通用效应因子tTF/SA选择性诱发肿瘤组织血管栓塞
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摘要
选择性诱发肿瘤组织血管血栓性栓塞从而导致肿瘤组织的缺血性坏死是一种很有前景的抗肿瘤策略。tTF融合蛋白利用导向载体将截短的组织因子tTF选择性地定位于肿瘤组织血管,可以诱发肿瘤组织血管栓塞,阻断肿瘤营养物质和氧气的供给,引发肿瘤缺血性坏死,发挥抗肿瘤作用。由于肿瘤组织单一靶点数量的有限性及表达的异质性,现使用单载体介导的肿瘤血管靶向治疗效果并不理想,多靶点联合治疗是克服这一缺点的有效策略。我们设想以生物素-亲和素体系作为载体与效应因子tTF的桥联系统,利用基因工程技术构建tTF与SA的融合蛋白作为通用效应因子,并与生物素化的肿瘤血管靶向载体联合应用,实现多靶点的肿瘤组织血管靶向治疗。
为了制备靶向通用效应因子tTF/SA融合蛋白,我们利用PCR技术分别克隆与合成截短组织因子tTF和链霉亲和素SA的基因,重组tTF与SA的融合基因,并克隆至表达载体pET22 b(+),在E.coli BL21(DE_3)中表达,镍亲和层析柱纯化tTF/SA融合蛋白。结果表明,我们获得了序列正确的tTF/SA/pET22 b(+)重组子,融合基因在E.coli BL21(DE_3)中获得高效表达。凝血实验和FX活化实验证实,纯化后的融合蛋白具有活化FX和引起血液凝固的能力;ELISA实验证实,融合蛋白能与生物素或生物素化的载体结合。
为了证实通用效应因子和生物素化载体的联合治疗的有效性,我们通过碳二亚胺交联法分别制备整合素配体(RGD)_3多肽和单链抗核抗体M7与生物素的交联物,治疗人胃癌MGC803肿瘤动物模型。生物素化的载体(RGD)_3和M7单独或联合注射后,再分别注射tTF/SA融合蛋白,连续给药5天。结果显示tTF/SA:M7-B组的抑瘤率为43.9%、tTF/SA:(RGD)_3-B组的抑瘤率为27.7%、tTF/SA:[M7+(RGD)_3]-B组的抑瘤率为59%。免疫组化结果显示,(RGD)_3-B能选择性定位于新生的肿瘤血管,M7-B能选择性定位于变性和坏死的肿瘤细胞;病理学观察发现,通用效应因子在生物素化靶向载体介导下能有效地诱发肿瘤组织血管栓塞,导致肿瘤细胞变性坏死;而对正常组织细胞没有毒副作用。
总之,利用基因工程技术表达的tTF/SA融合蛋白保持了组分tTF和SA的活性。在肿瘤动物模型治疗实验中,tTF/SA融合蛋白可以作为通用效应因子与生物素化载体(RGD)_3-B或M7-B或(RGD)_3-B+M7-B使用,并有效地诱发肿瘤组织血管血栓性栓塞、进而导致肿瘤组织细胞缺血坏死和抑制肿瘤生长。本研究证明tTF/SA通用效应因子与多种生物素化载体联合使用可以实现选择性肿瘤组织血管栓塞的多靶点联合治疗。
It is a promising anti-tumor strategy to selectively induce thrombosis in tumor vessels and cause necrosis of the tumor.The truncated Tissue Factor(tTF) could selectively induce thrombosis in tumor vasculature to cut off nutrition and oxygen supplies of tumor,subsequently resulted in necrosis of the tumor and attained anti-tumor effects,when tTF was targeted to the tumor vasculature by the targeting carriers of the tTF fusion protein.Owing to the fewer number and their heterogeneous expression of targets in tumor tissue,the effect of the targeted tTF therapy on tumor blood vessels mediated by single carrier is not satisfied,the multitarget combined therapy may be the promising strategy to overcome the shortcoming.It is assumed that the biotin-strepavidin system be used as the bridge to link the targeting carriers and effector tTF.The fusion proteins tTF/SA constructed by the gene engineering function as a universal effector and then is combined with the various biotinylated carriers,which targeted to tumor blood vessels,to implement the multitarget combination therapy for the thrombosis of tumor blood vessels.
