Nucleic acid aptamers are in vitro-selected small, single-stranded DNA or RNA oligonucleotides that can specifically recognize their target on the basis of their unique 3-dimensional structures. Recent advances in the development of escort aptamers to deliver and enhance the efficacy of other therapeutic agents have drawn enthusiasm in exploiting cell-type-specific aptamers as drug delivery vehicles. This review mainly focuses on the recent developments of aptamer-mediated targeted delivery systems. We also place particular emphasis on aptamers evolved against cell membrane receptors and possibilities for translation to clinical applications.
Get full access to this article
View all access options for this article.
References
1.
ALTSCHULERY., KINLOUGHC.L., POLANDP.A., BRUNSJ.B., APODACAG., WEISZO.A., HUGHEYR.P.2000. Clathrin-mediated endocytosis of MUC1 is modulated by its glycosylation state. Mol. Biol. Cell, 11:819–831.
2.
BAGALKOTV., FAROKHZADO.C., LANGERR., JONS.2006. An aptamer-doxorubicin physical conjugate as a novel targeted drug-delivery platform. Angew. Chem. Int. Ed. Engl., 45:8149–8152.
3.
BATESP.J., KAHLONJ.B., THOMASS.D., TRENTJ.O., MILLERD.M.1999. Antiproliferative activity of G-rich oligonucleotides correlates with protein binding. J. Biol. Chem., 274:26369–26377.
4.
BATESP.J., LABERD.A., MILLERD.M., THOMASS.D., TRENTJ.O.2009. Discovery and development of the G-rich oligonucleotide AS1411 as a novel treatment for cancer. Exp. Mol. Pathol., 86:151–164.
5.
BEREZOVSKIM., DRABOVICHA., KRYLOVAS.M., MUSHEEVM., OKHONINV., PETROVA., KRYLOVS.N.2005. Nonequilibrium capillary electrophoresis of equilibrium mixtures: a universal tool for development of aptamers. J. Am. Chem. Soc., 127:3165–3171.
6.
BEREZOVSKIM., MUSHEEVM., DRABOVICHA., KRYLOVS.N.2006. Non-SELEX selection of aptamers. J. Am. Chem. Soc., 128:1410–1411.
7.
BLANKM., WEINSCHENKT., PRIEMERM., SCHLUESENERH.2001. Systematic evolution of a DNA aptamer binding to rat brain tumor microvessels. selective targeting of endothelial regulatory protein pigpen. J. Biol. Chem., 276:16464–16468.
8.
CAOZ., TONGR., MISHRAA., XUW., WONGG.C., CHENGJ., LUY.2009. Reversible cell-specific drug delivery with aptamer-functionalized liposomes. Angew. Chem. Int. Ed. Engl., 48:6494–6498.
9.
CERIANIR.L., CHANC.M., BARATTAF.S., OZZELLOL., DEROSAC.M., HABIFD.V.1992. Levels of expression of breast epithelial mucin detected by monoclonal antibody BrE-3 in breast-cancer prognosis. Int. J. Cancer, 51:343–354.
10.
CHENC.H., DELLAMAGGIOREK.R., OUELLETTEC.P., SEDANOC.D., LIZADJOHRYM., CHERNISG.A., GONZALESM., BALTASARF.E., FANA.L., MYEROWITZR., NEUFELDE.F.2008. Aptamer-based endocytosis of a lysosomal enzyme. Proc. Natl. Acad. Sci. U. S. A., 105:15908–15913.
11.
CHENGJ., TEPLYB.A., SHERIFII., SUNGJ., LUTHERG., GUF.X., LEVY-NISSENBAUME., RADOVIC-MORENOA.F., LANGERR., FAROKHZADO.C.2007. Formulation of functionalized PLGA-PEG nanoparticles for in vivo targeted drug delivery. Biomaterials, 28:869–876.
12.
CHUT.C., MARKSJ.W.3RD, LAVERYL.A., FAULKNERS., ROSENBLUMM.G., ELLINGTONA.D., LEVYM.2006a. Aptamer:toxin conjugates that specifically target prostate tumor cells. Cancer Res., 66:5989–5992.
DEYA.K., KHATIM., TANGM., WYATTR., LEAS.M., JAMESW.2005. An aptamer that neutralizes R5 strains of human immunodeficiency virus type 1 blocks gp120-CCR5 interaction. J. Virol., 79:13806–13810.
16.
DHARS., GUF.X., LANGERR., FAROKHZADO.C., LIPPARDS.J.2008. Targeted delivery of cisplatin to prostate cancer cells by aptamer functionalized Pt(IV) prodrug-PLGA-PEG nanoparticles. Proc. Natl. Acad Sci. U. S. A., 105:17356–17361.
