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浙大王立教授和俞豪杰教授团队 ACS AMI:用于糖尿病治疗的静电作用增强的葡萄糖响应胰岛素递送微针贴
2024-02-09  来源:高分子科技

  糖尿病是一种由于患者胰岛素分泌功能缺失或受损而导致的以高血糖为主要特征的代谢性疾病。根据国际糖尿病联合会的调查显示,全世界糖尿病患者的人数已超过5.37亿。目前对于I型和重症II型糖尿病的治疗需要每日注射2~4胰岛素以维持正常血糖水平,给患者带来注射疼痛和生活不便,同时由于无法按需要实时给予合适剂量的胰岛素,存在过量给药低血糖风险。葡萄糖响应微针贴可根据血糖水平自适应调节胰岛素释放速率,在糖尿病治疗领域受到广泛关注。


  浙江大学王立教授和俞豪杰教授团队长期从事葡萄糖响应胰岛素递送水凝胶及微针贴方面的研究。20237月他们团队通过亲疏水作用和静电作用设计了一种葡萄糖响应负载胰岛素纳米微粒并制备了胰岛素递送微针贴,实现了糖尿病大鼠模拟一日三餐进食条件下的血糖控制(ACS Appl. Mater. Interfaces 2023, 15, 31330-31343)。近日,他们报道了一种对葡萄糖浓度波动响应更灵敏、制备更简便、安全性更好的苯硼酸基葡萄糖响应凝胶微针贴ACS Appl. Mater. Interfaces 2024, 16, 4449-4461他们基于4-羧基-3-氟苯硼酸改性ε-聚赖氨酸(FPBA-PL)与聚乙烯醇(PVA)构建了动态苯硼酸酯键交联水凝胶网络,利用质子化后带正电的氨基对胰岛素的静电吸引和动态硼酸酯键解离对胰岛素释放的促进作用,可以通过调节水凝胶中氨基和动态苯硼酸酯键的含量优化胰岛素释放葡萄糖响应性(Figure 1),在糖尿病大鼠模拟一日三餐进食的条件下,单片微针贴能够实时维持其血糖在正常水平24小时 


Figure 1. (a) The formation of a MNP. (b) The glucose-responsive insulin-releasing mechanism and the corresponding influence factors. (c) The illustration for the blood-glucose regulating performance of a MNP.


  体外胰岛素释放实验结果表明,通过优化FPBA-PL/PVA比例以及FPBA-PLFPBA的接枝率显著提高了胰岛素释放的葡萄糖响应灵敏性(Figure 2)。 


Figure 2. The cumulative-releasing tests for FITC-INS-loaded (a) MNP-1, (b) MNP-2, (c) MNP-3, (d) MNP-4, (e) MNP-5 and (f) MNP-6. (g) The comparison result among MNP-i and the previously reported phenylborate-ester-crosslinked MNPs. (h) The INS-releasing performance of MNP-5 under the changing glucose concentrations. (i) The 11B spectra to study the formation of phenylborate esters. (j) The formation of the phenylborate esters. The data of (a)-(f) and (h) were shown as the means ± SD (n = 3).


  基于糖尿病大鼠模型考察了所得苯硼酸基葡萄糖响应凝胶微针贴GR-MNP的血糖控制性能(Figure 3)。结果表明,微针贴GR-MNP具有优异的透皮胰岛素递送和血糖控制能力。与直接注射胰岛素(INS组)或使用非葡萄糖响应微针贴的nGR-MNP组相比,GR-MNP组具有更加稳定和长效的血糖控制性能。在糖尿病大鼠模拟一日三餐进食的条件下,1GR-MNP微针贴就可以维持血糖浓度在正常范围内约24小时,血糖水平基本与对照组的健康大鼠相同。 


Figure 3. (a1) A piece of GR-MNP was inserted in the rat skin and fixed by the TegadermTM film. (a2) The photos of the microneedle-induced micro-pores (scale bar = 2 mm) and the trypan-blue-staining result. (a3) The H & E-staining section of the microneedle-inserted skin (scale bar = 50 μm). (b) The anti-hypoglycemia test on the healthy rats and (c) the corresponding analytic result. (d) The BGL-lowering test on the diabetic rats and (e) the corresponding plasma INS levels. (f) The IPGTT schedule, (g) the IPGTT results and (h) the corresponding analytic result. (i) The plasma-INS curves in IPGTT with the statistical analysis between “nGR-MNP” and “GR-MNP” and (j) the corresponding analytic result. (k) The BGL-controlling test under the mimic three-meal-per-day mode. All the data of (b)-(e) and (g)-(k) were shown as the means ± SD (n = 5). The statistical analyses were performed by two-tailed Student’s t-test. * < 0.05, ** P < 0.01 and *** P < 0.001.


  以上成果近期发表在ACS Applied Materials & Interfaces上,论文题为Electrostatic-interaction-aided microneedle patch for enhanced glucose-responsive insulin delivery 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教授。


  论文信息:ACS Appl. Mater. Interfaces 2024, 16, 4449-4461

  论文链接:https://doi.org/10.1021/acsami.3c16540

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