To prepare the targeting universal effector tTF/SA fusion protein,the tTF gene and SA gene were cloned,respectively,and then the fusion gene tTF/SA was constructed by PCR.The fusion gene tTF/SA was inserted into expression vector pET22 b(+) and expressed in E.coli BL21(DE_3).The fusion proteins were purified using Nickel-affinity chromatography column.The results indicated that the recombinant plasmids tTF/SA/pET22 b(+) with correct gene sequence were obtained and expressed with high.yield in E.coli BL21(DE_3).The clotting assay and FX activation assay confirmed that the purified proteins attained the activity of activating FⅩand capacity of causing blood coagulation;the results of ELISA indicated that the fusion protein tTF/SA could bind with Biotin and biotinylated carriers.
To confirm the validity of the combination therapy of universal effector and the biotinylated carriers,the human gastric cancer MGC803 tumor mouse models were constructed,the biotinylated carriers(RGD)_3-B and M7-B,which crosslinked with Biotin by EDC,were injected individually or together,then the fusion proteins tTF/SA were continuously injected for 5 days.The results indicated that the inhibition rates of tTF/SA:M7-B,tTF/SA:(RGD)_3-B,and tTF/SA:[M7+(RGD)_3]-B were 43.9%, 27.7%,and 59%,respectively.The immunohistochemical results confirmed that the biotinylated targeting carriers could combine to their targets specifically.The histological results indicated that the universal effector tTF/SA could selectively and effectively induce thrombosis in tumor blood vessels and cause necrosis of the tumor cells directed by the biotinylated carriers,and no thrombosis and cell necrosis was observed in normal tissues of treated groups.
In summary,the universal effector tTF/SA retained the ability of both tTF and SA.In the treatment experiment,the fusion protein tTF/SA via the biotinylated carriers((RGD)_3-B,M7-B and(RGD)_3-B+M7-B) could selectively and effectively induce thrombosis in tumor blood vessels,inhibit the growth of tumor,and lead the necrosis of tumor tissues.These results testified that the combination of universal effector tTF/SA and various biotinylated carriers can implement the multi-target combination therapy of selective thrombosis in tumor blood vessels.
为了制备靶向通用效应因子tTF/SA融合蛋白,我们利用PCR技术分别克隆与合成截短组织因子tTF和链霉亲和素SA的基因,重组tTF与SA的融合基因,并克隆至表达载体pET22 b(+),在E.coli BL21(DE_3)中表达,镍亲和层析柱纯化tTF/SA融合蛋白。结果表明,我们获得了序列正确的tTF/SA/pET22 b(+)重组子,融合基因在E.coli BL21(DE_3)中获得高效表达。凝血实验和FX活化实验证实,纯化后的融合蛋白具有活化FX和引起血液凝固的能力;ELISA实验证实,融合蛋白能与生物素或生物素化的载体结合。
为了证实通用效应因子和生物素化载体的联合治疗的有效性,我们通过碳二亚胺交联法分别制备整合素配体(RGD)_3多肽和单链抗核抗体M7与生物素的交联物,治疗人胃癌MGC803肿瘤动物模型。生物素化的载体(RGD)_3和M7单独或联合注射后,再分别注射tTF/SA融合蛋白,连续给药5天。结果显示tTF/SA:M7-B组的抑瘤率为43.9%、tTF/SA:(RGD)_3-B组的抑瘤率为27.7%、tTF/SA:[M7+(RGD)_3]-B组的抑瘤率为59%。免疫组化结果显示,(RGD)_3-B能选择性定位于新生的肿瘤血管,M7-B能选择性定位于变性和坏死的肿瘤细胞;病理学观察发现,通用效应因子在生物素化靶向载体介导下能有效地诱发肿瘤组织血管栓塞,导致肿瘤细胞变性坏死;而对正常组织细胞没有毒副作用。
总之,利用基因工程技术表达的tTF/SA融合蛋白保持了组分tTF和SA的活性。在肿瘤动物模型治疗实验中,tTF/SA融合蛋白可以作为通用效应因子与生物素化载体(RGD)_3-B或M7-B或(RGD)_3-B+M7-B使用,并有效地诱发肿瘤组织血管血栓性栓塞、进而导致肿瘤组织细胞缺血坏死和抑制肿瘤生长。本研究证明tTF/SA通用效应因子与多种生物素化载体联合使用可以实现选择性肿瘤组织血管栓塞的多靶点联合治疗。