17.
DRABOVICHA.P., BEREZOVSKIM., OKHONINV., KRYLOVS.N.2006. Selection of smart aptamers by methods of kinetic capillary electrophoresis. Anal. Chem., 78:3171–3178.
18.
ELLINGTONA.D., SZOSTAKJ.W.1990. In vitro selection of RNA molecules that bind specific ligands. Nature, 346:818–822.
19.
ERICKSONH.P., BOURDONM.A.1989. Tenascin: an extracellular matrix protein prominent in specialized embryonic tissues and tumors. Annu. Rev. Cell Biol., 5:71–92.
20.
FAMULOKM., HARTIGJ.S., MAYERG.2007. Functional aptamers and aptazymes in biotechnology, diagnostics, and therapy. Chem. Rev., 107:3715–3743.
21.
FANGX., TANW.2009. Aptamers generated from cell-SELEX for molecular medicine: a chemical biology approach. Acc. Chem. Res, 43:48–57.
22.
FAROKHZADO.C., CHENGJ., TEPLYB.A., SHERIFII., JONS., KANTOFFP.W., RICHIEJ.P., LANGERR.2006. Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. Proc. Natl. Acad. Sci. U. S. A., 103:6315–6320.
23.
FAROKHZADO.C., JONS., KHADEMHOSSEINIA., TRANT.N., LAVAND.A., LANGERR.2004. Nanoparticle-aptamer bioconjugates: a new approach for targeting prostate cancer cells. Cancer Res., 64:7668–7672.
24.
FAROKHZADO.C., KHADEMHOSSEINIA., JONS., HERMMANNA., CHENGJ., CHINC., KISELYUKA., TEPLYB., ENGG., LANGERR.2005. Microfluidic system for studying the interaction of nanoparticles and microparticles with cells. Anal. Chem., 77:5453–5459.
25.
FERREIRAC.S., CHEUNGM.C., MISSAILIDISS., BISLANDS., GARIEPYJ.2009. Phototoxic aptamers selectively enter and kill epithelial cancer cells. Nucleic Acids Res., 37:866–876.
26.
GENDLERS.J.2001. MUC1, the renaissance molecule. J. Mammary Gland Biol. Neoplasia, 6:339–353.
27.
GUF., ZHANGL., TEPLYB.A., MANNN., WANGA., RADOVIC-MORENOA.F., LANGERR., FAROKHZADO.C.2008. Precise engineering of targeted nanoparticles by using self-assembled biointegrated block copolymers. Proc. Natl. Acad. Sci. U. S. A., 105:2586–2591.
28.
GUOP.2005. RNA nanotechnology: engineering, assembly and applications in detection, gene delivery and therapy. J. Nanosci. Nanotechnol., 5:1964–1982.
29.
GUOS., TSCHAMMERN., MOHAMMEDS., GUOP.2005. Specific delivery of therapeutic RNAs to cancer cells via the dimerization mechanism of phi29 motor pRNA. Hum. Gene Ther., 16:1097–1109.
30.
HESSELBERTHJ., ROBERTSONM.P., JHAVERIS., ELLINGTONA.D.2000. In vitro selection of nucleic acids for diagnostic applications. J. Biotechnol., 74:15–25.
31.
HICKEB.J., STEPHENSA.W.2000. Escort aptamers: a delivery service for diagnosis and therapy. J. Clin. Invest., 106:923–928.
32.
HICKEB.J., MARIONC., CHANGY.F., GOULDT., LYNOTTC.K., PARMAD., SCHMIDTP.G., WARRENS.2001. Tenascin-C aptamers are generated using tumor cells and purified protein. J. Biol. Chem., 276:48644–48654.
33.
HICKEB.J., STEPHENSA.W., GOULDT., CHANGY.F., LYNOTTC.K., HEILJ., BORKOWSKIS., HILGERC.S., COOKG., WARRENS., SCHMIDTP.G.2006. Tumor targeting by an aptamer. J. Nucl. Med., 47:668–678.
34.
HUANGY.F., CHANGH.T., TANW.2008. Cancer cell targeting using multiple aptamers conjugated on nanorods. Anal. Chem., 80:567–572.
35.
HUANGY.F., SHANGGUAND., LIUH., PHILLIPSJ.A., ZHANGX., CHENY., TANW.2009. Molecular assembly of an aptamer-drug conjugate for targeted drug delivery to tumor cells. Chembiochem, 10:862–868.
36.
JAVIERD.J., NITINN., LEVYM., ELLINGTONA., RICHARDS-KORTUMR.2008. Aptamer-targeted gold nanoparticles as molecular-specific contrast agents for reflectance imaging. Bioconjug. Chem., 19:1309–1312.
