肿瘤特异性标志及生物靶向纳米制剂的研究
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摘要
肿瘤的发生、发展、浸润和转移等生物学特性都是多基因参与、多步骤调控的过程。随着多种蛋白组学技术的发展，使得以承担生命活动的基本执行体的蛋白质水平的高通量研究成为可能，同样从蛋白质整体水平进行研究则更有可能来揭示肿瘤的本质，更有可能发现信号传导途径中的关键节点蛋白，找到具有应用价值的靶点蛋白，进而使得个体化诊断和靶向治疗得以飞速发展。
本课题首先采用比较蛋白组学的高通量技术，筛选和验证与乳腺癌耐药和转移相关蛋白质标志物。成功建立并优化了双向凝胶电泳分离细胞总蛋白的方法，并对部分存在显著差异表达的蛋白质进行了MALDI-TOF/MS质谱鉴定，获得了差异表达蛋白的肽质量指纹图谱（PMF），通过生物信息学的方法进行检索，最终识别出11个差异表达蛋白。这些差异表达蛋白分别涉及肿瘤转移、能量代谢、细胞增殖等，另外还包括一个功能未知蛋白。针对筛选并经过验证的相关基因Annexin a2，应用RNA干扰技术降低人高转移乳腺癌MDA-MB-231细胞中Annexin a2蛋白的表达水平，获得3株Annexin a2表达水平下降80%-100%的稳定细胞株。进一步的细胞功能学实验结果发现Annexin a2表达与高转移乳腺癌细胞的增殖、迁移和侵袭等生物学特性相关，并证实了Annexin a2通过与转录因子STAT3相互作用影响增殖相关基因（c-myc和cyclinD1）和转移相关基因（MMP-2及MMP-9）的表达的作用机制。结果证明Annexin a2在肿瘤进展过程中承担着重要作用，其有可能成为抑制肿瘤增殖和转移的有效的药物靶点。
同时在课题组前期工作基础上，我们以肿瘤细胞膜上高表达的叶酸受体作为靶点，通过将聚乳酸-羟基乙酸共聚物(poly(lactic-co-glycolic acid)，PLGA)微球制备技术同脂质体制备技术相结合，制备了具有核壳结构的纳米载体(folicacid modifed lipid-shell and polymer-core nanoparticles, FLPNPs)。该载体包括了核结构PLGA、赖氨酸壳聚糖十八烷基季铵盐（octadecyl-quaternized l ysinemodified chitosan,OQLCS）作为脂质体的壳、靶向制剂（叶酸）和胆固醇。我们的研究数据表明，包裹脂质体层后，纳米载体的突释作用得到了明显的减弱。流式细胞术和共聚焦显微镜证实，不仅在叶酸受体高表达的Hela细胞还是在叶酸受体低表达的A549细胞中，FLPNPs均显示出较强的细胞内吞能力。体内外实验证实，包载紫杉醇的FLPNPs具有较强的抗肿瘤作用，且毒副作用较小；体内药物分布实验证实，FLPNPs组肿瘤内的药物浓度高于紫杉醇注射液组。上述实验结果证明，包载紫杉醇的FLPNPs作为抗癌纳米药物制剂，具有较高的应用前景。
The de velopment and p rogression of c ancer a re c ommonly t hought t o be amultistep cell-biological process that involves multi-gene disorder and coordination ofmulti c ellular pa thways, thus, the s tudy of a s ingle gene of ten cannot reflect t heentire process of cancer pr ogression. W ith t he a dvancement of pr oteomics, hi ghthroughput techniques have been developed to make it possible to study the complexcellular activities, and to uncover the molecular mechanism of tumorigenesis and gainnew m echanistic i nsights i nto c ancer. In a ddition, i dentification of ke y proteinscontributed t o c ancer p rogression i n t he pr otein-protein i nteraction ne tworks w illprovide novel diagnostic and prognostic biomarkers and potential therapeutic targetsfor cancer, even facilitating the development of personalized, molecularly targetedtherapy.
