糖尿病正成為越來越嚴重的公共健康問題，全球糖尿病患者總數已超過5億。I型和重癥II型糖尿病的治療離不開胰島素，精準控制胰島素的給藥劑量對患者的治療至關重要。劑量過低起不到理想的治療效果，過高將導致低血糖，可能危及患者生命，其中以夜間低血糖最為致命，約占糖尿病總致死人數的6%。目前主要采用分次注射胰島素的方法改善夜間低血糖問題，但是該方法需要人工調節注射的胰島素劑量，操作較為麻煩。因此，設計具有葡萄糖響應性能的胰島素遞送體系，根據血糖濃度實時自適應地控制胰島素的釋放對夜間血糖控制具有重要意義。
近日，浙江大學王立教授和俞豪杰副教授團隊受脂肪酸/白蛋白疏水相互作用的啟發，基于分子對接技術設計了一種脂肪酸與苯硼酸衍生物雙修飾的納米粒子用于胰島素負載與血糖濃度響應釋放，其設計思路如Figure 1所示。通過分子對接技術將脂肪酸基團片段與胰島素的相互作用域可視化，并結合數據分析發現隨脂肪酸基團鏈長增長，其與胰島素間的疏水作用變強（Figure 2），這有利于抑制胰島素的突釋行為，從而避免胰島素釋放過快導致的低血糖癥狀。
通過實驗驗證了正丁酸、正己酸、正辛酸、正癸酸和月桂酸對納米粒子自組裝行為的影響，發現脂肪酸基團鏈長適中時，納米粒子自組裝形貌更規整，有利于胰島素的負載（Figure 3）。制備了9種脂肪酸與苯硼酸衍生物雙修飾納米粒子并篩選出性能最優的納米粒子C10MS，其胰島素負載量為0.17 g胰島素/g載體。C10MS能抑制胰島素的突釋行為，表現出穩定的糖敏胰島素釋放性能。
Figure 3. SEM images of (a) C4MS, (b) C6MS, (c) C8MS, (d) C10MS and (e) C12MS and the schematic diagrams (bar = 500 nm).
Figure 4. The glucose-responsive insulin-releasing mechanism.
Figure 5. (a, b) The hypoglycemia-avoiding performances of the anti-diabetes agents evaluated on healthy rats with (c) the statistical analysis. (d, e) The 8-h hyperglycemia-ameliorating and hypoglycemia-avoiding performances of the anti-diabetes agents evaluated on diabetic rats with (f) the statistical analysis. (g) The 14-h hyperglycemia-ameliorating and hypoglycemia-avoiding performances. The data of “Diabetic control” were shown as the means ± SD (n = 3). The data of “Healthy control”, “C6MS”, “C8MS”, “C10MS”, “INS”, “Det-INS”, “INS(H) + Det-INS(L)” and “INS(L) + Det-INS(H)” were shown as the means ± SD (n = 5). The statistical analyses were performed by two-tailed Student''s t-test. * P < 0.05 and ** P < 0.01.
Figure 6. (a) The MTT assays and live-dead cell staining assays for CnMSs (n = 6, 8 and 10, scale bar = 200 μm). (b) The hemolysis tests for CnMS (n = 4, 6, 8, 10 and 12) and the routine blood test for C10MS. (c) The in vivo fluorescence test on diabetic rats by using Cy5-labeled C10MS. (d) Histological analyses of C10MS on hearts, livers, spleens, lungs, and kidneys (scale bar = 100 μm). The data of MTT assays were shown as the means ± SD (n = 6). The data of hemolysis tests were shown as the means ± SD (n = 3). The data of the routine blood test were shown as the means ± SD (n = 4).
論文鏈接：https://doi.org/10.1016/j.jconrel.2022.10.044
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