贴,实现了糖尿病大鼠模拟一日三餐条件下的血糖控制(Figure 1)。 


Figure 1. The designing process of glucose-responsive microneedle patch with enhanced insulin-loading capacity and blood-glucose regulating performance.


  本研究合成了6R/4-羧基-3-氟苯硼酸改性ε-聚赖氨酸,命名为PL-R(y/x)/FPBA(z/x) y/xz/x分别代表RFPBA基团的接枝率),其中6R基团分别带有不同亲水/疏水和不同电荷性质(不带电荷、带正电荷和带负电荷)(Figure 2)。胰岛素负载实验表明,基于烟酸(NA)构建的PL-NA(20%)/FPBA(38%)纳米粒子具有最优的胰岛素负载量(ILC)。通过NA引入的吡啶环具有疏水性,质子化后带有正电荷;NA是一种维生素,具有良好的生物安全性。 


Figure 2. (a) Self-assembly of polymers and the INS-loading process. (b) ILCs of the polymers under the feed ratio of 1 g/g. (c) ILCs of PL-NA/FPBA under the feed ratio of 1 g/g. (d) ILCs of PL-NA(20%)/FPBA(38%) under different feed ratios. (e) ILCs (average) of different polymeric carriers in the previous reports. The carriers were labeled according to their main chains, including βCD, Alg, pAsp, HA, CS, Dex, PLGA and αPL. The data of “PL” referred to ILC of PL-NA(20%)/FPBA(38%) under the feed ratio of 2 g/g. The data of (b)-(d) were shown as the means ± SD (n = 3).


  将负载胰岛素的PL-NA(20%)/FPBA(38%)纳米粒子(NANP)填充在聚乙烯吡咯烷酮微针贴中,构建了具有葡萄糖响应性能的负载纳米粒子微针贴(NA-MNP)。NA-MNP的微针形貌规整,针尖尖锐(Figure 3)。 


Figure 3. The photos and SEM images for (a-d) nNA-MNP and (e-h) NA-MNP. The scale bars were 0.4 mm for (a, e), 0.1 mm for (b, d, f, h) and 1 mm for (c, g).


  由于纳米粒子中疏水的FPBA基团通过结合葡萄糖形成相对亲水的FPBA基团/葡萄糖复合物,从而诱导纳米粒子溶胀释放胰岛素,在体外胰岛素释放实验中,NANPNA-MNP均表现出葡萄糖响应胰岛素释放性能(Figure 4)。 


Figure 4. (a) The reaction between NANP and glucose. (b) The glucose-responsive INS-releasing mechanism of INS/NANP and (c) the corresponding in-vitro cumulative-releasing profiles. (d) The glucose-responsive INS-releasing mechanism of NA-MNP and (e) the corresponding in-vitro cumulative-releasing profiles. The data of (c) and (e) were shown as the means ± SD (n = 3).


  基于糖尿病大鼠模型考察NA-MNP的血糖控制性能(Figure 5)。结果表明,NA-MNP具有透皮胰岛素递送的能力。相比直接注射胰岛素或使用非葡萄糖响应型的微针贴nNA-MNPNA-MNP避免严重低血糖的发生,可以在模拟一日三餐的条件下,单次使用一片NA-MNP就可以克服三次进餐导致的血糖波动,并将血糖浓度维持在正常范围内约24小时。 


Figure 5. (a) The applied MNP on a rat with the skin repairing test (scale bar = 2 mm) and the trypan-blue staining test. (b) The 8-hour BGL-lowering test and (c) the corresponding BGL-lowering speeds (n = 5). (d) The 8-hour curves of plasma INS and (e) the calculation results of AUC (n = 5). (f) The hypoglycemia-avoiding test and (g) the calculation results of AUCHealth control (n = 5). (h) The IPGTT results (n = 5). (i) The curves of plasma INS (n = 5). (j) The BGL-monitoring procedure and (k) the corresponding BGL curves under the “three-meal-per-day” mode (n = 5). The data of (b-i, k) were shown as the means ± SD. The statistical analyses were performed by two-tailed Student’s t-test. The t-test of (h) was applied between “nNA-MNP” and “NA-MNP”. * P < 0.05, ** P < 0.01 and *** < 0.001.


  以上成果近期发表在ACS Applied Materials & Interfaces上,论文题为Molecular-docking-guided design on glucose-responsive nanoparticles for microneedle fabrication and “three-meal-per-day” blood-glucose regulation。论文的第一作者为浙江大学化学工程与生物工程学院2018级博士研究生沈迪,通讯作者为浙江大学化学工程与生物工程学院俞豪杰副教授。


  论文信息:ACS Appl. Mater. Interfaces 2023, 15, 31330-31343

  论文链接:https://doi.org/10.1021/acsami.3c06483

版权与免责声明:中国聚合物网原创文章。刊物或媒体如需转载,请联系邮箱:info@polymer.cn,并请注明出处。
(责任编辑:xu)
】【打印】【关闭

诚邀关注高分子科技

更多>>最新资讯
更多>>科教新闻