Virus-Mimicking Mesoporous Silica Nanoparticles with an Electrically Neutral and Hydrophilic Surface to Improve the Oral Absorption of Insulin by Breaking Through Dual Barriers of the Mucus Layer and the Intestinal Epithelium
Virus-Mimicking Mesoporous Silica Nanoparticles with an Electrically Neutral and Hydrophilic Surface to Improve the Oral Absorption of Insulin by Breaking Through Dual Barriers of the Mucus Layer and the Intestinal Epithelium
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具有电中性和亲水表面的病毒模拟介孔二氧化硅纳米颗粒，通过突破粘液层和肠上皮的双重屏障来改善胰岛素的口服吸收
DOI：
10.1021/acsami.1c00580
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发表时间：
2021
影响因子：
9.5
通讯作者：
Hu Haiyan
中科院分区：
文献类型：
--
作者：
Zhang Yi;Xiong Mengting;Ni Xiaomin;Wang Jingrou;Rong Hehui;Su Yuqing;Yu Shihui;Mohammad Imran Shair;Leung Sharon Shui Yee;Hu Haiyan
蛋白质和肽类药物口服具有极低的生物利用度，主要是因为复杂的胃肠道环境沿着难以通过粘液层和下面的上皮。在我们的工作中，我们制造了具有修饰基团（MSN-NH 2 @COOH/CPP 5）的介孔二氧化硅纳米颗粒，其通过模仿病毒表面有效地穿透粘液层并穿过肠上皮。制备裸纳米颗粒，其具有直径为6 nm的内孔以允许有效的胰岛素负载，并涂覆有阳离子细胞穿透KLPVM肽和阴离子葡聚糖酐以产生具有-0.49 mV的电势的亲水性MSN-NH 2 @COOH/CPP 5。模拟病毒纳米粒的表观渗透系数为14.61 × 10-5cm/s。与ζ-电位为+35.00 mV的带正电纳米颗粒（MSN@NH2）相比，病毒模拟纳米颗粒与粘蛋白的结合显着降低，并且对粘液层的渗透速度更快。通过共培养Caco-2和E12细胞作为肠上皮模型，KLPVM肽增强了MSN-NH 2 @COOH/CPP 5的摄取。MSN-NH 2 @COOH/CPP 5增强了顶端至基底的转胞吞作用，主要通过小窝介导的内吞作用内化。事实上，对于MSN-NH 2 @COOH/CPP 5，Caco-2细胞单层的跨上皮转运是MSN@NH2的2.4倍，是MSN-NH 2 @COOH的2.0倍。将胰岛素负载到MSN-NH 2@COOH/CPP 5中使糖尿病大鼠的血糖水平降低了近50%。当直接施用到空肠中时，封装在MSN-NH 2 @COOH/CPP 5纳米颗粒中的胰岛素的生物利用度是胰岛素的2.1倍。修饰后的纳米颗粒在体外和体内初步研究中没有明显的毒性。这些拟病毒纳米粒可有效克服粘液层和肠上皮的障碍，用于蛋白质和肽类药物的口服给药。
Protein and peptide drugs orally suffer from extremely low bioavailability principally for the complicated gastrointestinal environment along with the difficulty of passing through the mucus layer and the underlying epithelium. In our work, we fabricated mesoporous silica nanoparticles with modification groups (MSN-NH2@COOH/CPP5) that effectively penetrated the mucus layer and passed through the intestinal epithelium by mimicking the virus surface. Naked nanoparticles were prepared with inner pores of 6 nm diameter to allow efficient insulin loading and coated with the cationic cell-penetrating KLPVM peptide and the anionic glutaric anhydride to yield hydrophilic MSN-NH2@COOH/CPP5 with a ζ-potential of −0.49 mV. The apparent permeability coefficient of virus-mimicking nanoparticles was 14.61 × 10–5cm/s. The virus-mimicking nanoparticles showed dramatically lower binding to mucin and faster penetration of the mucus layer than positively charged nanoparticles (MSN@NH2) with a ζ-potential of +35.00 mV. The KLPVM peptide enhanced the uptake of MSN-NH2@COOH/CPP5 by coculturing Caco-2 and E12 cells as an intestinal epithelium model. MSN-NH2@COOH/CPP5 enhanced apical-to-basal transcytosis for being internalized primarily through caveolae-mediated endocytosis. Indeed, for MSN-NH2@COOH/CPP5, the transepithelial transport of the Caco-2 cell monolayer was 2.4-fold higher than MSN@NH2and 2.0-fold higher than MSN-NH2@COOH.In vitro, loading insulin into nanoparticles maintained the bioactivity of the protein under simulated intestinal conditions. Insulin loaded into MSN-NH2@COOH/CPP5 reduced the diabetic rats’ blood glucose level by nearly 50%. The bioavailability of insulin encapsulated in the MSN-NH2@COOH/CPP5 nanoparticles was 2.1-fold more than insulin when administered directly into the jejunum. Nanoparticles with modifications indicated no significant toxicity inin vitroorin vivopreliminary studies. The obstacles of the mucus layer and intestinal epithelium may be effectively conquered by these virus-mimicking nanoparticles for oral delivery of protein and peptide drugs.