肝癌靶向多肽的筛选及X1/MePEG-PLA-CS纳米粒的靶向性研究
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摘要
肝细胞癌(hepatocellular carcinoma, HCC)是我国最常见的恶性肿瘤之一,其死亡率居恶性肿瘤的第2位。HCC的治疗方法主要包括肝切除术、原位肝移植、肝动脉栓塞化疗、经皮无水酒精注射、射频消融、微波消融、冷冻术、放疗、抗激素疗法、生物治疗及中药治疗等。目前,手术切除仍是治疗原发性肝癌的首选方法,然而肝癌患者实施根治性切除后,5年复发率高、转移率高,仍是肝癌临床治疗的难题。
近年来,随着基因转移技术的日趋成熟,基因治疗已经成为生物科学和临床医学的研究热点之一。纳米粒基因转运体是近年发展起来的一种新型的非病毒基因转运载体。它是将DNA、RNA等基因治疗分子包裹在纳米颗粒之中或吸附在其表面,同时也在颗粒表面偶联特异性的靶向分子,通过靶向分子与细胞表面特异性受体结合,在细胞摄取作用下进入胞内,实现安全有效的靶向性基因治疗。筛选肝癌细胞特异性靶向分子,并将其与纳米基因载体结合,已成为提高纳米基因载体肝癌治疗效果的关键问题之一。
为此,本文通过噬菌体展示肽库技术,筛选获得了一批能够与肝癌细胞特异性结合的短肽,对其与肝癌细胞的结合特异性进行鉴定。本研究为制备纳米基因载体转运系统,使其能有效的保护转运基因不被核酶降解,并具备较高的基因转染效率、有效的输送基因至靶位点以及良好的生物相容性奠定了实验基础。
第一部分噬菌体肽库技术筛选人肝癌细胞HepG2特异性粘附肽
目的：
通过噬菌体展示肽库技术,使用体外细胞和动物体内,筛选出能够和人肝癌细胞HepG2结合紧密的短肽。
方法：
(1)以人肝癌细胞(HepG2)为筛选靶细胞,对噬菌体随机十二库(Ph.D.-12TMPhage Display Peptide Library Kit)进行三轮体外细胞筛选。建立HepG2荷瘤裸鼠实验动物模型,进行一轮动物体内筛选。
(2)通过体外、体内共四轮筛选后,随机挑取30个噬菌体克隆,取DNA序列测定,并进行氨基酸序列的同源性分析。
结果：
(1)经过筛选使噬菌体在HepG2细胞上出现了显著富集,回收噬菌体的滴度由第一轮的7.2×103pfu增加到第三轮筛选后的2.5×106pfu,增加了300余倍,回收率也显著提高,由第一轮的4.8×10-6增至第三轮筛选后的1.67×10-3。
(2)挑取的30个样本中有27个噬菌体克隆测序结果有效,这些噬菌体克隆的序列中有部分重复,其中序列X1重复19次,序列X2重复3次,序列X3重复4次,序列X4重复1次。重复最多的序列为X1 (QSFASLTDPRVL)。经BLAST分析发现,在已知蛋白质数据库中未发现与此短肽序列完全一致或具有较好同源性的蛋白质分子。
结论：
成功地从噬菌体随机12肽文库中筛选到了在体内、体外均具有特异性靶向肝癌细胞和肝癌组织能力的噬菌体克隆。
第二部分肝癌特异性粘附肽的特异性鉴定
目的：
分析鉴定X1噬菌体克隆及人工合成短肽SA1与肝癌细胞HepG2及肝癌组织结合的特异性。
方法：
(1)ELISA法鉴定所选噬菌体单克隆与HepG2细胞的结合特异性。
(2)通过免疫细胞化学染色,鉴定X1噬菌体克隆与肝癌细胞结合的特异性；通过免疫组织化学染色,鉴定X1噬菌体克隆与人肝癌组织结合的特异性。
(3)利用免疫荧光技术观察人工合成肽SA1与肝癌细胞HepG2的结合特异性。
(4)体内回输、免疫组织化学方法鉴定噬菌体克隆在体内的特异性靶向效果。
结果：
(1)所筛选出来的噬菌体都具有较好的肿瘤细胞特异性结合能力,其中阳性最高的克隆也正是在随机测序中重复频率最高的序列为X1的噬菌体克隆。
(2)免疫细胞化学染色及免疫组织化学染色均显示,X1噬菌体克隆对肝癌细胞的结合靶向性明显高于对照细胞,并能与肝癌组织特异性结合。
(3)免疫荧光显色证实,FITC-SA1肽能特异性地结合于肝癌细胞的胞膜及核周胞浆。
(4)噬菌体肽X1在肿瘤组织中比其他正常组织中有更高的富集效果,说明通过血液循环,此噬菌体肽能与肿瘤组织能特异性结合。
结论：
X1肽(QSFASLTDPRVL)是所有筛选得到的克隆中具有最强的特异性结合能力的,可以特异性地结合肝癌细胞和肝癌组织,而与正常肝细胞和肝组织没有明显的结合。同时X1肽具有很好的体内靶向活性,可以通过血液循环系统迅速、特异地富集到肿瘤组织中。
第三部分Xl/MePEG-PLA-CS纳米粒的制备及其靶向性研究
目的：
构建纳米基因载体转运系统,使其能有效的保护转运基因不被核酶降解,并具备较高的基因转染效率、有效的输送基因至靶位点以及良好的生物相容性。
方法：
(1)制备甲氧基聚乙二醇-聚乳酸-壳聚糖(MePEG-PLA-CS)纳米粒,检测其粒径、DNA结合效率及细胞毒性。
(2)将噬菌体X1肽与MePEG-PLA-CS纳米颗粒偶联,观察其对肝癌细胞转染效率的影响。
结果：
(1)制备的MePEG-PLA-CS纳米粒粒径为103.2±9.6nm,表面带正电荷,DNA结合效率为93.2±2.9%,可保护所携带DNA免受核酸酶的降解；对正常的肝细胞(L-02)在一定的剂量范围内无细胞毒性,只在高浓度下才会表现出一定的细胞毒性作用。
(2)与脂质体、MePEG-PLA-CS纳米粒比较,偶联了噬菌体X1肽的MePEG-PLA-CS纳米粒的转染效率更高。
