Multifunctional aptamer-miRNA conjugates for targeted cancer therapy.
While microRNAs (miRNAs) clearly regulate multiple pathways integral to disease development and progression, the lack of safe and reliable means for specific delivery of miRNAs to target tissues represents a major obstacle to their broad therapeutic application. Our objective was to explore the use of nucleic acid aptamers as carriers for cell-targeted delivery of a miRNA with tumor suppressor function, let-7g. Using an aptamer that binds to and antagonizes the oncogenic receptor tyrosine kinase Axl (GL21.T), here we describe the development of aptamer-miRNA conjugates as multifunctional molecules that inhibit the growth of Axl-expressing tumors. We conjugated the let-7g miRNA to GL21.T and demonstrate selective delivery to target cells, processing by the RNA interference machinery, and silencing of let-7g target genes. Importantly, the multifunctional conjugate reduced tumor growth in a xenograft model of lung adenocarcinoma. Therefore, our data establish aptamer-miRNA conjugates as a novel tool for targeted delivery of miRNAs with therapeutic potential.
Istituto di Endocrinologia ed Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (CNR), Naples, Italy.
Carla L
CL
Esposito
Istituto di Endocrinologia ed Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (CNR), Naples, Italy.
Laura
L
Cerchia
Istituto di Endocrinologia ed Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (CNR), Naples, Italy.
Silvia
S
Catuogno
Istituto di Endocrinologia ed Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (CNR), Naples, Italy.
Gennaro
G
De Vita
Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA.
Justin P
JP
Dassie
Laboratorio di Medicina Molecolare e Genomica, University of Salerno, Baronissi, Salerno, Italy.
Gianluca
G
Santamaria
Synthetic and Biopolymer Chemistry Core, Beckman research Institute of City of Hope, Duarte, California, USA.
Piotr
P
Swiderski
Istituto di Endocrinologia ed Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (CNR), Naples, Italy; Dipartimento di Medicina Molecolare e Biotecnologie Mediche, University of Naples "Federico II", Naples, Italy.
Gerolama
G
Condorelli
Department of Internal Medicine, University of Iowa, Iowa City, Iowa, USA; Molecular & Cellular Biology Program, University of Iowa, Iowa City, Iowa, USA.
Paloma H
PH
Giangrande
Istituto di Endocrinologia ed Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (CNR), Naples, Italy. Electronic address: defranci@unina.it.
Vittorio
V
de Franciscis
D000818:Animals; D052157:Aptamers, Nucleotide / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000494:pharmacology*; D058990:Molecular Targeted Therapy / Q000379:methods; D009369:Neoplasms / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D009374:Neoplasms, Experimental; D009928:Organ Specificity; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D000094963:Axl Receptor Tyrosine Kinase
D052157:Aptamers, Nucleotide; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; C487931:mirnlet7 microRNA, human; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase