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浙大王立教授和俞豪杰副教授團隊 ACS AMI:用于模擬一日三餐血糖控制的葡萄糖響應納米粒子及其微針貼
2023-07-08  來源:高分子科技

  糖尿病是一種以高血糖為主要特征的慢性疾病,型或嚴重的型糖尿病患者往往需要皮下注射胰島素來維持血糖穩(wěn)定。由于過量的胰島素可能導致低血糖,甚至危及生命,因此每日通常需要分2~4次注射,給糖尿病患者的日常生活帶來巨大不便。因此,設計具有葡萄糖響應性能的胰島素遞送體系,根據(jù)血糖濃度智能地控制胰島素釋放速率,對減少給藥次數(shù)、方便患者生活具有重要意義。


  近日,浙江大學王立教授和俞豪杰副教授團隊通過分子對接技術(shù)對配體與胰島素的相互作用域進行可視化分析,發(fā)現(xiàn)胰島素含有疏水氨基酸殘基并帶有負電荷,可以與疏水并帶有正電荷的配體發(fā)生疏水相互作用和靜電吸引作用。由此設計了一種葡萄糖響應苯硼酸基負載胰島素納米粒子,制備了相應的微針貼,實現(xiàn)了糖尿病大鼠模擬一日三餐條件下的血糖控制(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-聚賴氨酸,命名為PL-R(y/x)/FPBA(z/x) y/xz/x分別代表RFPBA基團的接枝率),其中6R基團分別帶有不同親水/疏水和不同電荷性質(zhì)(不帶電荷、帶正電荷和帶負電荷)(Figure 2)。胰島素負載實驗表明,基于煙酸(NA)構(gòu)建的PL-NA(20%)/FPBA(38%)納米粒子具有最優(yōu)的胰島素負載量(ILC)。通過NA引入的吡啶環(huán)具有疏水性,質(zhì)子化后帶有正電荷;NA是一種維生素,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).


  將負載胰島素的PL-NA(20%)/FPBA(38%)納米粒子(NANP)填充在聚乙烯吡咯烷酮微針貼中,構(gòu)建了具有葡萄糖響應性能的負載納米粒子微針貼(NA-MNP)。NA-MNP的微針形貌規(guī)整,針尖尖銳(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).


  由于納米粒子中疏水的FPBA基團通過結(jié)合葡萄糖形成相對親水的FPBA基團/葡萄糖復合物,從而誘導納米粒子溶脹釋放胰島素,在體外胰島素釋放實驗中,NANPNA-MNP均表現(xiàn)出葡萄糖響應胰島素釋放性能(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)。結(jié)果表明,NA-MNP具有透皮胰島素遞送的能力。相比直接注射胰島素或使用非葡萄糖響應型的微針貼nNA-MNP,NA-MNP避免嚴重低血糖的發(fā)生,可以在模擬一日三餐的條件下,單次使用一片NA-MNP就可以克服三次進餐導致的血糖波動,并將血糖濃度維持在正常范圍內(nèi)約24小時。 


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.


  以上成果近期發(fā)表在ACS Applied Materials & Interfaces上,論文題為Molecular-docking-guided design on glucose-responsive nanoparticles for microneedle fabrication and “three-meal-per-day” blood-glucose regulation。論文的第一作者為浙江大學化學工程與生物工程學院2018級博士研究生沈迪,通訊作者為浙江大學化學工程與生物工程學院俞豪杰副教授。


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

  論文鏈接:https://doi.org/10.1021/acsami.3c06483

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