一种新的胰高血糖素样肽-1类似物及其缓释技术的研究
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摘要
胰高血糖素样肽-1(glucagon-like peptide-1, GLP-1)是由肠道L细胞分泌的一种肠肽激素,具有多种生理功能,有显著的血糖浓度依赖的刺激胰岛素分泌作用,可以降低空腹和餐后血糖,在2型糖尿病的临床治疗中具有较好的应用前景。但由于GLP-1在体内半衰期很短,被二肽基肽酶-Ⅳ(DPP-IV)的快速降解和肾脏代谢作用,使其临床应用受到了很大限制。因此,开发更稳定的新型GLP-1类似物或缓释制剂,延长其体内有效作用时间已成为近年来关注的热门课题。
本文首先构建纤维素结合域(CBD)与链霉亲和素(SA)的融合蛋白,制备了表而生物偶联SA的纤维素磁性微球(SA-CBD-MCMS),通过生物素(biotin)结合的Oligo(dT),建立了从细胞或组织中快速提取mRNA的方法,并从大鼠胰腺中提取mRNA,克隆了大鼠GLP-1受体(GLP-1R)。并将含有GLP-1 R基因的重组表达载体pcDNA3.1(+)/GLP-]R转染含有增强型绿色荧光蛋白(EGFP)报告基因的CHO/EGFP细胞,经抗性筛选、流式细胞分选和功能性分析,得到了稳定转染的细胞系CHO/EGFP/GLP-1R。该功能性报告基因细胞分析系统可以剂量依赖性的通过EGFP表达,对GLP-1 R激动剂的体外活性进行定性定量分析,为研究、开发和评价长效GLP-1类似物奠定了基础。
本研究创新性地合成了含有31个氨基酸的新的GLP-1类似物KGLP-1,其结构是在天然GLP-1(7-37)酰胺的N端添加一个赖氨酸(Lys)。利用上述CHO/RGFP/GLP-1R细胞评价体系及自制DPP-IV粗酶液对KGLP-1的体外活性和稳定性进行分析。结果显示,KGLP-1能以剂量依赖的方式激活GLP-1 R,其EC50值(2.44 nmol/L)与天然GLP-1 (0.83 nmol/L)相比略有升高：但KGLP-1具有显著的抗DPP-Ⅳ降解作用,与DPP-Ⅳ粗提物作用12h后仍能保持80%的活性。进步体内活性分析结果表明,KGLP-1能以剂量依赖的方式显著降低小鼠体内的血糖水平,在同等剂量下,给药2h后仍具有明显的降血糖和促胰岛素分泌作用,而天然GLP-1在给药1h后活性即消失。在糖尿病模型小鼠实验中,KGLP-1也同样显示出了明显的降血糖作用(p<0.01)。
为了改善KGLP-1的肾脏清除,本研究制备了KGLP-1与HSA的融合蛋白KGLP-1/HSA,并对其体内外活性、稳定性进行了分析。体外分析结果表明,KGLP-1/HSA具有与GLP-1相似的GLP-1R激动剂活性,EC50值为314 nmol/L,虽然其活性低于天然的GLP-1及类似物KGLP-1,但显示了明显的抗DPP-Ⅳ降解作用,12 h后仍能刺激CHO/EGFP/GLP-1R细胞产生较强的荧光,其强度为原来的84%。体内活性分析结果表明,虽然KGLP-1/HSA在给药后1h才表现出明显的降血糖、促胰岛素分泌的作用,但这种活性可以维持8h以上,而GLP-1与KGLP-1在给药1至2h后效果即不显著。以上结果表明,通过与HSA的融合,KGLP-1/HSA能明显地减缓其体内代谢清除率,延长其体内作用时间。
此外,本研究还对KGLP-1的注射缓释制剂进行了探索。利用复乳(W/O/W)溶剂挥发法制备了载KGLP-1的PLA和PLGA微球,分别考察了高聚物的种类、平均分子量等因素对微球形态、平均粒径、包封率和体外释药特性的影响。结果发现,该类微球的包封率都小于40%,药物损失大。而采用S/O/O溶剂萃取法制备的载KGLP-1的PLGA长效注射微球其形态特征、包封率、体外释药均显示了较好的结果。电镜分析显示微球表面相对光滑致密,大小均一,平均粒径为33.5μm,包封率为85.5%,微球初始6h的突释为15.3%,14d的累计释放总量达到69.5%。采用糖尿病模型大鼠皮下注射给药,对血糖和血清胰岛素水平的考察结果显示,载有KGLP-1的PLGA微球可以提供稳定的药物释放,实现了给药一次,缓释10 d,控制血糖、促进胰岛素分泌的效果。
本论文以自行开发的SA-CBD-MCMS为工具,提取大鼠胰腺mRNA,克隆了大鼠GLP-1R。然后以GLP-1R为靶点构建了含有EGFP报告基因的功能性细胞分析系统CHO/EGFP/GLP-1R,以此作为GLP-1R激动剂体外活性评价的细胞模型。利用该模型对新型GLP-1类似物KGLP-1及其与HSA的融合蛋白KGLP-1/HSA进行体外活性、稳定性评价,结合KM小鼠、糖尿病模型动物的体内实验,证明了KGLP-1作为一种新的抗DPP-Ⅳ降解的GLP-1类似物的有效性,并通过与HSA的融合,可以延长其降低血糖、促进胰岛素分泌的作用时间。同时,采用PLGA为包埋材料,S/O/O溶剂萃取法成功制备了载KGLP-1的缓释微球制剂,实现了长效治疗的效果,为开发能够用于2型糖尿病临床治疗的长效GLP-1类药物及其缓释制剂奠定了理论基础。
Glucagon-like peptide-1 (GLP-1) is an incretin hormone that is released from intestinal L-cells into the circulation in response to orally ingested nutrients. The multifaceted physiological actions of GLP-1 include stimulation of insulin gene expression, stimulation of insulin secretion, tropic effects on beta-cells, inhibition of glucagon secretion, promotion of satiety, inhibition of food intake, and reduction of gastric emptying. all of which contribute to normalizing