几种纳米材料作为药物和基因运输载体的研究
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摘要
纳米材料在作为药物和基因输运载体中的应用是很广泛的,本文的主要研究内容是多种纳米材料作为药物载体和基因输运载体的研究,包括三部分,分别为:阳离子脂质体介导的细胞自噬的发生和细胞自噬对阳离子脂质体介导的基因输运的效率的影响;作为基因输运载体的多肽类研究;树枝状高分子聚合物PAMAM作为非甾体类抗炎药载体的研究。
第一部分:我们的研究显示,在使用阳离子脂质体核心的转染试剂进行细胞转染过程中,有细胞自噬的产生,同时阳离子脂质体本身也能诱导细胞自噬的发生。我们用一系列的细胞自噬的检测方法证明这种细胞自噬是完整的细胞自噬,是mTOR非依赖型的细胞自噬。同时细胞发生自噬的水平影响着阳离子脂质体转染的效率。与对照组比较,细胞自噬水平高,阳离子脂质体转染效率提高,相反,细胞自噬水平低,阳离子脂质体转染效率低。
第二部分:我们设计合成了一条15个氨基酸长度的双功能的基因输运短肽,Ac-CGKRKWSQPKKKRKV-Cysteamide,它包含一个核定位信号(NLS)结构域和一个肿瘤靶向结构域。核定位序列还可以通过电荷相互作用结合DNA。该多肽的最佳作用条件为DNA:RPC2=1:10(w/w),同时该多肽还能够促进阳离子脂质体转染试剂Lipofectamine2000的转染效率,这些结果显示,该多肽可以作为载体将外源DNA带入成骨细胞并表达基因产物,同时具有很低的细胞毒性,在组织工程领域具有一定的应用前景。
第三部分:我们的研究着重于:(1)通过用PAMAM作为非甾体类抗炎药(NSAIDs)的载体,以酮洛芬作为模式药物,通过口服给药,提高了该类药物的溶解度,在体内和体外产生缓释作用,延长药物的作用时间,同时动物的镇痛模型说明该复合物有较好的镇痛作用。(2)用PAMAM作为非甾体类抗炎药的载体,形成NSAIDs-PAMAM复合物,以酮洛芬和双氯芬酸钠作为模式药物,经皮肤给药,达到消炎镇痛的效果,提高了血药浓度,同时避免了该类药物的胃肠道毒性。两方面的研究显示,PAMAM是很有前景的非甾体类抗炎药的载体。
Nano materials are widely used as drug and gene carriers in the field of drug and gene delivery.There are three parts in this dissertation,including autophagy induced by cationic lipid and the effect of autophay on gene delivery efficiency mediated by cationic lipid;a synthetic peptide efficiently deliver gene into rat primary osteoblastic cells and PAMAM as drug carriers of NSAIDs.
In partⅠ,we reported that autophagy did happen when cells were transfected using cationic lipid based reagents.Also,autophagy could be induced by cationic lipid only.Steady state study and flux measurements all proved that the autophagy induced by cationic lipid was completed and mTOR independent.Moreover,autophagy positively regulated gene delivery efficiency during cationic lipid mediated transfection.
In partⅡ,we synthesized a 15-amino acid bi-functional synthetic peptide,RPC2, with the sequence Ac-CGKRKWSQPKKKRKV-Cysteamide,which consists of a 7-amino acid nuclear localization signal(NLS) domain at the carboxyl terminus that electrostatically binds DNA and a 5-amino-acid tumor-homing domain at the amino terminus.This peptide efficiently delivered GFP and Renilla luciferase reporter genes into rat primary osteoblastic cells while exhibiting low cytotoxicity.The optimal delivery was achieved when the ratio of DNA:RPC2 reached 1:10(w/w). Transfection efficiency could be further enhanced by the addition of Lipofectamine 2000 and modification of RPC2.These results indicated that RPC2 could deliver exogenous DNA into primary osteoblastic cells with low cytotoxicity and be potentially utilized in experimental and clinical applications in the field of bone tissue engineering.
In partⅢ,we investigated the potential of polyamidoamine(PAMAM) dendrimers as drug carriers of ketoprofen by in vitro and in vivo studies.The in vitro and in vivo study all suggested that the release of ketoprofen from the drug-dendrimer complex was significantly slower compared to pure ketoprofen.Anti-nociceptive studies using the acetic acid-induced writhing model in mice showed a prolonged pharmacodynamic behavior for the ketoprofen-PAMAM dendrimer complex.
Moreover,we have assessed the ability of polyamidoamine(PAMAM) dendrimers to facilitate transdermal delivery of NSAIDs,using Ketoprofen and Diflunisal as model drugs.The complexes formed by NSAIDs and PAMAM had a prolonged pharmacodynamic profile and a higher blood drug level.All these results demonstrated that PAMAM dendrimers might be considered as a potential drug carrier of NSAIDs.
第一部分:我们的研究显示,在使用阳离子脂质体核心的转染试剂进行细胞转染过程中,有细胞自噬的产生,同时阳离子脂质体本身也能诱导细胞自噬的发生。我们用一系列的细胞自噬的检测方法证明这种细胞自噬是完整的细胞自噬,是mTOR非依赖型的细胞自噬。同时细胞发生自噬的水平影响着阳离子脂质体转染的效率。与对照组比较,细胞自噬水平高,阳离子脂质体转染效率提高,相反,细胞自噬水平低,阳离子脂质体转染效率低。
第二部分:我们设计合成了一条15个氨基酸长度的双功能的基因输运短肽,Ac-CGKRKWSQPKKKRKV-Cysteamide,它包含一个核定位信号(NLS)结构域和一个肿瘤靶向结构域。核定位序列还可以通过电荷相互作用结合DNA。该多肽的最佳作用条件为DNA:RPC2=1:10(w/w),同时该多肽还能够促进阳离子脂质体转染试剂Lipofectamine2000的转染效率,这些结果显示,该多肽可以作为载体将外源DNA带入成骨细胞并表达基因产物,同时具有很低的细胞毒性,在组织工程领域具有一定的应用前景。
第三部分:我们的研究着重于:(1)通过用PAMAM作为非甾体类抗炎药(NSAIDs)的载体,以酮洛芬作为模式药物,通过口服给药,提高了该类药物的溶解度,在体内和体外产生缓释作用,延长药物的作用时间,同时动物的镇痛模型说明该复合物有较好的镇痛作用。(2)用PAMAM作为非甾体类抗炎药的载体,形成NSAIDs-PAMAM复合物,以酮洛芬和双氯芬酸钠作为模式药物,经皮肤给药,达到消炎镇痛的效果,提高了血药浓度,同时避免了该类药物的胃肠道毒性。两方面的研究显示,PAMAM是很有前景的非甾体类抗炎药的载体。
Nano materials are widely used as drug and gene carriers in the field of drug and gene delivery.There are three parts in this dissertation,including autophagy induced by cationic lipid and the effect of autophay on gene delivery efficiency mediated by cationic lipid;a synthetic peptide efficiently deliver gene into rat primary osteoblastic cells and PAMAM as drug carriers of NSAIDs.
In partⅠ,we reported that autophagy did happen when cells were transfected using cationic lipid based reagents.Also,autophagy could be induced by cationic lipid only.Steady state study and flux measurements all proved that the autophagy induced by cationic lipid was completed and mTOR independent.Moreover,autophagy positively regulated gene delivery efficiency during cationic lipid mediated transfection.
In partⅡ,we synthesized a 15-amino acid bi-functional synthetic peptide,RPC2, with the sequence Ac-CGKRKWSQPKKKRKV-Cysteamide,which consists of a 7-amino acid nuclear localization signal(NLS) domain at the carboxyl terminus that electrostatically binds DNA and a 5-amino-acid tumor-homing domain at the amino terminus.This peptide efficiently delivered GFP and Renilla luciferase reporter genes into rat primary osteoblastic cells while exhibiting low cytotoxicity.The optimal delivery was achieved when the ratio of DNA:RPC2 reached 1:10(w/w). Transfection efficiency could be further enhanced by the addition of Lipofectamine 2000 and modification of RPC2.These results indicated that RPC2 could deliver exogenous DNA into primary osteoblastic cells with low cytotoxicity and be potentially utilized in experimental and clinical applications in the field of bone tissue engineering.
In partⅢ,we investigated the potential of polyamidoamine(PAMAM) dendrimers as drug carriers of ketoprofen by in vitro and in vivo studies.The in vitro and in vivo study all suggested that the release of ketoprofen from the drug-dendrimer complex was significantly slower compared to pure ketoprofen.Anti-nociceptive studies using the acetic acid-induced writhing model in mice showed a prolonged pharmacodynamic behavior for the ketoprofen-PAMAM dendrimer complex.
Moreover,we have assessed the ability of polyamidoamine(PAMAM) dendrimers to facilitate transdermal delivery of NSAIDs,using Ketoprofen and Diflunisal as model drugs.The complexes formed by NSAIDs and PAMAM had a prolonged pharmacodynamic profile and a higher blood drug level.All these results demonstrated that PAMAM dendrimers might be considered as a potential drug carrier of NSAIDs.
引文
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