结论：
制备的MePEG-PLA-CS纳米粒是一种稳定、低毒高效的纳米基因载体；有X1肽靶向的MePEG-PLA-CS纳米粒,具有更高的转染效率,能进一步靶向肝癌HepG2细胞,为肝癌的靶向诊断及治疗奠定了实验基础。
Hepatocellular carcinoma(HCC) is one of the most common and malignant tumors, and it has the second mortality rate among malignant tumors in China. Thus, and treatment of HCC is extremely critical. The treatment of HCC include liver resection, orthotopic liver transplantation (OLT), transcatheter arterial chemoembolization (TACE), percutaneous ethanol injection (PEI), radiofrequency ablation (RFA), microwave ablation (MCT), frozen surgery, radiotherapy, anti-hormone therapy, biological therapy and traditional Chinese medicine treatment etc. At present, surgical resection of primary liver cancer is still the preferred method. However, after radical resection, high recurrence rate after 5 years and high metastasis ratio are still problems in clinical therapy for HCC.
In recent years, gene therapy has become popular in biological science and clinical research as the gene transfer techniques matures day by day. Nanoparticle is developing as a new non-viral gene delivery vector. Gene therapeutical molecules molecules, such as DNA, RNA, are are encapsulated into or loaded on the surface of nanoparticles. At the same time, specific ligands and monoclonal antibodies are linked to the surface of nanoparticles. The nanopartieles/DNA complexes can be taken into target cells by receptor-mediated endocytosis, so that the effective target gene therapy is achieved.
Therefore, we screened the peptides that bind specifically to the hepatoma cells using phage display peptides library, and identified the specificity of the phages to hepatoma cells. We also constructed a gene delivery system with high efficiency of gene transfer, targeting ability, efficiency of protection to DNA from DNase degradation and good biocompatibility, especially high stability and the ability to prolong gene transfer. Our research established good scientific foundation for the application of the nanoparticle-mediated gene delivery and gene therapy.
Chapter one
Screening for hepatocellular carcinoma cell specific binding peptides
Objective:
To screen the peptides that bind specifically to the hepatoma cells using in vitro and in vivo phage display technology.