elevated glucose levels and make GLP-1 attractive as a candidate for the treatment of type 2 diabetes mellitus. However, its rapid degradation by dipeptidyl-peptidase IV (DPP-IV) and its renal clearance have limited the use of the native peptide in clinical settings. Consequently. multiple efforts that focus on the design of novel DPP-IV-resistant GLP-1 analogs or sustained-release formulation of GLP-1 are being pursued.
In this study, by exploiting the affinity of cellulose binding domain (CBD) binding for cellulose, we creatively activated and connected biomatrices of micron-sized MCMS with SA. In addition, using biotinylated Oligo(dT) a one-step isolation method of mRNA from cells or tissues was developed and achieved. On this basis we successfully isolated mRNA from rat islet tissue and the gene encoding GLP-1R was amplified. The recombinant plasmid pcDNA3.1(+)/GLP-1R was conducted and transfected into a CHO/EGFP cell line. After resistance screening, flow cytometry sorting and functional analysis, the resulting stable recombinant CHO/EGFP/GLP-1R cell line was developed. This functional reporter gene assay system can be used to identify and for the quantitative analysis of in vitro activity of GLP-1R agonists. The results laid the approach foundation for the research and development on the long-acting GLP-1 analogs.
Then we reported a novel GLP-1 analog designated KGLP-1, which was designed with an extra Lys in front of the N-terminal His of the native GLP-1. By using the above constructed CHO/EGFP/GLP-1R cells and DPP-IV extract, we determined its plasma stability and biological activity in vitro. The results suggested that KGLP-1 activated GLP-1R in a dose-dependent manner. The EC50 for KGLP-1 was 2.44 nmol/L, which was higher than that of native GLP-1 (0.83 nmol/L). But KGLP-1 revealed a marked enzymatic resistance to DPP-IV. After 12 h incubation with the DPP-IV extract at 37℃,80% of active KGLP-1 still remained. Further animal experiments confirmed that KGLP-1 reduced the blood glucose levels after intraperitoneal administration to KM mice in a dose-dependent manner. At the same moderate dose, the glucose-lowering ability of KGLP-1 was comparable with native GLP-1. Although native GLP-1 immediately showed significant glucose-lowering and insulin-secreting effects after administration in normal or diabetic model mice, the effect disappeared 1h after administration. Compared with native GLP-1, the significant blood glucose-lowering and insulinotropic activity of KGLP-1 lasted for at least 2 h after administration, demonstrating that KGLP-1 had a longer biological action.
