肿瘤细胞靶向抗菌肽嵌合体的设计及其抗肿瘤活性机制研究
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摘要
目前肿瘤的治疗手段主要包括手术切除、放射线治疗、化学药物治疗、免疫治疗等。其中化学药物治疗在肿瘤治疗中一直发挥着重要作用,但是其治疗效果却受到其剂量依赖性毒性的影响，往往对患者造成二次伤害。因此，为了减少化学药物治疗的毒副作用，提高其治疗效果，将药物、抗体等有效成分靶向定位于肿瘤细胞的靶向治疗策略已经成为当前肿瘤治疗研究和临床实践的热点。抗菌肽（Antimicrobial peptides，AMPs）中的阳离子抗菌肽（Cationic antimicrobialpeptides, CAPs）具有分子量小、多存在内源性靶点、极易穿透肿瘤细胞膜、提高机体免疫应答、抑制肿瘤血管形成、抑制肿瘤生长和转移等特点。CAPs的抗肿瘤活性具有靶向性，肿瘤细胞和正常细胞的细胞膜组成上的基本差异可以解释CAPs对肿瘤细胞的选择性杀伤作用。虽然天然CAPs可以区别肿瘤细胞和正常细胞，但是不同CAPs对肿瘤细胞的特异性识别能力存在显著差异；此外，部分CAPs对正常细胞有一定的毒性和溶血作用。因此，目前急需通过对CAPs分子进行改造来提高其对肿瘤细胞的靶向性并降低其毒性。
本文通过对抗菌肽数据库(http://aps.unmc.edu/AP/main.php)中抗肿瘤抗菌肽进行生物信息学分析，得出净电荷数、疏水性、疏水力矩、两亲性等参数决定抗肿瘤抗菌肽的靶向性能。因此，本研究以以上参数为筛选原则，从本研究室发现的牛蛙抗菌肽中筛选抗肿瘤抗菌肽。因子分析结果显示，净电荷数对于其他参数相对独立，净电荷数分布区域从+1~+5，这一发现就为以改变电荷来进行抗菌肽设计提供了理论基础。Temporin-La是本研究室通过对牛蛙皮肤cDNA文库的筛选所得到的阳离子两亲抗菌肽。Temporin-La属于Temporins家族，对多种肿瘤细胞均有杀伤活性。经过MEGA软件比对分析得到序列中氨基酸的组成特点，总结得到序列模版：F/L/I+L/F+P+L/I/F+L/I/V+G/A+N/S/K+L/F+L+S/N/G+K/G/S+L+L，是典型的α-螺旋结构。根据以上生物信息学分析，将Temporin-La序列中第10位谷氨酸替换为丝氨酸，得到净电荷数为+4的Temporin-Las。RGD肽是一类含有Arg-Gly-Asp氨基酸残基的小肽，RGD肽可以与整合素αvβ3发生特异性结合,抑制肿瘤新生血管的生成并启动肿瘤细胞凋亡。将RGD基序与Temporin-La进行偶联设计得到Temporin-La的三个类似物，分别是Temporin-Las、RGD-La和RGD-Las，应用Antheprot软件和chembiooffice2008进行二级结构和3D结构模拟，结果显示四种多肽均具有α-螺旋二级结构，RGD基序的加入，并不影响抗菌肽部分的3D空间结构。
本文采用MTT细胞毒性实验、ZETA电位测定、流式细胞仪检测整合素表达实验、多肽-细胞PULL-DOWN实验、扫描电镜观察和激光共聚焦实时监测实验等体外实验，研究了Temporin-La及其三个类似物对6种肿瘤细胞（人肺腺癌细胞系A549、人结肠癌细胞系SW1116、人胃癌细胞系BGC-823、人宫颈癌细胞系Hela、人肝癌细胞系HepG2和人肝癌细胞系SMMC-7721）的抗肿瘤活性。并重点对比研究了Temporin-La和嵌合体RGD-Las在抗肿瘤活性和机制上的差异。细胞毒性实验结果表明，四种抗菌肽对以上肿瘤细胞均有杀伤作用，呈浓度依赖性，50μg/mL以下对正常细胞无毒性。ZETA电位测定和多肽-细胞PULL-DOWN实验结果表明正电荷是影响抗菌肽和嵌合体与肿瘤细胞膜结合的主要因素，而α-螺旋的两亲性结构则在抗菌肽插入脂质双分子层中起重要作用。因此本文在维持保守氨基酸不变的情况下，在适当位置改变或置换一些氨基酸，对天然抗菌肽进行改造或人工合成具有更高活性的抗肿瘤抗菌肽。嵌合体RGD-La和RGD-Las对整合素过表达的肿瘤细胞具有选择性。扫描电镜观察发现，Temporin-La和嵌合体RGD-Las均具有极强的膜裂解作用，作用时间迅速，但两种抗菌肽作用位置则具有差异。激光共聚焦显微镜实时监测Temporin-La和嵌合体RGD-Las进入肿瘤细胞人肝癌SMMC-7721动态过程，结果显示，两种多肽穿过细胞膜，进入细胞内部的时间和现象无明显差别，随着时间的递增，大量细胞碎片脱落，细胞核明显皱缩。
本文通过建立裸鼠人肝癌SMMC-7721原位移植瘤模型，采用小动物成像系统观察实验、体内系统穿透实验、体外肿瘤穿透实验（Ex vivo tumor penetrationassay）和肿瘤组织和正常组织中多柔比星(DOX)定量等实验研究了嵌合体RGD-Las的体内靶向性和与DOX联合用药的协同作用。结果显示，RGD-Las具有良好的肿瘤组织靶向性，尾静脉注射药物30min采样，肝部肿瘤部位可见明显绿色荧光，而其他器官组织未见荧光。同样剂量的Temporin-La和RGD-Las作用于荷瘤裸鼠，RGD-Las作用的裸鼠肿瘤组织的伊文斯蓝渗透能力明显强于Temporin-La。两种多肽对心脏、脾脏、肾和脑均无穿透。嵌合体RGD-Las可以增强化疗药物DOX的肿瘤组织穿透深度。HE染色结果显示，嵌合体RGD-Las经尾静脉注射裸鼠作用24h后，可以引起肿瘤组织坏死，使其成为潜在的靶向抗肿瘤药物。
