适配子靶向治疗药物的研究进展
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摘要
适配子(aptamer)是通过体外指数级富集的配体系统进化(SELEX)技术筛选得到的能折叠成三维空间结构的单链DNA/RNA寡核苷酸。适配子可特异性识别细胞表面的分子标记,与单克隆抗体相比,具有相似甚至优于抗体的特征,如高特异性、高亲和力、易于修饰、化学性质稳定、无毒性及低免疫原性等。基于适配子的这些优势,除了自身用作治疗剂,也能特异性地运载药物、纳米粒子、核酸治疗剂到靶细胞内,成为一种能靶向递送治疗药物到细胞、低毒高效的新型工具。文章论述近几年适配子用于靶向治疗的最新进展,为肿瘤等疾病的治疗提供新思路。
Aptamers,screened by the in vitro process known as Systematic Evolution of Ligands by EXponential Enrichment( SELEX),are single stranded DNA/RNA oligonucleotides that can be folded into three dimensional spatialstructure. They can specifically recognize the molecular markers on the cell surface. Compared with monoclonal antibodies,aptamers possess similar or even superior characteristics,such as high specificity and affinity,easy for modification,excellet chemical stability,non-toxicity and low immunogenicity. Due to these advantages,aptamers are emerging as a promising tool to targeted delivery of therapeutic drugs into cells,with low toxicity and high efficacy. They can not only be used as therapeutic agent,specific drug carrier,to deliver such as drugs,nanoparticles,nucleic acids to targeted cells. This review discusses recent advances of aptamers applied for targeted therapy.
Aptamers,screened by the in vitro process known as Systematic Evolution of Ligands by EXponential Enrichment( SELEX),are single stranded DNA/RNA oligonucleotides that can be folded into three dimensional spatialstructure. They can specifically recognize the molecular markers on the cell surface. Compared with monoclonal antibodies,aptamers possess similar or even superior characteristics,such as high specificity and affinity,easy for modification,excellet chemical stability,non-toxicity and low immunogenicity. Due to these advantages,aptamers are emerging as a promising tool to targeted delivery of therapeutic drugs into cells,with low toxicity and high efficacy. They can not only be used as therapeutic agent,specific drug carrier,to deliver such as drugs,nanoparticles,nucleic acids to targeted cells. This review discusses recent advances of aptamers applied for targeted therapy.
引文
[1]Zhou J,Rossi J.Aptamers as targeted therapeutics:current potential and challenges[J].Nat Rev Drug Discov,2016,16(3):181-202.
[2]Chen K,Liu B,Yu B,et al.Advances in the development of aptamer drug conjugates for targeted drug delivery[J].Wiley Interdiscip Rev Nanomed Nanobiotechnol,2017,9(3):e1438.
[3]Zhu G,Niu G,Chen X.Aptamer-Drug Conjugates[J].Bioconjug Chem,2015,26(11SI):2186-2197.
[4]Zhu H,Li J,Zhang X,et al.Nucleic Acid Aptamer-Mediated Drug Delivery for Targeted Cancer Therapy[J].Chem Med Chem,2015,10(1):39-45.
[5]Yu Y,Liang C,Lv Q,et al.Molecular Selection,Modification and Development of Therapeutic Oligonucleotide Aptamers[J].Int J Mol Sci,2016,17(3):358.
[6]Drolet DW,Green LS,Gold L,et al.Fit for the Eye:Aptamers in Ocular Disorders[J].Nucleic Acid Ther,2016,26(3):127-146.
[7]Cheng Y,Zhao G,Zhang S,et al.AS1411-Induced Growth Inhibition of Glioma Cells by Up-Regulation of p53 and Down-Regulation of Bcl-2 and Akt1 via Nucleolin[J].PLo S One,2016,11(12):e167094.
[8]Cataland SR,Peyvandi F,Mannucci PM,et al.Initial experience from a double-blind,placebo-controlled,clinical outcome study of ARC1779 in patients with thrombotic thrombocytopenic purpura[J].Am J Hematol,2012,87(4):430-432.
[9]Firbas C,Siller-Matula JM,Jilma B.Targeting von Willebrand factor and platelet glycoprotein Ibreceptor[J].Expert Rev Cardiovasc Ther,2010,8(12):1689-1701.
[10]Menne J,Eulberg D,Beyer D,et al.C-C motif-ligand 2 inhibition with emapticap pegol(NOX-E36)in type 2 diabetic patients with albuminuria[J].Nephrol Dial Transplant,2017,32(2):307-315.
[11]张鲜惠,甘龙杰,王开宇,等.适配子治疗获得性免疫缺陷综合征的研究进展[J].医学研究生学报,2012,25(1):80-84.
[12]Shum K,Zhou J,Rossi JJ.Nucleic Acid Aptamers as Potential Therapeutic and Diagnostic Agents for Lymphoma[J].J Cancer Ther,2013,4(4):872-890.
[13]何蕴藉,李星霖,刘宝瑞,等.CE-SELEX法筛选Mucin16胞外域的核酸适配体[J].医学研究生学报,2016,29(5):480-484.
[14]Kruspe S,Mittelberger F,Szameit K,et al.Aptamers as Drug Delivery Vehicles[J].Chem Med Chem,2014,9(9SI):1998-2011.
[15]Zhao N,Pei S,Qi J,et al.Oligonucleotide aptamer-drug conjugates for targeted therapy of acute myeloid leukemia[J].Biomaterials,2015,67:42-51.
[16]Boyacioglu O,Stuart CH,Kulik G,et al.Dimeric DNA Aptamer Complexes for High-capacity-targeted Drug Delivery Using p Hsensitive Covalent Linkages[J].Mol Ther Nucleic Acids,2013,2(7):e107.
[17]Wang R,Zhu G,Mei L,et al.Automated Modular Synthesis of Aptamer-Drug Conjugates for Targeted Drug Delivery[J].J Am Chem Soc,2014,136(7):2731-2734.
[18]Zhu G,Zheng J,Song E,et al.Self-assembled,aptamer-tethered DNA nanotrains for targeted transport of molecular drugs in cancer theranostics[J].Proc Natl Acad Sci USA,2013,110(20):7998-8003.
[19]Zhu G,Meng L,Ye M,et al.Self-assembled aptamer-based drug carriers for bispecific cytotoxicity to cancer cells[J].Chem Asian J,2012,7(7):1630-1636.
[20]Sun H,Zu Y.Aptamers and Their Applications in Nanomedicine[J].Small,2015,11(20):2352-2364.
[21]Xiao Z,Farokhzad OC.Aptamer-Functionalized Nanoparticles for Medical Applications:Challenges and Opportunities[J].ACS Nano,2012,6(5):3670-3676.
[22]Latorre A,Posch C,Garcimartin Y,et al.DNA and aptamer stabilized gold nanoparticles for targeted delivery of anticancer therapeutics[J].Nanoscale,2014,6(13):7436-7442.
[23]Danesh NM,Lavaee P,Ramezani M,et al.Targeted and controlled release delivery of daunorubicin to T-cell acute lymphoblastic leukemia by aptamer-modified gold nanoparticles[J].Int J Pharm,2015,489(1-2):311-317.
[24]Wang J,Sefah K,Altman MB,et al.Aptamer-conjugated nanorods for targeted photothermal therapy of prostate cancer stem cells[J].Chem Asian J,2013,8(10):2417-2422.
[25]Yang L,Tseng YT,Suo G,et al.Photothermal therapeutic response of cancer cells to aptamer-gold nanoparticle-hybridized graphene oxide under NIR illumination[J].ACS Appl Mater Interfaces,2015,7(9):5097-5106.
[26]Wang J,Zhu G,You M,et al.Assembly of Aptamer Switch Probes and Photosensitizer on Gold Nanorods for Targeted Photothermal and Photodynamic Cancer Therapy[J].ACS Nano,2012,6(6):5070-5077.
[27]Wang K,Yao H,Meng Y,et al.Specific aptamer-conjugated mesoporous silica-carbon nanoparticles for HER2-targeted chemophotothermal combined therapy[J].Acta Biomater,2015,16:196-205.
[28]Farokhzad OC,Cheng J,Teply BA,et al.Targeted nanoparticleaptamer bioconjugates for cancer chemotherapy in vivo[J].Proc Natl Acad Sci USA,2006,103(16):6315-6320.
[29]Guo J,Gao X,Su L,et al.Aptamer-functionalized PEG-PLGA nanoparticles for enhanced anti-glioma drug delivery[J].Biomaterials,2011,32(31):8010-8020.
[30]Xing H,Tang L,Yang X,et al.Selective delivery of an anticancer drug with aptamer-functionalized liposomes to breast cancer cells in vitro and in vivo[J].J Mater Chem B Mater Biol Med,2013,1(39):5288-5297.
[31]Mc Namara JO,Andrechek ER,Wang Y,et al.Cell type-specific delivery of siRNAs with aptamer-siRNA chimeras[J].Nat Biotechnol,2006,24(8):1005-1015.
[32]Ni X,Zhang Y,Ribas J,et al.Prostate-targeted radiosensitization via aptamer-shRNA chimeras in human tumor xenografts[J].J Clin Invest,2011,121(6):2383-2390.