To delay the rapid renal clearance, we prepared a fusion protein of KGLP-1 with HSA. And the therapeutic potential of KGLP-1/HSA, with respect to its biological activity and metabolic stability in vitro and its in vivo antihyperglycemic and insulinotropic effects were investigated. It was found in vitro study that KGLP-1/HSA activated GLP-1R in a dose-dependent manner that paralleled GLP-1 and KGLP-1. The EC 50 value for KGLP-1/HSA was calculated to be 314 nmol/L, while KGLP-1 and native GLP-1, exhibited much smaller EC50 values. But KGLP-1/HSA revealed significant enzymatic resistance, and it still stimulated EGFP expression at 84.0% activity after incubation for 12 h. The in vivo test confirmed that although KGLP-1/HSA did not show marked antihyperglycemic and insulinotropic effects until 1 h after administration, the glucose-lowering and insulin-releasing effect of KGLP-1/HSA was still evident up to 8 h after administration. In contrast, although the blood glucose and insulin responses for both GLP-1 and KGLP-1 showed significant glucose-lowering and insulin-releasing effects immediately after administration, the effects of GLP-1 or KGLP-1 at a dose of 0.1μmol/kg disappeared 1-2 h after administration. Overall, The fusion protein KGLP-1/HSA maintained the glucose-lowering and insulinotropic action of native GLP-1, together with increased resistance to DPP-IV mediated inactivation and prolonged duration of action.
Meanwhile, we made active exploration on injectable sustained-release formulation of KGLP-1. Firstly, using W/O/W emulsion method, we prepared KGLP-1-loaded PLA MS and PLGA MS, and examined the type of polymer, polymer average molecular weight on morphology, average particle size, encapsulation efficiency and release characteristics in vitro of MS. The results showed that their encapsulation efficiencies were all below 40%, which would cause big losses of drugs. Then KGLP-1 entrapped in long-acting injectable PLGA MS were prepared using the S/O/O solvent extraction method. The surface morphology of MS was examined by SEM and micrographs showed that the MS had a regular spherical shape with a relatively smooth surface and a homogeneous size. The particle diameter was 33.5μm, and the encapsulation efficiency was 85.5%. The MS released the entrapped peptide with a release rate of approximately 15.3% peptide during the first 6 h, followed by the release of 54.2% of the peptide over 2 weeks. Animal studies using alloxan-induced diabetic rats have been performed and the results suggested that the continuous release of KGLP-1 from the subcutaneously injected KGLP-1-loaded PLGA MS had sustained glucose-lowering and insulinotropic effects. The KGLP-1 MS formulation achieved controlled release in vivo for 10 days and exhibited sustained long-term pharmacological efficacy to maintain stable blood glucose level in a diabetic model.
In summary, the thesis made use of self-developed SA-CBD-MCMS, isolated the mRNA of rat islet tissue and cloned the gene coding rat GLP-1R. Then the functional cell assay system CHO/EGFP/GLP-1R containing EGFP reporter gene was successfully developed for the analysis of in vitro activity of GLP-1R agonists. Using this cell line, the plasma stability and biological activity in vitro of a novel GLP-1 analogue (KGLP-1) and its fusion protein with HSA (KGLP-1/HSA) were examined. In combination with tests in KM mice and alloxan-induced diabetic animals, we confirmed that KGLP-1 is an effective GLP-1 analog with marked resistance to DPP-IV degradation and retained bioactivity that is normally associated with native GLP-1 both in vitro and in vivo. And the fusion protein of KGLP-1 with HSA maintained the glucose-lowering and insulinotropic action of native GLP-1, together with increased resistance to DPP-Ⅳmediated inactivation and prolonged duration of action. Furthermore, KGLP-1-loaded PLGA MS were prepared using the S/O/O solvent extraction method and, after a single injection in diabetic rats, the effects of KGLP-1 on glucose control were sustained for 10 days. It laid the well foundation for the development of long-acting GLP-1 drugs and their sustained-release formulations for the treatment of 2DM.
