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  糖尿病正成為越來(lái)越嚴(yán)重的公共健康問(wèn)題，全球糖尿病患者總數(shù)已超過(guò)5億。I型和重癥II型糖尿病的治療離不開(kāi)胰島素，精準(zhǔn)控制胰島素的給藥劑量對(duì)患者的治療至關(guān)重要。劑量過(guò)低起不到理想的治療效果，過(guò)高將導(dǎo)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(shù)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(wèn)題，但是該方法需要人工調(diào)節(jié)注射的胰島素劑量，操作較為麻煩。因此，設(shè)計(jì)具有葡萄糖響應(yīng)性能的胰島素遞送體系，根據(jù)血糖濃度實(shí)時(shí)自適應(yīng)地控制胰島素的釋放對(duì)夜間血糖控制具有重要意義。

  近日，浙江大學(xué)王立教授和俞豪杰副教授團(tuán)隊(duì)受脂肪酸/白蛋白疏水相互作用的啟發(fā)，基于分子對(duì)接技術(shù)設(shè)計(jì)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(fù)載與血糖濃度響應(yīng)釋放，其設(shè)計(jì)思路如Figure 1所示。通過(guò)分子對(duì)接技術(shù)將脂肪酸基團(tuán)片段與胰島素的相互作用域可視化，并結(jié)合數(shù)據(jù)分析發(fā)現(xiàn)隨脂肪酸基團(tuán)鏈長(zhǎng)增長(zhǎng)，其與胰島素間的疏水作用變強(qiáng)（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(guò)快導(dǎo)致的低血糖癥狀。

  通過(guò)實(shí)驗(yàn)驗(yàn)證了正丁酸、正己酸、正辛酸、正癸酸和月桂酸對(duì)納米粒子自組裝行為的影響，發(fā)現(xiàn)脂肪酸基團(tuán)鏈長(zhǎng)適中時(shí)，納米粒子自組裝形貌更規(guī)整，有利于胰島素的負(fù)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(yōu)的納米粒子C10MS，其胰島素負(fù)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(xiàn)出穩(wěn)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