Methods:
(1) Three rounds of panning were conducted in vitro, which were targeted at HepG2 cell lines. Experimental Animal Models of hepatoma were established on nude mouse, and one round of panning was conducted in vivo.
(2) After 4 rounds of panning,30 phage clones picked randomly were sequenced to identify the consensus sequence.
Results:
(1) After 4 rounds of panning in vitro, phages that bind to the HepG2 cells were enriched from 7.2×103pfu at the first round to 2.5×106pfu at the third round of panning (with an increase of more than 300-fold); the output/input ratio was also increased from 4.8×10-6 at the first round to 1.67x 10"3 at the third round of panning.
(2) After panning from hepatoma cells in vitro and in vivo,30 phage clones were randomly picked and sequenced.4 sequences were obtained from these 30 clones. X1 was repeated 19 times, X2 was repeated 3 times, X3 was repeated 4 times, and X4 was repeated 1 time. Among them, X1 (QSFASLTDPRVL) was the most repeats. Low homology between the peptide sequences was displayed by the phages and no known proteins was identified by BLAST analysis.
Conclusions:
Peptides that can specifically bind to hepato-carcinoma cells both in vitro and in vivo were selected from 12-phage display library by in vitro and in vivo phage display technology.
Chapter Two
Identification of binding specificity of X1 phage and peptide SA1 to Hepatoma cells
Objective:
To identify the affinity of X1 phage and peptide SA1 to hepatoma carcinoma cells in order to make nano-drug carrier with high target to hepatoma in the future.
Methods:
(1) The affinity of phages with hepatoma cells was examined by enzyme-linked immunosorbent assay (ELISA).
(2) Immunocytochemical staining were performed to determine the specificity of the phages to hepatoma cells, and immunohistochemical staining was used to examine the binding specificity of the phages to hepatoma tissues.
(3) Immunoflurescence microscopy was used to study the binding of synthesized peptides to hepatoma cells.
(4) Identifying the targeting effectiveness of phages by injection in vivo and immunohistochemical staining.
Results:
(1) The phages selected by screening all have specific binding affinity to hepatoma cells, and the highest positive is the phage X1 (QSFASLTDPRVL) the most repeats.
(2) Immunocytochemical staining and immunohistochemical staining suggested that X1 phage preferably binds to hepatoma cells rather than controls, and phage was also found to be able to bind to hepatoma tissue sections.
(3) Using immunofluorescence microscopy, fluorescence labeled FITC-SA1 peptide was observed on the membrane and in the perinuclear cytoplasm of hepatoma cells.
(4) The X1 phage shows higher enrichment in tissue of tumor than normal tissue, it could specifically bind to hepatoma tissues after blood circulation.
Conclusions:
The peptide X1 (QSFASLTDPRVL) has the best targeting ability among all candidates. It can bind to hepatocarcinoma cells and hepatocarcinoma tissues, but not delete normal liver cells. And this peptide also has the specific binding ability in vivo; it can accumulate to the tumor tissues rapidly through the blood vessel system.
Chapter Three
The preparation and targeting study of X1/MePEG-PLA-CS nanoparticle
Objective:
To construct an idea gene delivery system with high efficacy of gene transfer, targeting ability, effect of protection to DNA from DNase degradation and good biocompatibility, especially high stability and the ability to prolong gene transfer.
Methods:
(1) Using copolymer methoxypolyethyleneglycol-PLA (MePEG-PLA), and chitosan (CS) to prepare MePEG-PLA-CS nanoparticle. Detect the particle diameter and efficiency of DNA and cytotoxicity.
(2) Coupling the peptide X1 and MePEG-PLA, observing the effect of transfection efficiency with X1/MePEG-PLA-CS nanoparticle.
Results:
(1) The particle diameter of MePEG-PLA-CS is 103.2±9.6 nm, the surface bands positive charge, efficiency of DNA is 93.2±2.9%, MePEG-PLA-CS/DNA complexes could protect the DNA from degradation of DNaseⅠ.In our research,we found that MePEG-PLA-CS nanoparticles had no obvious cell toxicity to L-02 cells at proper concentration,but cell toxicity could be showed at high concentration.
(2) The MePEG-PLA-CS nanoparticle that binds phage X1 has higher transfection efficiency compared with MePEG-PLA-CS nanoparticle.