本研究首次建立筛选抗肿瘤抗菌肽的整体分析法，设计并得到具有自主知识产权的肿瘤细胞靶向抗菌肽嵌合体。通过体外实验证实了Temporin-La、Temporin-Las、RGD-La和RGD-Las具有肿瘤细胞靶向杀伤活性，初步阐明抗菌肽嵌合体对肿瘤细胞膜的作用机制；体内实验研究显示Temporin-La和嵌合体RGD-Las具有体内肿瘤组织靶向性，RGD-Las可以增强化疗药物DOX对实体瘤穿透能力。因此，本研究为抗肿瘤抗菌肽在肿瘤靶向治疗上的应用奠定了的理论与实验基础。
Nowadays, the primary treatment of cancer includes surgery, radiotherapy,chemotherapy, immune therapy, monoclonal antibody therapy or other methods.While many chemotherapeutic agents have been developed, most have deleteriousside effects，because they are cytotoxic to both cancer cells and healthy cells andtissues. How to target cancer cells with high specificity and kill cancer cells with highefficiency remains an urgent demand for anticancer drugs. Antimicrobial peptides(AMPs), especially cationic antimicrobial peptides (CAPs), derived from variousspecies (including insects, amphibians, and humans) are bioactive peptides withpotential applications as anticancer agents. As new candidates for anticancer drugs,AMPs possess the advantages of high positive charges, amphipathic α-helices, shortamino acid sequences, low molecular weights, and weak antigenicity.
We first used a whole bioinformatic analysis method as a platform to identifynew anticancer antimicrobial peptides (AMPs). Factor analysis was used to determinehow six parameters (net positive charges,%hydrophobic residues, meanhydrophobicity, Grand average of hydropathicity, amphiphilicity <μH>, andsecondary structure) contributed to structure and activity relationship. We found thatthe net charges was the relative independent factor, which could be used for peptidesdesign. We derived a conserved sequence template (F/L/I+L/F+P+L/I/F+L/I/V+G/A+N/S/K+L/F+L+S/N/G+K/G/S+L+L) from temporins peptides. Thehydrophobic residues were at positions1,2,4,5,8,9,12, and13. Polar residues withpositive charges were most common at position3,7, and11, and position10was themost common site for polar residues with no charges or negative charges.Correspondingly, Glu-10was replaced by a Ser residue (temporin-Las) and thisanalog as well as the parent temporin-La were extended N-terminally with RGDwithout spacing to incorporate into the temporin sequence the integrin αvβ3homingdomain (RGD-La and RGD-Las). Based on these results, we designed a temporin-La analogue (temporin-Las) and related constructs containg the RGD tripeptide, theintegrin αvβ3homing domain (RGD-La and RGD-Las).