37.
KANGH., O'DONOGHUEM.B., LIUH., TANW.2010. A liposome-based nanostructure for aptamer directed delivery. Chem. Commun. (Camb.), 46:249–251.
KHALEDA., GUOS., LIF., GUOP.2005. Controllable self-assembly of nanoparticles for specific delivery of multiple therapeutic molecules to cancer cells using RNA nanotechnology. Nano Lett., 5:1797–1808.
40.
KHATIM., SCHUMANM., IBRAHIMJ., SATTENTAUQ., GORDONS., JAMESW.2003. Neutralization of infectivity of diverse R5 clinical isolates of human immunodeficiency virus type 1 by gp120-binding 2′F-RNA aptamers. J. Virol., 77:12692–12698.
41.
KRAUSE., JAMESW., BARCLAYA.N.1998. Cutting edge: novel RNA ligands able to bind CD4 antigen and inhibit CD4+ T lymphocyte function. J. Immunol., 160:5209–5212.
LEVY-NISSENBAUME., RADOVIC-MORENOA.F., WANGA.Z., LANGERR., FAROKHZADO.C.2008. Nanotechnology and aptamers: applications in drug delivery. Trends Biotechnol., 26:442–449.
44.
LIN., EBRIGHTJ.N., STOVALLG.M., CHENX., NGUYENH.H., SINGHA., SYRETTA., ELLINGTONA.D.2009. Technical and biological issues relevant to cell typing with aptamers. J. Proteome Res., 8:2438–2448.
45.
LIN., LARSONT., NGUYENH.H., SOKOLOVK.V., ELLINGTONA.D.2010. Directed evolution of gold nanoparticle delivery to cells. Chem. Commun. (Camb.), 46:392–394.
46.
LIUH., RAJASEKARANA.K., MOYP., XIAY., KIMS., NAVARROV., RAHMATIR., BANDERN.H.1998. Constitutive and antibody-induced internalization of prostate-specific membrane antigen. Cancer Res., 58:4055–4060.
47.
LORGERM., ENGSTLERM., HOMANNM., GORINGERH.U.2003. Targeting the variable surface of African trypanosomes with variant surface glycoprotein-specific, serum-stable RNA aptamers. Eukaryot. Cell, 2:84–94.
48.
LUPOLDS.E., HICKEB.J., LINY., COFFEYD.S.2002. Identification and characterization of nuclease-stabilized RNA molecules that bind human prostate cancer cells via the prostate-specific membrane antigen. Cancer Res., 62:4029–4033.
49.
MALLIKARATCHYP., STAHELINR.V., CAOZ., CHOW., TANW.2006. Selection of DNA ligands for protein kinase C-delta. Chem. Commun. (Camb.), 14:3229–3231.
50.
MAYERG.2009. The chemical biology of aptamers. Angew. Chem. Int. Ed. Engl., 48:2672–2689.
51.
MCNAMARAJ.O.2ND, ANDRECHEKE.R., WANGY., VILESK.D., REMPELR.E., GILBOAE., SULLENGERB.A., GIANGRANDEP.H.2006. Cell type-specific delivery of siRNAs with aptamer-siRNA chimeras. Nat. Biotechnol., 24:1005–1015.
52.
MOSINGR.K., MENDONSAS.D., BOWSERM.T.2005. Capillary electrophoresis-SELEX selection of aptamers with affinity for HIV-1 reverse transcriptase. Anal. Chem., 77:6107–6112.
53.
NIMJEES.M., RUSCONIC.P., SULLENGERB.A.2005. Aptamers: an emerging class of therapeutics. Annu. Rev. Med., 56:555–583.
54.
PHILLIPSJ.A., LOPEZ-COLOND., ZHUZ., XUY., TANW.2008. Applications of aptamers in cancer cell biology. Anal. Chim. Acta., 621:101–108.
55.
SASSANFARM., SZOSTAKJ.W.1993. An RNA motif that binds ATP. Nature, 364:550–553.
56.
SAYERN., IBRAHIMJ., TURNERK., TAHIRI-ALAOUIA., JAMESW.2002. Structural characterization of a 2′F-RNA aptamer that binds a HIV-1 SU glycoprotein, gp120. Biochem. Biophys. Res. Commun., 293:924–931.
57.
SHANGGUAND., CAOZ.C., LIY., TANW.2007. Aptamers evolved from cultured cancer cells reveal molecular differences of cancer cells in patient samples. Clin. Chem., 53:1153–1155.
58.
SHANGGUAND., LIY., TANGZ., CAOZ.C., CHENH.W., MALLIKARATCHYP., SEFAHK., YANGC.J., TANW.2006. Aptamers evolved from live cells as effective molecular probes for cancer study. Proc. Natl. Acad. Sci. U. S. A., 103:11838–11843.
59.
SHAWB.R., MOUSSAL., SHARAFM., CHEEKM., DOBRIKOVM.2008. Boranophosphate siRNA-aptamer chimeras for tumor-specific downregulation of cancer receptors and modulators. Nucleic Acids Symp. Ser. (Oxf.), 52:655–656.
60.
SINGHA.B., HARRISR.C.2005. Autocrine, paracrine and juxtacrine signaling by EGFR ligands. Cell Signal., 17:1183–1193.
61.
TAGHDISIS.M., ABNOUSK., MOSAFFAF., BEHRAVANJ.2009. Targeted delivery of daunorubicin to T-cell acute lymphoblastic leukemia by aptamer. J. Drug Target, 18:277–281.
62.
TANGZ., PAREKHP., TURNERP., MOYERR.W., TANW.2009. Generating aptamers for recognition of virus-infected cells. Clin. Chem., 55:813–822.
63.
TASCHJ., GONGM., SADELAINM., HESTONW.D.2001. A unique folate hydrolase, prostate-specific membrane antigen (PSMA): a target for immunotherapy? Crit. Rev. Immunol., 21:249–261.
64.
THIELK.W., GIANGRANDEP.H.2009. Therapeutic applications of DNA and RNA aptamers. Oligonucleotides, 19:209–222.
65.
TONGG.J., HSIAOS.C., CARRICOZ.M., FRANCISM.B.2009. Viral capsid DNA aptamer conjugates as multivalent cell-targeting vehicles. J. Am. Chem. Soc., 131:11174–11178.
66.
TUERKC., GOLDL.1990. Systematic evolution of ligands by exponential enrichment: RNA ligands to bacteriophage T4 DNA polymerase. Science, 249:505–510.
67.
VEEDUR.N., VESTERB., WENGELJ.2009. Efficient enzymatic synthesis of LNA-modified DNA duplexes using KOD DNA polymerase. Org. Biomol. Chem., 7:1404–1409.
68.
WANGA.Z., BAGALKOTV., VASILLIOUC.C., GUF., ALEXISF., ZHANGL., SHAIKHM., YUETK., CIMAM.J., LANGERR., KANTOFFP.W., BANDERN.H., JONS., FAROKHZADO.C.2008. Superparamagnetic iron oxide nanoparticle-aptamer bioconjugates for combined prostate cancer imaging and therapy. Chem. Med. Chem., 3:1311–1315.
69.
WULLNERU., NEEFI., ELLERA., KLEINESM., TURM.K., BARTHS.2008. Cell-specific induction of apoptosis by rationally designed bivalent aptamer-siRNA transcripts silencing eukaryotic elongation factor 2. Curr. Cancer Drug Targets, 8:554–565.
70.
XIAOZ., SHANGGUAND., CAOZ., FANGX., TANW.2008. Cell-specific internalization study of an aptamer from whole cell selection. Chemistry, 14:1769–1775.
71.
XUY., PHILLIPSJ.A., YANJ., LIQ., FANZ.H., TANW.2009. Aptamer-based microfluidic device for enrichment, sorting, and detection of multiple cancer cells. Anal. Chem., 81:7436–7442.
72.
YANA.C., LEVYM.2009. Aptamers and aptamer targeted delivery. RNA Biol., 6:316–320.
73.
ZHANGL., RADOVIC-MORENOA.F., ALEXISF., GUF.X., BASTOP.A., BAGALKOTV., JONS., LANGERR.S., FAROKHZADO.C.2007. Co-delivery of hydrophobic and hydrophilic drugs from nanoparticle-aptamer bioconjugates. Chem. Med. Chem., 2:1268–1271.
74.
ZHOUJ., ROSSIJ.J.2009. The therapeutic potential of cell-internalizing aptamers. Curr. Top. Med. Chem., 9:1144–1157.
75.
ZHOUJ., LIH., LIS., ZAIAJ., ROSSIJ.J.2008. Novel dual inhibitory function aptamer-siRNA delivery system for HIV-1 therapy. Mol. Ther., 16:1481–1489.
76.
ZHOUJ., SWIDERSKIP., LIH., ZHANGJ., NEFFC.P., AKKINAR., ROSSIJ.J.2009. Selection, characterization and application of new RNA HIV gp 120 aptamers for facile delivery of Dicer substrate siRNAs into HIV infected cells. Nucleic Acids Res., 37:3094–3109.