本文首先构建纤维素结合域(CBD)与链霉亲和素(SA)的融合蛋白,制备了表而生物偶联SA的纤维素磁性微球(SA-CBD-MCMS),通过生物素(biotin)结合的Oligo(dT),建立了从细胞或组织中快速提取mRNA的方法,并从大鼠胰腺中提取mRNA,克隆了大鼠GLP-1受体(GLP-1R)。并将含有GLP-1 R基因的重组表达载体pcDNA3.1(+)/GLP-]R转染含有增强型绿色荧光蛋白(EGFP)报告基因的CHO/EGFP细胞,经抗性筛选、流式细胞分选和功能性分析,得到了稳定转染的细胞系CHO/EGFP/GLP-1R。该功能性报告基因细胞分析系统可以剂量依赖性的通过EGFP表达,对GLP-1 R激动剂的体外活性进行定性定量分析,为研究、开发和评价长效GLP-1类似物奠定了基础。
本研究创新性地合成了含有31个氨基酸的新的GLP-1类似物KGLP-1,其结构是在天然GLP-1(7-37)酰胺的N端添加一个赖氨酸(Lys)。利用上述CHO/RGFP/GLP-1R细胞评价体系及自制DPP-IV粗酶液对KGLP-1的体外活性和稳定性进行分析。结果显示,KGLP-1能以剂量依赖的方式激活GLP-1 R,其EC50值(2.44 nmol/L)与天然GLP-1 (0.83 nmol/L)相比略有升高：但KGLP-1具有显著的抗DPP-Ⅳ降解作用,与DPP-Ⅳ粗提物作用12h后仍能保持80%的活性。进步体内活性分析结果表明,KGLP-1能以剂量依赖的方式显著降低小鼠体内的血糖水平,在同等剂量下,给药2h后仍具有明显的降血糖和促胰岛素分泌作用,而天然GLP-1在给药1h后活性即消失。在糖尿病模型小鼠实验中,KGLP-1也同样显示出了明显的降血糖作用(p<0.01)。
为了改善KGLP-1的肾脏清除,本研究制备了KGLP-1与HSA的融合蛋白KGLP-1/HSA,并对其体内外活性、稳定性进行了分析。体外分析结果表明,KGLP-1/HSA具有与GLP-1相似的GLP-1R激动剂活性,EC50值为314 nmol/L,虽然其活性低于天然的GLP-1及类似物KGLP-1,但显示了明显的抗DPP-Ⅳ降解作用,12 h后仍能刺激CHO/EGFP/GLP-1R细胞产生较强的荧光,其强度为原来的84%。体内活性分析结果表明,虽然KGLP-1/HSA在给药后1h才表现出明显的降血糖、促胰岛素分泌的作用,但这种活性可以维持8h以上,而GLP-1与KGLP-1在给药1至2h后效果即不显著。以上结果表明,通过与HSA的融合,KGLP-1/HSA能明显地减缓其体内代谢清除率,延长其体内作用时间。
此外,本研究还对KGLP-1的注射缓释制剂进行了探索。利用复乳(W/O/W)溶剂挥发法制备了载KGLP-1的PLA和PLGA微球,分别考察了高聚物的种类、平均分子量等因素对微球形态、平均粒径、包封率和体外释药特性的影响。结果发现,该类微球的包封率都小于40%,药物损失大。而采用S/O/O溶剂萃取法制备的载KGLP-1的PLGA长效注射微球其形态特征、包封率、体外释药均显示了较好的结果。电镜分析显示微球表面相对光滑致密,大小均一,平均粒径为33.5μm,包封率为85.5%,微球初始6h的突释为15.3%,14d的累计释放总量达到69.5%。采用糖尿病模型大鼠皮下注射给药,对血糖和血清胰岛素水平的考察结果显示,载有KGLP-1的PLGA微球可以提供稳定的药物释放,实现了给药一次,缓释10 d,控制血糖、促进胰岛素分泌的效果。
本论文以自行开发的SA-CBD-MCMS为工具,提取大鼠胰腺mRNA,克隆了大鼠GLP-1R。然后以GLP-1R为靶点构建了含有EGFP报告基因的功能性细胞分析系统CHO/EGFP/GLP-1R,以此作为GLP-1R激动剂体外活性评价的细胞模型。利用该模型对新型GLP-1类似物KGLP-1及其与HSA的融合蛋白KGLP-1/HSA进行体外活性、稳定性评价,结合KM小鼠、糖尿病模型动物的体内实验,证明了KGLP-1作为一种新的抗DPP-Ⅳ降解的GLP-1类似物的有效性,并通过与HSA的融合,可以延长其降低血糖、促进胰岛素分泌的作用时间。同时,采用PLGA为包埋材料,S/O/O溶剂萃取法成功制备了载KGLP-1的缓释微球制剂,实现了长效治疗的效果,为开发能够用于2型糖尿病临床治疗的长效GLP-1类药物及其缓释制剂奠定了理论基础。
Glucagon-like peptide-1 (GLP-1) is an incretin hormone that is released from intestinal L-cells into the circulation in response to orally ingested nutrients. The multifaceted physiological actions of GLP-1 include stimulation of insulin gene expression, stimulation of insulin secretion, tropic effects on beta-cells, inhibition of glucagon secretion, promotion of satiety, inhibition of food intake, and reduction of gastric emptying. all of which contribute to normalizing elevated glucose levels and make GLP-1 attractive as a candidate for the treatment of type 2 diabetes mellitus. However, its rapid degradation by dipeptidyl-peptidase IV (DPP-IV) and its renal clearance have limited the use of the native peptide in clinical settings. Consequently. multiple efforts that focus on the design of novel DPP-IV-resistant GLP-1 analogs or sustained-release formulation of GLP-1 are being pursued.
