title: Ets1 identified as a novel molecular target of RNA aptamer selected against metastatic cells for targeted delivery of nano-formulation.
abstract: Nanomedicine era is not far from its realization, but a major concern of targeted delivery still stands tall in its way. Herein we demonstrate the mechanism underlying the anticancer activity of an RNA aptamer (Apt) conjugated to gefitinib-loaded poly (lactic co-glycolic acid) nanoparticles (GNPs). Apt was selected through Cell-SELEX (systemic evolution of ligands by exponential enrichment) process against gefitinib-resistant H1975 lung cancer cells. The selected aptamer exhibited high specificity toward H1975 cells, both qualitatively as well as quantitatively. Software analysis using the MATCH tool predicted Ets1, a proto-oncoprotein, to be the target of the selected aptamer. Interestingly, the localization of identified aptamer varied in descending order of Ets1 expression, wherein maximum localization was observed in H1975 cells than in MDA-MB231, DU-145, H23, H460, A431, A549 and MCF-7 cells, and minimum in L132 cells. Furthermore, Apt-GNP bio-conjugate showed augmented anticancer activity specifically in Ets1-overexpressing cells. In addition, partial depletion of Ets1 in H1975 cells and overexpression of Ets1 in L132 cells reversed the targeting efficacy of the aptamer. Notably, a single intratumoral injection of the Apt-GNP bio-conjugate abrogated the growth of tumor in H1975 xenograft nude mice. Altogether, we present a pioneering platform, involving aptamers, which can be clinically used as a diagnostic marker for metastasis as well as an effective delivery system to escort the pharmaceutical cargo specifically to Ets1-overexpressing highly progressive tumors.
authors: Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, SAS Nagar (formerly Mohali), Punjab, India.
authors: J
authors: J
authors: Kaur
authors: Laboratory of Epigenetics and Diseases, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, SAS Nagar (formerly Mohali), Punjab, India.
authors: K
authors: K
authors: Tikoo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D052157:Aptamers, Nucleotide / Q000378:metabolism*; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D004337:Drug Carriers / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D000077156:Gefitinib; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008819:Mice, Nude; D053758:Nanoparticles / Q000378:metabolism; D009362:Neoplasm Metastasis; D011100:Polyglycolic Acid / Q000378:metabolism; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism*; D011799:Quinazolines / Q000378:metabolism / Q000494:pharmacology; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D052157:Aptamers, Nucleotide; D004337:Drug Carriers; C494041:ETS1 protein, human; D050784:Proto-Oncogene Protein c-ets-1; D011799:Quinazolines; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D000077156:Gefitinib
references: PLoS One. 2010;5(11):e13770
references: 21072169
references: Curr Opin Oncol. 2001 Nov;13(6):491-8
references: 11673690
references: ACS Nano. 2012 Jan 24;6(1):696-704
references: 22214176
references: Nat Rev Drug Discov. 2008 Sep;7(9):771-82
references: 18758474
references: Mol Ther. 2014 Nov;22(11):1910-22
references: 24954476
references: Cancer Res. 2002 Jul 15;62(14):4029-33
references: 12124337
references: Br J Cancer. 2004 Oct 4;91(7):1308-15
references: 15365563
references: Int J Biochem Cell Biol. 1997 Dec;29(12):1371-87
references: 9570133
references: Science. 1990 Aug 3;249(4968):505-10
references: 2200121
references: Mod Pathol. 2001 May;14(5):415-22
references: 11353051
references: Nat Chem Biol. 2010 Jan;6(1):22-4
references: 19946274
references: Nat Rev Drug Discov. 2010 Jul;9(7):537-50
references: 20592747
references: Nat Rev Mol Cell Biol. 2001 Nov;2(11):827-37
references: 11715049
references: Biochim Biophys Acta. 2013 May;1833(5):1028-40
references: 23384777
references: Oncogene. 2000 Dec 18;19(55):6514-23
references: 11175367
references: Oncogene. 2000 Dec 18;19(55):6533-48
references: 11175369
references: Nat Rev Cancer. 2005 May;5(5):341-54
references: 15864276
references: Cancer Res. 2004 Nov 1;64(21):7668-72
references: 15520166
references: Cancer Res. 2006 Jun 15;66(12):5989-92
references: 16778167
references: Eur Respir J. 2002 Oct;20(4):975-81
references: 12412692
references: Int J Mol Sci. 2008 Apr;9(4):668-78
references: 19325777
references: Nucleic Acids Res. 2003 Jul 1;31(13):3576-9
references: 12824369
references: Anal Chem. 2008 Feb 1;80(3):721-8
references: 18177018
references: PLoS One. 2011;6(6):e20299
references: 21687663
references: Nat Rev Drug Discov. 2010 Aug;9(8):615-27
references: 20616808
references: Cancer Res. 2013 Aug 1;73(15):4923-36
references: 23796560
references: Cancer Res. 1999 Nov 1;59(21):5608-14
references: 10554042
references: Leukemia. 1988 Jan;2(1):12-8
references: 2448555
references: Proc Natl Acad Sci U S A. 2006 Apr 18;103(16):6315-20
references: 16606824
references: Nature. 1990 Aug 30;346(6287):818-22
references: 1697402