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Oral GLP1 Gene Delivery by an Antibody-Guided Nanomaterial to Treat Type 2 Diabetes Mellitus.
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2020-08-05 , DOI: 10.1021/acsami.0c09814
Mohammad Nazmul Hasan 1 , Yong Hwa Hwang 2 , Jeong Man An 3 , S M Shatil Shahriar 3 , Sungpil Cho 2, 4 , Yong-Kyu Lee 1, 2, 3, 4
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2020-08-05 , DOI: 10.1021/acsami.0c09814
Mohammad Nazmul Hasan 1 , Yong Hwa Hwang 2 , Jeong Man An 3 , S M Shatil Shahriar 3 , Sungpil Cho 2, 4 , Yong-Kyu Lee 1, 2, 3, 4
Affiliation
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Type 2 diabetes mellitus (T2DM) is a chronic and progressive hyperglycemic condition. Glucagon-like peptide-1 (GLP1) is an incretin secreted from pancreatic β-cells and helps to produce insulin to balance the blood glucose level without the risk of hypoglycemia. However, the therapeutic application of GLP1 is limited by its intrinsic short half-life and rapid metabolic clearance in the body. To enhance the antidiabetic effect of GLP1, we designed a human cysteine-modified IgG1-Fc antibody-mediated oral gene delivery vehicle, which helps to produce GLP1 sustainably in the target site with the help of increased half-life of the Fc-conjugated nanocarrier, protects GLP1 from acidic and enzymatic degradation in the gastrointestinal (GI) tract, uptakes and transports the GLP1 formulation through the neonatal Fc receptor (FcRn), and helps to release the GLP1 gene in the intestine. Our formulation could reduce the blood glucose from about an average of 320 mg/dL (hyperglycemic) to 150 mg/dL (normal blood glucose concentration) in diabetic mice, which is about 50% reduction of the total blood glucose concentration. GLP1 (500 μg) complexed with the IgG1-Fc carrier was proven to be the optimal dose for a complete reduction of hyperglycemic conditions in diabetic mice. A significant amount of insulin production and the presence of GLP1 peptide were observed in the pancreatic islets of oral GLP1 formulation-treated diabetic mice in immunohistochemistry analysis compared to nontreated diabetic mice. The orally given formulation was completely nontoxic according to the histopathology analysis of mice organ tissues, and no mice death was observed. Our antibody-mediated oral gene delivery system is a promising tool for various oral therapeutic gene delivery applications to treat diseases like diabetes.
中文翻译：
通过抗体引导的纳米材料进行口服GLP1基因递送，以治疗2型糖尿病。
2型糖尿病（T2DM）是一种慢性和进行性高血糖症。胰高血糖素样肽1（GLP1）是胰岛β细胞分泌的肠降血糖素，有助于产生胰岛素来平衡血糖水平，而无低血糖风险。但是，GLP1的治疗应用受到其固有的短半衰期和体内快速代谢清除的限制。为了增强GLP1的抗糖尿病作用，我们设计了一种人半胱氨酸修饰的IgG1-Fc抗体介导的口服基因递送载体，其通过增加Fc缀合的纳米载体的半衰期来帮助在靶位点可持续产生GLP1。可以保护GLP1免受胃肠道（GI）中酸性和酶促降解的影响，并通过新生儿Fc受体（FcRn）吸收和运输GLP1制剂，并有助于在肠中释放GLP1基因。我们的制剂可以使糖尿病小鼠的血糖从平均320毫克/分升（高血糖）降低到150毫克/分升（正常血糖浓度），这相当于降低总血糖浓度约50％。事实证明，与IgG1-Fc载体复合的GLP1（500μg）是完全减轻糖尿病小鼠高血糖状况的最佳剂量。与未治疗的糖尿病小鼠相比，在口服GLP1制剂治疗的糖尿病小鼠的胰岛中观察到大量胰岛素产生和GLP1肽的存在。根据小鼠器官组织的组织病理学分析，口服制剂完全无毒，没有观察到小鼠死亡。
更新日期：2020-09-02
中文翻译：
通过抗体引导的纳米材料进行口服GLP1基因递送，以治疗2型糖尿病。
2型糖尿病（T2DM）是一种慢性和进行性高血糖症。胰高血糖素样肽1（GLP1）是胰岛β细胞分泌的肠降血糖素，有助于产生胰岛素来平衡血糖水平，而无低血糖风险。但是，GLP1的治疗应用受到其固有的短半衰期和体内快速代谢清除的限制。为了增强GLP1的抗糖尿病作用，我们设计了一种人半胱氨酸修饰的IgG1-Fc抗体介导的口服基因递送载体，其通过增加Fc缀合的纳米载体的半衰期来帮助在靶位点可持续产生GLP1。可以保护GLP1免受胃肠道（GI）中酸性和酶促降解的影响，并通过新生儿Fc受体（FcRn）吸收和运输GLP1制剂，并有助于在肠中释放GLP1基因。我们的制剂可以使糖尿病小鼠的血糖从平均320毫克/分升（高血糖）降低到150毫克/分升（正常血糖浓度），这相当于降低总血糖浓度约50％。事实证明，与IgG1-Fc载体复合的GLP1（500μg）是完全减轻糖尿病小鼠高血糖状况的最佳剂量。与未治疗的糖尿病小鼠相比，在口服GLP1制剂治疗的糖尿病小鼠的胰岛中观察到大量胰岛素产生和GLP1肽的存在。根据小鼠器官组织的组织病理学分析，口服制剂完全无毒，没有观察到小鼠死亡。
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