MTT assay showed that temporin-La and its synthetic analogs inhibited cancercell proliferation in a dose-dependent manner. We detected a link between the netcharges and integrin αvβ3expression of cancer cell lines and the antitumor activitiesof these peptides. Peptide-cell pull-down experiments revealed that the bindingefficiency of temporin-Las (+4) was higher than that of temporin-La (+3), whileRGD-Las had the strongest affinity. Furthermore, the effect of cell surface charges onpeptide affinity was examined. The zeta potential of the cancer cell lines showed thatall the cell lines carried negative charges. Evidence was provided that the affinitybetween RGD-Las and tumor cell membranes was stronger than other tested peptidesusing a pull-down assay. Morphological changes on the cell membrane induced bytemporin-La and RDG-Las, respectively, were examined by scanning electronmicroscopy (SEM). Additionally, time-dependent morphological changes weredetected by confocal microscopy, where the binding process of RGD-Las to the cellmembrane could be monitored. Since no apoptotic mechanism could be detected ontumor cells treated with RGD-Las, a membrane-disturbing action seems to be themajor mechanism for cell death. At the same time, we observed a lot of pores on thedamaged cell membranes, consistent with the carpet model mechanism. The resultsindicate that the electrostatic interaction between these cationic peptides and theanionic cell membrane is a major determinant of selective cell killing. Thus, the RGDtripeptide is a valuable ligand motif for tumor targeting, which leads to an increasedanticancer efficiency by RGD-Las. These AMPs-derived peptides have clinicalpotential as specifically targeting agents for the treatment of αvβ3positive tumors.Poor penetration of anti-cancer drugs into tumors can be an important factor limitingtheir efficacy.
Studying mouse SMMC-7721tumor models, we show that chimera RGD-Lasincreased tissue permeability in a tumor-specific manner, allowing co-administereddrugs (DOX) to penetrate into extravascular tumor tissue. Importantly, this effect didnot require the drugs to be chemically conjugated to the peptide. HE results showedthat the RGD-Las may induce necrosis of SMMC-7721xenografts in nude mice. Thus, co-administration of chimera RGD-Las may be a valuable way to enhance theefficacy of anti-cancer drugs while reducing their side effects, a primary goal ofcancer therapy research.
In this study, we successfully set a whole bioinformatic analysis method as aplatform to identify new anticancer antimicrobial peptides (AMPs). We found that thenet charges was the relative independent factor, which could be used for peptidesdesign. We detected a link between the net charges and integrin αvβ3expression ofcancer cell lines and the antitumor activities of these peptides.The designed peptidesin tumor imaging showed that chimera RGD-Las could target tumor tissue in vivo,and allowing co-administered drugs (DOX) to penetrate into extravascular tumortissue. The results revealed increased anticancer efficiency of these analogssuggesting clinical potential as specifically targeted anticancer agents.