In the present study, we employ a2D-PAGE and MS based high throughputcomparative proteomics approach t o s creen a nd i dentify pr oteins responsible f ormetastasis and drug resistance of breast cancer. We have successfully established andoptimized two-dimensional ge l e lectrophoresis method f or t he s eparation of t otalcellular protein and identify11di fferentially expressed proteins by using MALDI-TOF/MS followed by a database search. S everal reports showed that these proteinsare involved in tumor metastasis, energy metabolism, and cell proliferation. Withinthese proteins, Anxa2was significantly up-regulated and was further confirmed usingwestern blotting assay. S mall int erference R NA-mediated gene dow n r egulationdemonstrated that Anxa2was responsible for enhanced cell proliferation, migrationand invasion of the MDA-MB-231cells. Further analysis also found that Anxa2alsoplays an important role in the regulation of the expression of proliferation associatedgenes (c-myc and cyclin D1) and metastasis associated genes (MMP-2and MMP-9)through interaction with STAT3. Take together, our results showed that Anxa2maybe a pot ential biomarker f or cancer and m ay b e de veloped i nto a n e ffective drugtargets to inhibit tumor growth and metastasis.
Meanwhile, we also produced a nanocarrier with folic acid modifed lipid-shelland pol ymer-core na noparticles (FLPNPs) by c ombining poly(D,L-lactide-co-glycolide)(PLGA) microspheres w ith l iposome technology. T he na nocarrier w ascomposed of a P LGA core s urrounded b y a s hell m ade of PEGylated octadecyl-quaternized lysine modifed chitosan (PEG-OQLCS), and targeted to folate receptor, which was highly expressed on t he tumor cell membrane. Our data showed that thetrend of burst release was more apparent for P LGANPs than that of LPNPs andFLPNP. The lipid and FAmodfied lipid outside the PLGA NPs retarded the PTXrelease f rom t he P LGAN Ps. The i nternalization fecfiency of FLPNPs weredemonstrated i n FR-positive H ela can cer cell a nd FR-negative A549c ell b yfowcytometry and confocal microscopy. In vitro and in vivo studies demonstrated thatPTX l oaded F LPNPs not onl y e xhibits a hi gher a ntitumor a ctivity but a lsosignifcantly reduces the toxicity and improves the bioavailability as compared to thatof the commercial PTX formulation (Taxol). Our data indicate that PTX loadedFLPNPs are a promising nano-sized drug formulation for cancer therapy.
本课题首先采用比较蛋白组学的高通量技术，筛选和验证与乳腺癌耐药和转移相关蛋白质标志物。成功建立并优化了双向凝胶电泳分离细胞总蛋白的方法，并对部分存在显著差异表达的蛋白质进行了MALDI-TOF/MS质谱鉴定，获得了差异表达蛋白的肽质量指纹图谱（PMF），通过生物信息学的方法进行检索，最终识别出11个差异表达蛋白。这些差异表达蛋白分别涉及肿瘤转移、能量代谢、细胞增殖等，另外还包括一个功能未知蛋白。针对筛选并经过验证的相关基因Annexin a2，应用RNA干扰技术降低人高转移乳腺癌MDA-MB-231细胞中Annexin a2蛋白的表达水平，获得3株Annexin a2表达水平下降80%-100%的稳定细胞株。进一步的细胞功能学实验结果发现Annexin a2表达与高转移乳腺癌细胞的增殖、迁移和侵袭等生物学特性相关，并证实了Annexin a2通过与转录因子STAT3相互作用影响增殖相关基因（c-myc和cyclinD1）和转移相关基因（MMP-2及MMP-9）的表达的作用机制。结果证明Annexin a2在肿瘤进展过程中承担着重要作用，其有可能成为抑制肿瘤增殖和转移的有效的药物靶点。
同时在课题组前期工作基础上，我们以肿瘤细胞膜上高表达的叶酸受体作为靶点，通过将聚乳酸-羟基乙酸共聚物(poly(lactic-co-glycolic acid)，PLGA)微球制备技术同脂质体制备技术相结合，制备了具有核壳结构的纳米载体(folicacid modifed lipid-shell and polymer-core nanoparticles, FLPNPs)。该载体包括了核结构PLGA、赖氨酸壳聚糖十八烷基季铵盐（octadecyl-quaternized l ysinemodified chitosan,OQLCS）作为脂质体的壳、靶向制剂（叶酸）和胆固醇。我们的研究数据表明，包裹脂质体层后，纳米载体的突释作用得到了明显的减弱。流式细胞术和共聚焦显微镜证实，不仅在叶酸受体高表达的Hela细胞还是在叶酸受体低表达的A549细胞中，FLPNPs均显示出较强的细胞内吞能力。体内外实验证实，包载紫杉醇的FLPNPs具有较强的抗肿瘤作用，且毒副作用较小；体内药物分布实验证实，FLPNPs组肿瘤内的药物浓度高于紫杉醇注射液组。上述实验结果证明，包载紫杉醇的FLPNPs作为抗癌纳米药物制剂，具有较高的应用前景。