In this study, by exploiting the affinity of cellulose binding domain (CBD) binding for cellulose, we creatively activated and connected biomatrices of micron-sized MCMS with SA. In addition, using biotinylated Oligo(dT) a one-step isolation method of mRNA from cells or tissues was developed and achieved. On this basis we successfully isolated mRNA from rat islet tissue and the gene encoding GLP-1R was amplified. The recombinant plasmid pcDNA3.1(+)/GLP-1R was conducted and transfected into a CHO/EGFP cell line. After resistance screening, flow cytometry sorting and functional analysis, the resulting stable recombinant CHO/EGFP/GLP-1R cell line was developed. This functional reporter gene assay system can be used to identify and for the quantitative analysis of in vitro activity of GLP-1R agonists. The results laid the approach foundation for the research and development on the long-acting GLP-1 analogs.
Then we reported a novel GLP-1 analog designated KGLP-1, which was designed with an extra Lys in front of the N-terminal His of the native GLP-1. By using the above constructed CHO/EGFP/GLP-1R cells and DPP-IV extract, we determined its plasma stability and biological activity in vitro. The results suggested that KGLP-1 activated GLP-1R in a dose-dependent manner. The EC50 for KGLP-1 was 2.44 nmol/L, which was higher than that of native GLP-1 (0.83 nmol/L). But KGLP-1 revealed a marked enzymatic resistance to DPP-IV. After 12 h incubation with the DPP-IV extract at 37℃,80% of active KGLP-1 still remained. Further animal experiments confirmed that KGLP-1 reduced the blood glucose levels after intraperitoneal administration to KM mice in a dose-dependent manner. At the same moderate dose, the glucose-lowering ability of KGLP-1 was comparable with native GLP-1. Although native GLP-1 immediately showed significant glucose-lowering and insulin-secreting effects after administration in normal or diabetic model mice, the effect disappeared 1h after administration. Compared with native GLP-1, the significant blood glucose-lowering and insulinotropic activity of KGLP-1 lasted for at least 2 h after administration, demonstrating that KGLP-1 had a longer biological action.
To delay the rapid renal clearance, we prepared a fusion protein of KGLP-1 with HSA. And the therapeutic potential of KGLP-1/HSA, with respect to its biological activity and metabolic stability in vitro and its in vivo antihyperglycemic and insulinotropic effects were investigated. It was found in vitro study that KGLP-1/HSA activated GLP-1R in a dose-dependent manner that paralleled GLP-1 and KGLP-1. The EC 50 value for KGLP-1/HSA was calculated to be 314 nmol/L, while KGLP-1 and native GLP-1, exhibited much smaller EC50 values. But KGLP-1/HSA revealed significant enzymatic resistance, and it still stimulated EGFP expression at 84.0% activity after incubation for 12 h. The in vivo test confirmed that although KGLP-1/HSA did not show marked antihyperglycemic and insulinotropic effects until 1 h after administration, the glucose-lowering and insulin-releasing effect of KGLP-1/HSA was still evident up to 8 h after administration. In contrast, although the blood glucose and insulin responses for both GLP-1 and KGLP-1 showed significant glucose-lowering and insulin-releasing effects immediately after administration, the effects of GLP-1 or KGLP-1 at a dose of 0.1μmol/kg disappeared 1-2 h after administration. Overall, The fusion protein KGLP-1/HSA maintained the glucose-lowering and insulinotropic action of native GLP-1, together with increased resistance to DPP-IV mediated inactivation and prolonged duration of action.
Meanwhile, we made active exploration on injectable sustained-release formulation of KGLP-1. Firstly, using W/O/W emulsion method, we prepared KGLP-1-loaded PLA MS and PLGA MS, and examined the type of polymer, polymer average molecular weight on morphology, average particle size, encapsulation efficiency and release characteristics in vitro of MS. The results showed that their encapsulation efficiencies were all below 40%, which would cause big losses of drugs. Then KGLP-1 entrapped in long-acting injectable PLGA MS were prepared using the S/O/O solvent extraction method. The surface morphology of MS was examined by SEM and micrographs showed that the MS had a regular spherical shape with a relatively smooth surface and a homogeneous size. The particle diameter was 33.5μm, and the encapsulation efficiency was 85.5%. The MS released the entrapped peptide with a release rate of approximately 15.3% peptide during the first 6 h, followed by the release of 54.2% of the peptide over 2 weeks. Animal studies using alloxan-induced diabetic rats have been performed and the results suggested that the continuous release of KGLP-1 from the subcutaneously injected KGLP-1-loaded PLGA MS had sustained glucose-lowering and insulinotropic effects. The KGLP-1 MS formulation achieved controlled release in vivo for 10 days and exhibited sustained long-term pharmacological efficacy to maintain stable blood glucose level in a diabetic model.
In summary, the thesis made use of self-developed SA-CBD-MCMS, isolated the mRNA of rat islet tissue and cloned the gene coding rat GLP-1R. Then the functional cell assay system CHO/EGFP/GLP-1R containing EGFP reporter gene was successfully developed for the analysis of in vitro activity of GLP-1R agonists. Using this cell line, the plasma stability and biological activity in vitro of a novel GLP-1 analogue (KGLP-1) and its fusion protein with HSA (KGLP-1/HSA) were examined. In combination with tests in KM mice and alloxan-induced diabetic animals, we confirmed that KGLP-1 is an effective GLP-1 analog with marked resistance to DPP-IV degradation and retained bioactivity that is normally associated with native GLP-1 both in vitro and in vivo. And the fusion protein of KGLP-1 with HSA maintained the glucose-lowering and insulinotropic action of native GLP-1, together with increased resistance to DPP-Ⅳmediated inactivation and prolonged duration of action. Furthermore, KGLP-1-loaded PLGA MS were prepared using the S/O/O solvent extraction method and, after a single injection in diabetic rats, the effects of KGLP-1 on glucose control were sustained for 10 days. It laid the well foundation for the development of long-acting GLP-1 drugs and their sustained-release formulations for the treatment of 2DM.
引文
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