It is a promising anti-tumor strategy to selectively induce thrombosis in tumor vessels and cause necrosis of the tumor.The truncated Tissue Factor(tTF) could selectively induce thrombosis in tumor vasculature to cut off nutrition and oxygen supplies of tumor,subsequently resulted in necrosis of the tumor and attained anti-tumor effects,when tTF was targeted to the tumor vasculature by the targeting carriers of the tTF fusion protein.Owing to the fewer number and their heterogeneous expression of targets in tumor tissue,the effect of the targeted tTF therapy on tumor blood vessels mediated by single carrier is not satisfied,the multitarget combined therapy may be the promising strategy to overcome the shortcoming.It is assumed that the biotin-strepavidin system be used as the bridge to link the targeting carriers and effector tTF.The fusion proteins tTF/SA constructed by the gene engineering function as a universal effector and then is combined with the various biotinylated carriers,which targeted to tumor blood vessels,to implement the multitarget combination therapy for the thrombosis of tumor blood vessels.
To prepare the targeting universal effector tTF/SA fusion protein,the tTF gene and SA gene were cloned,respectively,and then the fusion gene tTF/SA was constructed by PCR.The fusion gene tTF/SA was inserted into expression vector pET22 b(+) and expressed in E.coli BL21(DE_3).The fusion proteins were purified using Nickel-affinity chromatography column.The results indicated that the recombinant plasmids tTF/SA/pET22 b(+) with correct gene sequence were obtained and expressed with high.yield in E.coli BL21(DE_3).The clotting assay and FX activation assay confirmed that the purified proteins attained the activity of activating FⅩand capacity of causing blood coagulation;the results of ELISA indicated that the fusion protein tTF/SA could bind with Biotin and biotinylated carriers.
To confirm the validity of the combination therapy of universal effector and the biotinylated carriers,the human gastric cancer MGC803 tumor mouse models were constructed,the biotinylated carriers(RGD)_3-B and M7-B,which crosslinked with Biotin by EDC,were injected individually or together,then the fusion proteins tTF/SA were continuously injected for 5 days.The results indicated that the inhibition rates of tTF/SA:M7-B,tTF/SA:(RGD)_3-B,and tTF/SA:[M7+(RGD)_3]-B were 43.9%, 27.7%,and 59%,respectively.The immunohistochemical results confirmed that the biotinylated targeting carriers could combine to their targets specifically.The histological results indicated that the universal effector tTF/SA could selectively and effectively induce thrombosis in tumor blood vessels and cause necrosis of the tumor cells directed by the biotinylated carriers,and no thrombosis and cell necrosis was observed in normal tissues of treated groups.
In summary,the universal effector tTF/SA retained the ability of both tTF and SA.In the treatment experiment,the fusion protein tTF/SA via the biotinylated carriers((RGD)_3-B,M7-B and(RGD)_3-B+M7-B) could selectively and effectively induce thrombosis in tumor blood vessels,inhibit the growth of tumor,and lead the necrosis of tumor tissues.These results testified that the combination of universal effector tTF/SA and various biotinylated carriers can implement the multi-target combination therapy of selective thrombosis in tumor blood vessels.
引文
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