[33]Lai W,Wang W,Chang Y,et al.Synergistic inhibition of lung cancer cell invasion,tumor growth and angiogenesis using aptamer-siRNA chimeras[J].Biomaterials,2014,35(9):2905-2914.
[34]Liu HY,Yu X,Liu H,et al.Co-targeting EGFR and survivin with a bivalent aptamer-dual siRNA chimera effectively suppresses prostate cancer[J].Sci Rep,2016,6(1):30346.
[35]Zhang X,Liang H,Tan Y,et al.A U87-EGFRv III cell-specific aptamer mediates small interfering RNA delivery[J].Biomed Rep,2014,2(4):495-499.
[36]Subramanian N,Kanwar JR,Athalya P,et al.Ep CAM aptamer mediated cancer cell specific delivery of Ep CAM siRNA using polymeric nanocomplex[J].J Biomed Sci,2015,22(1):4.
[37]Taghavi S,Nia AH,Abnous K,et al.Polyethylenimine-functionalized carbon nanotubes tagged with AS1411 aptamer for combination gene and drug delivery into human gastric cancer cells[J].Int J Pharm,2017,516(1-2):301-312.
[2]Chen K,Liu B,Yu B,et al.Advances in the development of aptamer drug conjugates for targeted drug delivery[J].Wiley Interdiscip Rev Nanomed Nanobiotechnol,2017,9(3):e1438.
[3]Zhu G,Niu G,Chen X.Aptamer-Drug Conjugates[J].Bioconjug Chem,2015,26(11SI):2186-2197.
[4]Zhu H,Li J,Zhang X,et al.Nucleic Acid Aptamer-Mediated Drug Delivery for Targeted Cancer Therapy[J].Chem Med Chem,2015,10(1):39-45.
[5]Yu Y,Liang C,Lv Q,et al.Molecular Selection,Modification and Development of Therapeutic Oligonucleotide Aptamers[J].Int J Mol Sci,2016,17(3):358.
[6]Drolet DW,Green LS,Gold L,et al.Fit for the Eye:Aptamers in Ocular Disorders[J].Nucleic Acid Ther,2016,26(3):127-146.
[7]Cheng Y,Zhao G,Zhang S,et al.AS1411-Induced Growth Inhibition of Glioma Cells by Up-Regulation of p53 and Down-Regulation of Bcl-2 and Akt1 via Nucleolin[J].PLo S One,2016,11(12):e167094.
[8]Cataland SR,Peyvandi F,Mannucci PM,et al.Initial experience from a double-blind,placebo-controlled,clinical outcome study of ARC1779 in patients with thrombotic thrombocytopenic purpura[J].Am J Hematol,2012,87(4):430-432.
[9]Firbas C,Siller-Matula JM,Jilma B.Targeting von Willebrand factor and platelet glycoprotein Ibreceptor[J].Expert Rev Cardiovasc Ther,2010,8(12):1689-1701.
[10]Menne J,Eulberg D,Beyer D,et al.C-C motif-ligand 2 inhibition with emapticap pegol(NOX-E36)in type 2 diabetic patients with albuminuria[J].Nephrol Dial Transplant,2017,32(2):307-315.
[11]张鲜惠,甘龙杰,王开宇,等.适配子治疗获得性免疫缺陷综合征的研究进展[J].医学研究生学报,2012,25(1):80-84.
[12]Shum K,Zhou J,Rossi JJ.Nucleic Acid Aptamers as Potential Therapeutic and Diagnostic Agents for Lymphoma[J].J Cancer Ther,2013,4(4):872-890.
[13]何蕴藉,李星霖,刘宝瑞,等.CE-SELEX法筛选Mucin16胞外域的核酸适配体[J].医学研究生学报,2016,29(5):480-484.
[14]Kruspe S,Mittelberger F,Szameit K,et al.Aptamers as Drug Delivery Vehicles[J].Chem Med Chem,2014,9(9SI):1998-2011.
[15]Zhao N,Pei S,Qi J,et al.Oligonucleotide aptamer-drug conjugates for targeted therapy of acute myeloid leukemia[J].Biomaterials,2015,67:42-51.
[16]Boyacioglu O,Stuart CH,Kulik G,et al.Dimeric DNA Aptamer Complexes for High-capacity-targeted Drug Delivery Using p Hsensitive Covalent Linkages[J].Mol Ther Nucleic Acids,2013,2(7):e107.
[17]Wang R,Zhu G,Mei L,et al.Automated Modular Synthesis of Aptamer-Drug Conjugates for Targeted Drug Delivery[J].J Am Chem Soc,2014,136(7):2731-2734.