The de velopment and p rogression of c ancer a re c ommonly t hought t o be amultistep cell-biological process that involves multi-gene disorder and coordination ofmulti c ellular pa thways, thus, the s tudy of a s ingle gene of ten cannot reflect t heentire process of cancer pr ogression. W ith t he a dvancement of pr oteomics, hi ghthroughput techniques have been developed to make it possible to study the complexcellular activities, and to uncover the molecular mechanism of tumorigenesis and gainnew m echanistic i nsights i nto c ancer. In a ddition, i dentification of ke y proteinscontributed t o c ancer p rogression i n t he pr otein-protein i nteraction ne tworks w illprovide novel diagnostic and prognostic biomarkers and potential therapeutic targetsfor cancer, even facilitating the development of personalized, molecularly targetedtherapy.
In the present study, we employ a2D-PAGE and MS based high throughputcomparative proteomics approach t o s creen a nd i dentify pr oteins responsible f ormetastasis and drug resistance of breast cancer. We have successfully established andoptimized two-dimensional ge l e lectrophoresis method f or t he s eparation of t otalcellular protein and identify11di fferentially expressed proteins by using MALDI-TOF/MS followed by a database search. S everal reports showed that these proteinsare involved in tumor metastasis, energy metabolism, and cell proliferation. Withinthese proteins, Anxa2was significantly up-regulated and was further confirmed usingwestern blotting assay. S mall int erference R NA-mediated gene dow n r egulationdemonstrated that Anxa2was responsible for enhanced cell proliferation, migrationand invasion of the MDA-MB-231cells. Further analysis also found that Anxa2alsoplays an important role in the regulation of the expression of proliferation associatedgenes (c-myc and cyclin D1) and metastasis associated genes (MMP-2and MMP-9)through interaction with STAT3. Take together, our results showed that Anxa2maybe a pot ential biomarker f or cancer and m ay b e de veloped i nto a n e ffective drugtargets to inhibit tumor growth and metastasis.
Meanwhile, we also produced a nanocarrier with folic acid modifed lipid-shelland pol ymer-core na noparticles (FLPNPs) by c ombining poly(D,L-lactide-co-glycolide)(PLGA) microspheres w ith l iposome technology. T he na nocarrier w ascomposed of a P LGA core s urrounded b y a s hell m ade of PEGylated octadecyl-quaternized lysine modifed chitosan (PEG-OQLCS), and targeted to folate receptor, which was highly expressed on t he tumor cell membrane. Our data showed that thetrend of burst release was more apparent for P LGANPs than that of LPNPs andFLPNP. The lipid and FAmodfied lipid outside the PLGA NPs retarded the PTXrelease f rom t he P LGAN Ps. The i nternalization fecfiency of FLPNPs weredemonstrated i n FR-positive H ela can cer cell a nd FR-negative A549c ell b yfowcytometry and confocal microscopy. In vitro and in vivo studies demonstrated thatPTX l oaded F LPNPs not onl y e xhibits a hi gher a ntitumor a ctivity but a lsosignifcantly reduces the toxicity and improves the bioavailability as compared to thatof the commercial PTX formulation (Taxol). Our data indicate that PTX loadedFLPNPs are a promising nano-sized drug formulation for cancer therapy.
引文
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