The high frequency of hTERT-promoting mutations and the increased expression of hTERT mRNA in anaplastic thyroid cancer (ATC) make TERT a suitable molecular target for the treatment of this lethal neoplasm. In this study, we encapsulated an anti-hTERT oligonucleotide in biocompatible nanoparticles and analyzed the effects of this novel pharmaceutical preparation in preclinical models of ATC. Biocompatible nanoparticles were obtained in an acidified aqueous solution containing chitosan, anti-hTERT oligoRNAs and poloxamer 188 as a stabilizer. The effects of these anti-hTERT -nanoparticles (Na-siTERT) were tested in vitro on ATC cell lines (CAL-62 and 8505C) and in vivo on xenograft tumors obtained by flank injection of CAL-62 cells into SCID-mice. The Na-siTERT reduced the viability and migration of CAL-62 and 8505C cells after 48 h incubation. Intra-venous administration (every 48 h for 13 days) of this encapsulated drug in mice hosting a xenograft thyroid cancer determined a great reduction in the growth of the neoplasm (about 50% vs untreated animals or mice receiving empty nanoparticles), and decreased levels of Ki67 associated with lower hTERT expression. Moreover, the treatment resulted in minimal invasion of near-by tissues and reduced the vascularity of the xenograft tumor. No signs of toxicity appeared following this treatment. Telomere length was not modified by the Na-siTERT, indicating that the inhibitory effects of neoplasm growth was independent from the enzymatic telomerase function. These findings demonstrate the potential suitability of this anti-TERT nanoparticle formulation as a novel tool for ATC treatment.

Anti-hTERT siRNA-loaded nanoparticles block the growth of anaplastic thyroid cancer xenograft / Lombardo, Giovanni E; Maggisano, Valentina; Celano, Marilena; Cosco, Donato; Mignogna, Chiara; Baldan, Federica; Lepore, Saverio M; Allegri, Lorenzo; Moretti, Sonia; Durante, Cosimo; Damante, Giuseppe; Fresta, Massimo; Russo, Diego; Bulotta, Stefania; Puxeddu, Efisio. - In: MOLECULAR CANCER THERAPEUTICS. - ISSN 1535-7163. - STAMPA. - 17:6(2018), pp. 1187-1195. [10.1158/1535-7163.MCT-17-0559]

Anti-hTERT siRNA-loaded nanoparticles block the growth of anaplastic thyroid cancer xenograft

Maggisano, Valentina;Baldan, Federica;Durante, Cosimo;
2018

Abstract

The high frequency of hTERT-promoting mutations and the increased expression of hTERT mRNA in anaplastic thyroid cancer (ATC) make TERT a suitable molecular target for the treatment of this lethal neoplasm. In this study, we encapsulated an anti-hTERT oligonucleotide in biocompatible nanoparticles and analyzed the effects of this novel pharmaceutical preparation in preclinical models of ATC. Biocompatible nanoparticles were obtained in an acidified aqueous solution containing chitosan, anti-hTERT oligoRNAs and poloxamer 188 as a stabilizer. The effects of these anti-hTERT -nanoparticles (Na-siTERT) were tested in vitro on ATC cell lines (CAL-62 and 8505C) and in vivo on xenograft tumors obtained by flank injection of CAL-62 cells into SCID-mice. The Na-siTERT reduced the viability and migration of CAL-62 and 8505C cells after 48 h incubation. Intra-venous administration (every 48 h for 13 days) of this encapsulated drug in mice hosting a xenograft thyroid cancer determined a great reduction in the growth of the neoplasm (about 50% vs untreated animals or mice receiving empty nanoparticles), and decreased levels of Ki67 associated with lower hTERT expression. Moreover, the treatment resulted in minimal invasion of near-by tissues and reduced the vascularity of the xenograft tumor. No signs of toxicity appeared following this treatment. Telomere length was not modified by the Na-siTERT, indicating that the inhibitory effects of neoplasm growth was independent from the enzymatic telomerase function. These findings demonstrate the potential suitability of this anti-TERT nanoparticle formulation as a novel tool for ATC treatment.
2018
Anaplastic thyroid cancer, telomerase, siRNA, nanoparticles, xenograft tumor
01 Pubblicazione su rivista::01a Articolo in rivista
Anti-hTERT siRNA-loaded nanoparticles block the growth of anaplastic thyroid cancer xenograft / Lombardo, Giovanni E; Maggisano, Valentina; Celano, Marilena; Cosco, Donato; Mignogna, Chiara; Baldan, Federica; Lepore, Saverio M; Allegri, Lorenzo; Moretti, Sonia; Durante, Cosimo; Damante, Giuseppe; Fresta, Massimo; Russo, Diego; Bulotta, Stefania; Puxeddu, Efisio. - In: MOLECULAR CANCER THERAPEUTICS. - ISSN 1535-7163. - STAMPA. - 17:6(2018), pp. 1187-1195. [10.1158/1535-7163.MCT-17-0559]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1241533
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