本文通过对抗菌肽数据库(http://aps.unmc.edu/AP/main.php)中抗肿瘤抗菌肽进行生物信息学分析，得出净电荷数、疏水性、疏水力矩、两亲性等参数决定抗肿瘤抗菌肽的靶向性能。因此，本研究以以上参数为筛选原则，从本研究室发现的牛蛙抗菌肽中筛选抗肿瘤抗菌肽。因子分析结果显示，净电荷数对于其他参数相对独立，净电荷数分布区域从+1~+5，这一发现就为以改变电荷来进行抗菌肽设计提供了理论基础。Temporin-La是本研究室通过对牛蛙皮肤cDNA文库的筛选所得到的阳离子两亲抗菌肽。Temporin-La属于Temporins家族，对多种肿瘤细胞均有杀伤活性。经过MEGA软件比对分析得到序列中氨基酸的组成特点，总结得到序列模版：F/L/I+L/F+P+L/I/F+L/I/V+G/A+N/S/K+L/F+L+S/N/G+K/G/S+L+L，是典型的α-螺旋结构。根据以上生物信息学分析，将Temporin-La序列中第10位谷氨酸替换为丝氨酸，得到净电荷数为+4的Temporin-Las。RGD肽是一类含有Arg-Gly-Asp氨基酸残基的小肽，RGD肽可以与整合素αvβ3发生特异性结合,抑制肿瘤新生血管的生成并启动肿瘤细胞凋亡。将RGD基序与Temporin-La进行偶联设计得到Temporin-La的三个类似物，分别是Temporin-Las、RGD-La和RGD-Las，应用Antheprot软件和chembiooffice2008进行二级结构和3D结构模拟，结果显示四种多肽均具有α-螺旋二级结构，RGD基序的加入，并不影响抗菌肽部分的3D空间结构。
本文采用MTT细胞毒性实验、ZETA电位测定、流式细胞仪检测整合素表达实验、多肽-细胞PULL-DOWN实验、扫描电镜观察和激光共聚焦实时监测实验等体外实验，研究了Temporin-La及其三个类似物对6种肿瘤细胞（人肺腺癌细胞系A549、人结肠癌细胞系SW1116、人胃癌细胞系BGC-823、人宫颈癌细胞系Hela、人肝癌细胞系HepG2和人肝癌细胞系SMMC-7721）的抗肿瘤活性。并重点对比研究了Temporin-La和嵌合体RGD-Las在抗肿瘤活性和机制上的差异。细胞毒性实验结果表明，四种抗菌肽对以上肿瘤细胞均有杀伤作用，呈浓度依赖性，50μg/mL以下对正常细胞无毒性。ZETA电位测定和多肽-细胞PULL-DOWN实验结果表明正电荷是影响抗菌肽和嵌合体与肿瘤细胞膜结合的主要因素，而α-螺旋的两亲性结构则在抗菌肽插入脂质双分子层中起重要作用。因此本文在维持保守氨基酸不变的情况下，在适当位置改变或置换一些氨基酸，对天然抗菌肽进行改造或人工合成具有更高活性的抗肿瘤抗菌肽。嵌合体RGD-La和RGD-Las对整合素过表达的肿瘤细胞具有选择性。扫描电镜观察发现，Temporin-La和嵌合体RGD-Las均具有极强的膜裂解作用，作用时间迅速，但两种抗菌肽作用位置则具有差异。激光共聚焦显微镜实时监测Temporin-La和嵌合体RGD-Las进入肿瘤细胞人肝癌SMMC-7721动态过程，结果显示，两种多肽穿过细胞膜，进入细胞内部的时间和现象无明显差别，随着时间的递增，大量细胞碎片脱落，细胞核明显皱缩。
本文通过建立裸鼠人肝癌SMMC-7721原位移植瘤模型，采用小动物成像系统观察实验、体内系统穿透实验、体外肿瘤穿透实验（Ex vivo tumor penetrationassay）和肿瘤组织和正常组织中多柔比星(DOX)定量等实验研究了嵌合体RGD-Las的体内靶向性和与DOX联合用药的协同作用。结果显示，RGD-Las具有良好的肿瘤组织靶向性，尾静脉注射药物30min采样，肝部肿瘤部位可见明显绿色荧光，而其他器官组织未见荧光。同样剂量的Temporin-La和RGD-Las作用于荷瘤裸鼠，RGD-Las作用的裸鼠肿瘤组织的伊文斯蓝渗透能力明显强于Temporin-La。两种多肽对心脏、脾脏、肾和脑均无穿透。嵌合体RGD-Las可以增强化疗药物DOX的肿瘤组织穿透深度。HE染色结果显示，嵌合体RGD-Las经尾静脉注射裸鼠作用24h后，可以引起肿瘤组织坏死，使其成为潜在的靶向抗肿瘤药物。
本研究首次建立筛选抗肿瘤抗菌肽的整体分析法，设计并得到具有自主知识产权的肿瘤细胞靶向抗菌肽嵌合体。通过体外实验证实了Temporin-La、Temporin-Las、RGD-La和RGD-Las具有肿瘤细胞靶向杀伤活性，初步阐明抗菌肽嵌合体对肿瘤细胞膜的作用机制；体内实验研究显示Temporin-La和嵌合体RGD-Las具有体内肿瘤组织靶向性，RGD-Las可以增强化疗药物DOX对实体瘤穿透能力。因此，本研究为抗肿瘤抗菌肽在肿瘤靶向治疗上的应用奠定了的理论与实验基础。
Nowadays, the primary treatment of cancer includes surgery, radiotherapy,chemotherapy, immune therapy, monoclonal antibody therapy or other methods.While many chemotherapeutic agents have been developed, most have deleteriousside effects，because they are cytotoxic to both cancer cells and healthy cells andtissues. How to target cancer cells with high specificity and kill cancer cells with highefficiency remains an urgent demand for anticancer drugs. Antimicrobial peptides(AMPs), especially cationic antimicrobial peptides (CAPs), derived from variousspecies (including insects, amphibians, and humans) are bioactive peptides withpotential applications as anticancer agents. As new candidates for anticancer drugs,AMPs possess the advantages of high positive charges, amphipathic α-helices, shortamino acid sequences, low molecular weights, and weak antigenicity.
We first used a whole bioinformatic analysis method as a platform to identifynew anticancer antimicrobial peptides (AMPs). Factor analysis was used to determinehow six parameters (net positive charges,%hydrophobic residues, meanhydrophobicity
MTT assay showed that temporin-La and its synthetic analogs inhibited cancercell proliferation in a dose-dependent manner. We detected a link between the netcharges and integrin αvβ3expression of cancer cell lines and the antitumor activitiesof these peptides. Peptide-cell pull-down experiments revealed that the bindingefficiency of temporin-Las (+4) was higher than that of temporin-La (+3), whileRGD-Las had the strongest affinity. Furthermore, the effect of cell surface charges onpeptide affinity was examined. The zeta potential of the cancer cell lines showed thatall the cell lines carried negative charges. Evidence was provided that the affinitybetween RGD-Las and tumor cell membranes was stronger than other tested peptidesusing a pull-down assay. Morphological changes on the cell membrane induced bytemporin-La and RDG-Las, respectively, were examined by scanning electronmicroscopy (SEM). Additionally, time-dependent morphological changes weredetected by confocal microscopy, where the binding process of RGD-Las to the cellmembrane could be monitored. Since no apoptotic mechanism could be detected ontumor cells treated with RGD-Las, a membrane-disturbing action seems to be themajor mechanism for cell death. At the same time, we observed a lot of pores on thedamaged cell membranes, consistent with the carpet model mechanism. The resultsindicate that the electrostatic interaction between these cationic peptides and theanionic cell membrane is a major determinant of selective cell killing. Thus, the RGDtripeptide is a valuable ligand motif for tumor targeting, which leads to an increasedanticancer efficiency by RGD-Las. These AMPs-derived peptides have clinicalpotential as specifically targeting agents for the treatment of αvβ3positive tumors.Poor penetration of anti-cancer drugs into tumors can be an important factor limitingtheir efficacy.
Studying mouse SMMC-7721tumor models, we show that chimera RGD-Lasincreased tissue permeability in a tumor-specific manner, allowing co-administereddrugs (DOX) to penetrate into extravascular tumor tissue. Importantly, this effect didnot require the drugs to be chemically conjugated to the peptide. HE results showedthat the RGD-Las may induce necrosis of SMMC-7721xenografts in nude mice. Thus, co-administration of chimera RGD-Las may be a valuable way to enhance theefficacy of anti-cancer drugs while reducing their side effects, a primary goal ofcancer therapy research.
In this study, we successfully set a whole bioinformatic analysis method as aplatform to identify new anticancer antimicrobial peptides (AMPs). We found that thenet charges was the relative independent factor, which could be used for peptidesdesign. We detected a link between the net charges and integrin αvβ3expression ofcancer cell lines and the antitumor activities of these peptides.The designed peptidesin tumor imaging showed that chimera RGD-Las could target tumor tissue in vivo,and allowing co-administered drugs (DOX) to penetrate into extravascular tumortissue. The results revealed increased anticancer efficiency of these analogssuggesting clinical potential as specifically targeted anticancer agents.
引文
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