Conclusions:
The MePEG-PLA-CS is a stable nanoparticle and had higher transfection efficiency while with much lowert oxicity in vivo. The MePEG-PLA-CS nanoparticle binding with phage X1 has higher transfection efficiency compared with MePEG-PLA-CS nanoparticle. Furtherly targeting to hepatoma carcinoma cell, established experimental fundament for Diagnosis and treatment of HCC.
近年来,随着基因转移技术的日趋成熟,基因治疗已经成为生物科学和临床医学的研究热点之一。纳米粒基因转运体是近年发展起来的一种新型的非病毒基因转运载体。它是将DNA、RNA等基因治疗分子包裹在纳米颗粒之中或吸附在其表面,同时也在颗粒表面偶联特异性的靶向分子,通过靶向分子与细胞表面特异性受体结合,在细胞摄取作用下进入胞内,实现安全有效的靶向性基因治疗。筛选肝癌细胞特异性靶向分子,并将其与纳米基因载体结合,已成为提高纳米基因载体肝癌治疗效果的关键问题之一。
为此,本文通过噬菌体展示肽库技术,筛选获得了一批能够与肝癌细胞特异性结合的短肽,对其与肝癌细胞的结合特异性进行鉴定。本研究为制备纳米基因载体转运系统,使其能有效的保护转运基因不被核酶降解,并具备较高的基因转染效率、有效的输送基因至靶位点以及良好的生物相容性奠定了实验基础。
第一部分噬菌体肽库技术筛选人肝癌细胞HepG2特异性粘附肽
目的：
通过噬菌体展示肽库技术,使用体外细胞和动物体内,筛选出能够和人肝癌细胞HepG2结合紧密的短肽。
方法：
(1)以人肝癌细胞(HepG2)为筛选靶细胞,对噬菌体随机十二库(Ph.D.-12TMPhage Display Peptide Library Kit)进行三轮体外细胞筛选。建立HepG2荷瘤裸鼠实验动物模型,进行一轮动物体内筛选。
(2)通过体外、体内共四轮筛选后,随机挑取30个噬菌体克隆,取DNA序列测定,并进行氨基酸序列的同源性分析。
结果：
(1)经过筛选使噬菌体在HepG2细胞上出现了显著富集,回收噬菌体的滴度由第一轮的7.2×103pfu增加到第三轮筛选后的2.5×106pfu,增加了300余倍,回收率也显著提高,由第一轮的4.8×10-6增至第三轮筛选后的1.67×10-3。
(2)挑取的30个样本中有27个噬菌体克隆测序结果有效,这些噬菌体克隆的序列中有部分重复,其中序列X1重复19次,序列X2重复3次,序列X3重复4次,序列X4重复1次。重复最多的序列为X1 (QSFASLTDPRVL)。经BLAST分析发现,在已知蛋白质数据库中未发现与此短肽序列完全一致或具有较好同源性的蛋白质分子。
结论：
成功地从噬菌体随机12肽文库中筛选到了在体内、体外均具有特异性靶向肝癌细胞和肝癌组织能力的噬菌体克隆。
第二部分肝癌特异性粘附肽的特异性鉴定
目的：
分析鉴定X1噬菌体克隆及人工合成短肽SA1与肝癌细胞HepG2及肝癌组织结合的特异性。
方法：
(1)ELISA法鉴定所选噬菌体单克隆与HepG2细胞的结合特异性。
(2)通过免疫细胞化学染色,鉴定X1噬菌体克隆与肝癌细胞结合的特异性；通过免疫组织化学染色,鉴定X1噬菌体克隆与人肝癌组织结合的特异性。
(3)利用免疫荧光技术观察人工合成肽SA1与肝癌细胞HepG2的结合特异性。
(4)体内回输、免疫组织化学方法鉴定噬菌体克隆在体内的特异性靶向效果。
结果：
(1)所筛选出来的噬菌体都具有较好的肿瘤细胞特异性结合能力,其中阳性最高的克隆也正是在随机测序中重复频率最高的序列为X1的噬菌体克隆。
(2)免疫细胞化学染色及免疫组织化学染色均显示,X1噬菌体克隆对肝癌细胞的结合靶向性明显高于对照细胞,并能与肝癌组织特异性结合。
(3)免疫荧光显色证实,FITC-SA1肽能特异性地结合于肝癌细胞的胞膜及核周胞浆。
(4)噬菌体肽X1在肿瘤组织中比其他正常组织中有更高的富集效果,说明通过血液循环,此噬菌体肽能与肿瘤组织能特异性结合。
结论：
X1肽(QSFASLTDPRVL)是所有筛选得到的克隆中具有最强的特异性结合能力的,可以特异性地结合肝癌细胞和肝癌组织,而与正常肝细胞和肝组织没有明显的结合。同时X1肽具有很好的体内靶向活性,可以通过血液循环系统迅速、特异地富集到肿瘤组织中。
第三部分Xl/MePEG-PLA-CS纳米粒的制备及其靶向性研究
目的：
构建纳米基因载体转运系统,使其能有效的保护转运基因不被核酶降解,并具备较高的基因转染效率、有效的输送基因至靶位点以及良好的生物相容性。
方法：
(1)制备甲氧基聚乙二醇-聚乳酸-壳聚糖(MePEG-PLA-CS)纳米粒,检测其粒径、DNA结合效率及细胞毒性。
(2)将噬菌体X1肽与MePEG-PLA-CS纳米颗粒偶联,观察其对肝癌细胞转染效率的影响。
结果：
(1)制备的MePEG-PLA-CS纳米粒粒径为103.2±9.6nm,表面带正电荷,DNA结合效率为93.2±2.9%,可保护所携带DNA免受核酸酶的降解；对正常的肝细胞(L-02)在一定的剂量范围内无细胞毒性,只在高浓度下才会表现出一定的细胞毒性作用。
(2)与脂质体、MePEG-PLA-CS纳米粒比较,偶联了噬菌体X1肽的MePEG-PLA-CS纳米粒的转染效率更高。
结论：
制备的MePEG-PLA-CS纳米粒是一种稳定、低毒高效的纳米基因载体；有X1肽靶向的MePEG-PLA-CS纳米粒,具有更高的转染效率,能进一步靶向肝癌HepG2细胞,为肝癌的靶向诊断及治疗奠定了实验基础。
Hepatocellular carcinoma(HCC) is one of the most common and malignant tumors, and it has the second mortality rate among malignant tumors in China. Thus, and treatment of HCC is extremely critical. The treatment of HCC include liver resection, orthotopic liver transplantation (OLT), transcatheter arterial chemoembolization (TACE), percutaneous ethanol injection (PEI), radiofrequency ablation (RFA), microwave ablation (MCT), frozen surgery, radiotherapy, anti-hormone therapy, biological therapy and traditional Chinese medicine treatment etc. At present, surgical resection of primary liver cancer is still the preferred method. However, after radical resection, high recurrence rate after 5 years and high metastasis ratio are still problems in clinical therapy for HCC.
In recent years, gene therapy has become popular in biological science and clinical research as the gene transfer techniques matures day by day. Nanoparticle is developing as a new non-viral gene delivery vector. Gene therapeutical molecules molecules, such as DNA, RNA, are are encapsulated into or loaded on the surface of nanoparticles. At the same time, specific ligands and monoclonal antibodies are linked to the surface of nanoparticles. The nanopartieles/DNA complexes can be taken into target cells by receptor-mediated endocytosis, so that the effective target gene therapy is achieved.
Therefore, we screened the peptides that bind specifically to the hepatoma cells using phage display peptides library, and identified the specificity of the phages to hepatoma cells. We also constructed a gene delivery system with high efficiency of gene transfer, targeting ability, efficiency of protection to DNA from DNase degradation and good biocompatibility, especially high stability and the ability to prolong gene transfer. Our research established good scientific foundation for the application of the nanoparticle-mediated gene delivery and gene therapy.
Chapter one
Screening for hepatocellular carcinoma cell specific binding peptides
Objective:
To screen the peptides that bind specifically to the hepatoma cells using in vitro and in vivo phage display technology.
Methods:
(1) Three rounds of panning were conducted in vitro, which were targeted at HepG2 cell lines. Experimental Animal Models of hepatoma were established on nude mouse, and one round of panning was conducted in vivo.
(2) After 4 rounds of panning,30 phage clones picked randomly were sequenced to identify the consensus sequence.
Results:
(1) After 4 rounds of panning in vitro, phages that bind to the HepG2 cells were enriched from 7.2×103pfu at the first round to 2.5×106pfu at the third round of panning (with an increase of more than 300-fold); the output/input ratio was also increased from 4.8×10-6 at the first round to 1.67x 10"3 at the third round of panning.
(2) After panning from hepatoma cells in vitro and in vivo,30 phage clones were randomly picked and sequenced.4 sequences were obtained from these 30 clones. X1 was repeated 19 times, X2 was repeated 3 times, X3 was repeated 4 times, and X4 was repeated 1 time. Among them, X1 (QSFASLTDPRVL) was the most repeats. Low homology between the peptide sequences was displayed by the phages and no known proteins was identified by BLAST analysis.
Conclusions:
Peptides that can specifically bind to hepato-carcinoma cells both in vitro and in vivo were selected from 12-phage display library by in vitro and in vivo phage display technology.
Chapter Two
Identification of binding specificity of X1 phage and peptide SA1 to Hepatoma cells
Objective:
To identify the affinity of X1 phage and peptide SA1 to hepatoma carcinoma cells in order to make nano-drug carrier with high target to hepatoma in the future.
Methods:
(1) The affinity of phages with hepatoma cells was examined by enzyme-linked immunosorbent assay (ELISA).
(2) Immunocytochemical staining were performed to determine the specificity of the phages to hepatoma cells, and immunohistochemical staining was used to examine the binding specificity of the phages to hepatoma tissues.
(3) Immunoflurescence microscopy was used to study the binding of synthesized peptides to hepatoma cells.
(4) Identifying the targeting effectiveness of phages by injection in vivo and immunohistochemical staining.
Results:
(1) The phages selected by screening all have specific binding affinity to hepatoma cells, and the highest positive is the phage X1 (QSFASLTDPRVL) the most repeats.
(2) Immunocytochemical staining and immunohistochemical staining suggested that X1 phage preferably binds to hepatoma cells rather than controls, and phage was also found to be able to bind to hepatoma tissue sections.
(3) Using immunofluorescence microscopy, fluorescence labeled FITC-SA1 peptide was observed on the membrane and in the perinuclear cytoplasm of hepatoma cells.
(4) The X1 phage shows higher enrichment in tissue of tumor than normal tissue, it could specifically bind to hepatoma tissues after blood circulation.
Conclusions:
The peptide X1 (QSFASLTDPRVL) has the best targeting ability among all candidates. It can bind to hepatocarcinoma cells and hepatocarcinoma tissues, but not delete normal liver cells. And this peptide also has the specific binding ability in vivo; it can accumulate to the tumor tissues rapidly through the blood vessel system.
Chapter Three
The preparation and targeting study of X1/MePEG-PLA-CS nanoparticle
Objective:
To construct an idea gene delivery system with high efficacy of gene transfer, targeting ability, effect of protection to DNA from DNase degradation and good biocompatibility, especially high stability and the ability to prolong gene transfer.
Methods:
(1) Using copolymer methoxypolyethyleneglycol-PLA (MePEG-PLA), and chitosan (CS) to prepare MePEG-PLA-CS nanoparticle. Detect the particle diameter and efficiency of DNA and cytotoxicity.
(2) Coupling the peptide X1 and MePEG-PLA, observing the effect of transfection efficiency with X1/MePEG-PLA-CS nanoparticle.
Results:
(1) The particle diameter of MePEG-PLA-CS is 103.2±9.6 nm, the surface bands positive charge, efficiency of DNA is 93.2±2.9%, MePEG-PLA-CS/DNA complexes could protect the DNA from degradation of DNaseⅠ.In our research,we found that MePEG-PLA-CS nanoparticles had no obvious cell toxicity to L-02 cells at proper concentration,but cell toxicity could be showed at high concentration.
(2) The MePEG-PLA-CS nanoparticle that binds phage X1 has higher transfection efficiency compared with MePEG-PLA-CS nanoparticle.
Conclusions:
The MePEG-PLA-CS is a stable nanoparticle and had higher transfection efficiency while with much lowert oxicity in vivo. The MePEG-PLA-CS nanoparticle binding with phage X1 has higher transfection efficiency compared with MePEG-PLA-CS nanoparticle. Furtherly targeting to hepatoma carcinoma cell, established experimental fundament for Diagnosis and treatment of HCC.
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