[18]Zhu G,Zheng J,Song E,et al.Self-assembled,aptamer-tethered DNA nanotrains for targeted transport of molecular drugs in cancer theranostics[J].Proc Natl Acad Sci USA,2013,110(20):7998-8003.
[19]Zhu G,Meng L,Ye M,et al.Self-assembled aptamer-based drug carriers for bispecific cytotoxicity to cancer cells[J].Chem Asian J,2012,7(7):1630-1636.
[20]Sun H,Zu Y.Aptamers and Their Applications in Nanomedicine[J].Small,2015,11(20):2352-2364.
[21]Xiao Z,Farokhzad OC.Aptamer-Functionalized Nanoparticles for Medical Applications:Challenges and Opportunities[J].ACS Nano,2012,6(5):3670-3676.
[22]Latorre A,Posch C,Garcimartin Y,et al.DNA and aptamer stabilized gold nanoparticles for targeted delivery of anticancer therapeutics[J].Nanoscale,2014,6(13):7436-7442.
[23]Danesh NM,Lavaee P,Ramezani M,et al.Targeted and controlled release delivery of daunorubicin to T-cell acute lymphoblastic leukemia by aptamer-modified gold nanoparticles[J].Int J Pharm,2015,489(1-2):311-317.
[24]Wang J,Sefah K,Altman MB,et al.Aptamer-conjugated nanorods for targeted photothermal therapy of prostate cancer stem cells[J].Chem Asian J,2013,8(10):2417-2422.
[25]Yang L,Tseng YT,Suo G,et al.Photothermal therapeutic response of cancer cells to aptamer-gold nanoparticle-hybridized graphene oxide under NIR illumination[J].ACS Appl Mater Interfaces,2015,7(9):5097-5106.
[26]Wang J,Zhu G,You M,et al.Assembly of Aptamer Switch Probes and Photosensitizer on Gold Nanorods for Targeted Photothermal and Photodynamic Cancer Therapy[J].ACS Nano,2012,6(6):5070-5077.
[27]Wang K,Yao H,Meng Y,et al.Specific aptamer-conjugated mesoporous silica-carbon nanoparticles for HER2-targeted chemophotothermal combined therapy[J].Acta Biomater,2015,16:196-205.
[28]Farokhzad OC,Cheng J,Teply BA,et al.Targeted nanoparticleaptamer bioconjugates for cancer chemotherapy in vivo[J].Proc Natl Acad Sci USA,2006,103(16):6315-6320.
[29]Guo J,Gao X,Su L,et al.Aptamer-functionalized PEG-PLGA nanoparticles for enhanced anti-glioma drug delivery[J].Biomaterials,2011,32(31):8010-8020.
[30]Xing H,Tang L,Yang X,et al.Selective delivery of an anticancer drug with aptamer-functionalized liposomes to breast cancer cells in vitro and in vivo[J].J Mater Chem B Mater Biol Med,2013,1(39):5288-5297.
[31]Mc Namara JO,Andrechek ER,Wang Y,et al.Cell type-specific delivery of siRNAs with aptamer-siRNA chimeras[J].Nat Biotechnol,2006,24(8):1005-1015.
[32]Ni X,Zhang Y,Ribas J,et al.Prostate-targeted radiosensitization via aptamer-shRNA chimeras in human tumor xenografts[J].J Clin Invest,2011,121(6):2383-2390.
[33]Lai W,Wang W,Chang Y,et al.Synergistic inhibition of lung cancer cell invasion,tumor growth and angiogenesis using aptamer-siRNA chimeras[J].Biomaterials,2014,35(9):2905-2914.
[34]Liu HY,Yu X,Liu H,et al.Co-targeting EGFR and survivin with a bivalent aptamer-dual siRNA chimera effectively suppresses prostate cancer[J].Sci Rep,2016,6(1):30346.
[35]Zhang X,Liang H,Tan Y,et al.A U87-EGFRv III cell-specific aptamer mediates small interfering RNA delivery[J].Biomed Rep,2014,2(4):495-499.
[36]Subramanian N,Kanwar JR,Athalya P,et al.Ep CAM aptamer mediated cancer cell specific delivery of Ep CAM siRNA using polymeric nanocomplex[J].J Biomed Sci,2015,22(1):4.
[37]Taghavi S,Nia AH,Abnous K,et al.Polyethylenimine-functionalized carbon nanotubes tagged with AS1411 aptamer for combination gene and drug delivery into human gastric cancer cells[J].Int J Pharm,2017,516(1-2):301-312.