含苯硼酸基生物粘附性材料作为胰岛素跨鼻粘膜转运载体的研究
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摘要
多肽、蛋白等药物如胰岛素,因其不可替代的生物活性和良好的临床效果,成为了临床应用的首选。但因该类药物易降解、难以跨膜转运和生物利用度低,目前临床只能采用注射方式给药。但长期治疗给病人带来极大痛苦,迫切需要研究此类药物的非注射给药制剂。粘附性材料作为多肽、蛋白药物载体,能够延长药物在粘膜上的滞留时间,增加药物上皮屏障的透过性,提高药物的生物利用度。因此该类材料在多肽、蛋白药物非注射给药途径的研究中受到了研究者们的广泛关注。本文从粘膜给药体系的角度出发,以药物载体为突破口,着重解决载体的粘附性、相容性,以期为生物大分子药物鼻腔给药提供一种具有良好粘附性、能促进其跨膜转运的药物载体。
一、基于苯硼酸的两亲性含糖共聚物作为鼻腔给药载体的性能研究
硼酸及其衍生物能与1,2-或1,3-二醇以及多醇羟基相互作用,形成负电性的硼酯结构,而生物的细胞膜上均含有糖脂或糖蛋白等糖基化合物,这就使硼酸及其衍生物与细胞表面上的糖类物质结合成为可能,呈现粘附性。硼酸的这一特性使其在生物粘附材料方面备受关注。本文中,通过常规自由基聚合成功制备了含有苯硼酸基团和乳糖基团的两亲性共聚物p(LAMA-r-AAPBA);由于苯硼酸基团和乳糖基团之间的相互作用以及共聚物的两亲性,p(LAMA-r-AAPBA)在水溶液中易于自组装形成粒径为289～353nm的纳米粒,zeta电位为-22～-27mV；该纳米粒作为载体可对胰岛素进行有效包埋,其包封率和载药量分别高达90%和12%；体外药物释药结果显示,载药p(LAMA-r-AAPBA)纳米粒能缓慢释放胰岛素；通过MTT法测定纳米粒对Calu-3细胞的细胞毒性试验表明,p(LAMA-r-AAPBA)纳米粒的细胞相容性良好,说明乳糖基团的引入可有效改善含苯硼酸基团聚合物的生物相容性；粘蛋白吸附试验表明p(LAMA-r-AAPBA)纳米粒具有一定的粘附性；负载FITC荧光标记胰岛素的p(LAMA-r-AAPBA)纳米粒进行细胞吸收试验发现,由于纳米粒中苯硼酸基团能与细胞表面的糖类化合物结合,增强了纳米粒对细胞的粘附能力,该纳米粒能通过细胞内在化作用成功进入到细胞内。同时,内吞机理试验结果表明,p(LAMA-r-AAPBA)纳米粒可通过两种机制内化进入细胞,即通过网格蛋白介导和脂筏/胞膜窖介导的协同作用完成细胞内化；大鼠鼻腔给药实验表明,p(LAMA-r-AAPBA)内米粒能够作为胰岛素的良好载体增强胰岛素在鼻腔内的吸收,并且能控制胰岛素在大鼠体内缓慢释放,在8h内维持血糖在较低水平。因此,p(LAMA-r-AAPBA)纳米粒有望成为生物大分子药物的理想纳米载体,促进药物进行跨膜转运,增强药物吸收。
二、生物可降解的含苯硼酸基葡聚糖作为鼻腔给药载体的性能研究
由于常规自由基聚合的方法是采用不饱和单体进行聚合,聚合物的主链结构是由C-C键组成,不具备可降解性。为了使含苯硼酸的大分子具有可降解性,本文中合成一种具有生物可降解性的含有苯硼酸基团的高分子Dex-PBA。利用Dex-PBA的两亲性,使用自组装的方法制备了的Dex-PBA纳米粒,纳米粒粒径在300nm左右,具有良好的稳定性；通过疏水-亲水等相互作用该纳米粒成功负载胰岛素,其包封率和载药量分别高达40%和22%；粘附性试验结果表明,Dex-PBA纳米粒能够结合粘蛋白,说明纳米粒具有一点的粘附性能,同时DSC曲线证明了Dex-PBA纳米粒与粘蛋白之间存在着相互作用；细胞相容性试验表明,Dex-PBA纳米粒具有良好的细胞相容性；细胞吸收试验表明,该纳米粒能通过细胞内在化作用成功进入到细胞内；同时,内吞机理试验结果表明,p(LAMA-r-AAPBA)纳米粒可通过两种机制内化进入细胞,即通过网格蛋白介导和脂筏／胞膜窖介导的协同作用完成细胞内化；大鼠鼻腔给药试验表明,Dex-PBA纳米粒能够作为胰岛素的良好载体增强胰岛素在鼻腔内的吸收,并且能控制胰岛素在大鼠体内缓慢释放,在7h内维持血糖在较低水平；免疫组化分析结果表明,Dex-PBA纳米粒经鼻腔给药后并未诱导鼻粘膜的炎症反应,对鼻粘膜无刺激作用。因此,该纳米粒有望成为生物大分子药物鼻腔给药的良好纳米载体。
综上所述,含苯硼酸的高分子药物载体,具有良好生物相容性和粘附性,且能对生物大分子药物进行保护,解决了生物大分子药物给药系统中出现的粘膜透过性差,生物利用率低等问题,是促进生物大分子药物传递的良好载体。
Protein and peptide drugs possess biological activities that mark them as potential therapeutics in diagnosis, medical treatment for various diseases. Therapeutic peptides and proteins are typically administered by injection due to their fragile nature and the low bioavailability. Thus, chronic treatment brings incontinences and pains to the patient. Recently, researchers have paid more attention to adhesive polymers. The polymers as carriers could prolong the retention time of drugs on the mucous membrane, improve the permeability of drug epithelial barrier and the bioavailability of drugs. In this work, we focus to offer the mucosal drugs delivery systems, in order to find the protein drug carriers with mucoadhesion which could promote the transport of drugs across the membrane
1) Amphiphilic glycopolymer nanoparticles as vehicles for nasal delivery of insulin
Boronic acid and its derivatives are known to possess the ability to reversibly interact with diols, sugars, and glycoproteins, and transport saccharide across lipid bilayers. Since all cell membranes virtually include glycoproteins and/or glycolipids, which facilitates compounds containing boronic acid groups to bind to cell surfaces. In this work, we propose to design new drug delivery vehicles based poly (2-lactobionamidoethyl methacrylate-r-3-acrylamidophenylboronic acid). The glycopolymer could assemble into the nanoparticles with the size in the range of289～353nm, and zeta potential was-22～27mV. Insulin, as a model drug, was efficiently encapsulated within the nanoparticles, and loading capacity was up to12%. In vitro study revealed that the insulin release could be controlled by modifying the composition of glycopolymers. Cell viability test showed that p(LAMA-r-AAPBA) nanoparticles had good cytocompatibility. Moreover, the mechanism of nanoparticle internalization into Calu-3cells was a combination mechanism of clathrin-mediated endocytosis and lipid raft/caveolae-mediated endocytosis. Importantly, there was a significant decrease in the blood glucose levels after the nasal administration of p(LAMA-r-AAPBA) nanoparticles to diabetic rats. Therefore, p(LAMA-r-AAPBA) glycopolymers have a potential application as a nasal delivery systems for proteins and peptides.
2) Biodegrable phenylboronic acid-containing Dextran as vehicles for nasal delivery of insulin
The main chain of the p(LAMA-r-AAPBA) is made up by the C-C bonds, and it is non-degradation in the body. In order to improve the degradation of polymer with phenylboronic acid, we further synthesized phenylboronic acid-graft-Dextran (Dex-PBA). Dex-PBA could assemble into the nanoparticles with size about300nm. Insulin could be efficiently encapsulated within the nanoparticles, and loading capacity was up to22%. The mucoadhesion test show that the Dex-PBA nanoparticles could interact with mucin, and the DSC test demonstrated the interaction between the Dex-PBA nanoparticles and mucin. Cell viability test showed that Dex-PBA nanoparticles had good cytocompatibility. Moreover, the mechanism of nanoparticle internalization into Calu-3cells was a combination mechanism of clathrin-mediated endocytosis and lipid raft/caveolae-mediated endocytosis. Importantly, there was a significant decrease in the blood glucose levels after the nasal administration of Dex-PBA nanoparticles to diabetic rats. Therefore, Dex-PBA glycopolymers have a potential application as nasal carrier for proteins and peptides.
In summary, the phenylboronic acid-contained polymer carriers possess the good biocompatibility and mucoadhesion, could protect the protein drugs from being degraded and deliver them into cells or tissues with high bioavailability.
一、基于苯硼酸的两亲性含糖共聚物作为鼻腔给药载体的性能研究
硼酸及其衍生物能与1,2-或1,3-二醇以及多醇羟基相互作用,形成负电性的硼酯结构,而生物的细胞膜上均含有糖脂或糖蛋白等糖基化合物,这就使硼酸及其衍生物与细胞表面上的糖类物质结合成为可能,呈现粘附性。硼酸的这一特性使其在生物粘附材料方面备受关注。本文中,通过常规自由基聚合成功制备了含有苯硼酸基团和乳糖基团的两亲性共聚物p(LAMA-r-AAPBA);由于苯硼酸基团和乳糖基团之间的相互作用以及共聚物的两亲性,p(LAMA-r-AAPBA)在水溶液中易于自组装形成粒径为289～353nm的纳米粒,zeta电位为-22～-27mV；该纳米粒作为载体可对胰岛素进行有效包埋,其包封率和载药量分别高达90%和12%；体外药物释药结果显示,载药p(LAMA-r-AAPBA)纳米粒能缓慢释放胰岛素；通过MTT法测定纳米粒对Calu-3细胞的细胞毒性试验表明,p(LAMA-r-AAPBA)纳米粒的细胞相容性良好,说明乳糖基团的引入可有效改善含苯硼酸基团聚合物的生物相容性；粘蛋白吸附试验表明p(LAMA-r-AAPBA)纳米粒具有一定的粘附性；负载FITC荧光标记胰岛素的p(LAMA-r-AAPBA)纳米粒进行细胞吸收试验发现,由于纳米粒中苯硼酸基团能与细胞表面的糖类化合物结合,增强了纳米粒对细胞的粘附能力,该纳米粒能通过细胞内在化作用成功进入到细胞内。同时,内吞机理试验结果表明,p(LAMA-r-AAPBA)纳米粒可通过两种机制内化进入细胞,即通过网格蛋白介导和脂筏/胞膜窖介导的协同作用完成细胞内化；大鼠鼻腔给药实验表明,p(LAMA-r-AAPBA)内米粒能够作为胰岛素的良好载体增强胰岛素在鼻腔内的吸收,并且能控制胰岛素在大鼠体内缓慢释放,在8h内维持血糖在较低水平。因此,p(LAMA-r-AAPBA)纳米粒有望成为生物大分子药物的理想纳米载体,促进药物进行跨膜转运,增强药物吸收。
二、生物可降解的含苯硼酸基葡聚糖作为鼻腔给药载体的性能研究
由于常规自由基聚合的方法是采用不饱和单体进行聚合,聚合物的主链结构是由C-C键组成,不具备可降解性。为了使含苯硼酸的大分子具有可降解性,本文中合成一种具有生物可降解性的含有苯硼酸基团的高分子Dex-PBA。利用Dex-PBA的两亲性,使用自组装的方法制备了的Dex-PBA纳米粒,纳米粒粒径在300nm左右,具有良好的稳定性；通过疏水-亲水等相互作用该纳米粒成功负载胰岛素,其包封率和载药量分别高达40%和22%；粘附性试验结果表明,Dex-PBA纳米粒能够结合粘蛋白,说明纳米粒具有一点的粘附性能,同时DSC曲线证明了Dex-PBA纳米粒与粘蛋白之间存在着相互作用；细胞相容性试验表明,Dex-PBA纳米粒具有良好的细胞相容性；细胞吸收试验表明,该纳米粒能通过细胞内在化作用成功进入到细胞内；同时,内吞机理试验结果表明,p(LAMA-r-AAPBA)纳米粒可通过两种机制内化进入细胞,即通过网格蛋白介导和脂筏／胞膜窖介导的协同作用完成细胞内化；大鼠鼻腔给药试验表明,Dex-PBA纳米粒能够作为胰岛素的良好载体增强胰岛素在鼻腔内的吸收,并且能控制胰岛素在大鼠体内缓慢释放,在7h内维持血糖在较低水平；免疫组化分析结果表明,Dex-PBA纳米粒经鼻腔给药后并未诱导鼻粘膜的炎症反应,对鼻粘膜无刺激作用。因此,该纳米粒有望成为生物大分子药物鼻腔给药的良好纳米载体。
综上所述,含苯硼酸的高分子药物载体,具有良好生物相容性和粘附性,且能对生物大分子药物进行保护,解决了生物大分子药物给药系统中出现的粘膜透过性差,生物利用率低等问题,是促进生物大分子药物传递的良好载体。
Protein and peptide drugs possess biological activities that mark them as potential therapeutics in diagnosis, medical treatment for various diseases. Therapeutic peptides and proteins are typically administered by injection due to their fragile nature and the low bioavailability. Thus, chronic treatment brings incontinences and pains to the patient. Recently, researchers have paid more attention to adhesive polymers. The polymers as carriers could prolong the retention time of drugs on the mucous membrane, improve the permeability of drug epithelial barrier and the bioavailability of drugs. In this work, we focus to offer the mucosal drugs delivery systems, in order to find the protein drug carriers with mucoadhesion which could promote the transport of drugs across the membrane
1) Amphiphilic glycopolymer nanoparticles as vehicles for nasal delivery of insulin
Boronic acid and its derivatives are known to possess the ability to reversibly interact with diols, sugars, and glycoproteins, and transport saccharide across lipid bilayers. Since all cell membranes virtually include glycoproteins and/or glycolipids, which facilitates compounds containing boronic acid groups to bind to cell surfaces. In this work, we propose to design new drug delivery vehicles based poly (2-lactobionamidoethyl methacrylate-r-3-acrylamidophenylboronic acid). The glycopolymer could assemble into the nanoparticles with the size in the range of289～353nm, and zeta potential was-22～27mV. Insulin, as a model drug, was efficiently encapsulated within the nanoparticles, and loading capacity was up to12%. In vitro study revealed that the insulin release could be controlled by modifying the composition of glycopolymers. Cell viability test showed that p(LAMA-r-AAPBA) nanoparticles had good cytocompatibility. Moreover, the mechanism of nanoparticle internalization into Calu-3cells was a combination mechanism of clathrin-mediated endocytosis and lipid raft/caveolae-mediated endocytosis. Importantly, there was a significant decrease in the blood glucose levels after the nasal administration of p(LAMA-r-AAPBA) nanoparticles to diabetic rats. Therefore, p(LAMA-r-AAPBA) glycopolymers have a potential application as a nasal delivery systems for proteins and peptides.
2) Biodegrable phenylboronic acid-containing Dextran as vehicles for nasal delivery of insulin
The main chain of the p(LAMA-r-AAPBA) is made up by the C-C bonds, and it is non-degradation in the body. In order to improve the degradation of polymer with phenylboronic acid, we further synthesized phenylboronic acid-graft-Dextran (Dex-PBA). Dex-PBA could assemble into the nanoparticles with size about300nm. Insulin could be efficiently encapsulated within the nanoparticles, and loading capacity was up to22%. The mucoadhesion test show that the Dex-PBA nanoparticles could interact with mucin, and the DSC test demonstrated the interaction between the Dex-PBA nanoparticles and mucin. Cell viability test showed that Dex-PBA nanoparticles had good cytocompatibility. Moreover, the mechanism of nanoparticle internalization into Calu-3cells was a combination mechanism of clathrin-mediated endocytosis and lipid raft/caveolae-mediated endocytosis. Importantly, there was a significant decrease in the blood glucose levels after the nasal administration of Dex-PBA nanoparticles to diabetic rats. Therefore, Dex-PBA glycopolymers have a potential application as nasal carrier for proteins and peptides.
In summary, the phenylboronic acid-contained polymer carriers possess the good biocompatibility and mucoadhesion, could protect the protein drugs from being degraded and deliver them into cells or tissues with high bioavailability.
引文
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