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Targeted siRNA Nanoparticles for Mammary Carcinoma Therapy

Non-viral, polymeric-based, siRNA nanoparticles (NPs) have been proposed as promising gene delivery systems. Encapsulating siRNA in targeted NPs could confer improved biological stability, extended half-life, enhanced permeability, effective tumor accumulation, and therapy. In this work, a peptide d...

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Autores principales: Ben-David-Naim, Meital, Dagan, Arie, Grad, Etty, Aizik, Gil, Nordling-David, Mirjam M., Morss Clyne, Alisa, Granot, Zvi, Golomb, Gershon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521050/
https://www.ncbi.nlm.nih.gov/pubmed/30934857
http://dx.doi.org/10.3390/cancers11040442
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author Ben-David-Naim, Meital
Dagan, Arie
Grad, Etty
Aizik, Gil
Nordling-David, Mirjam M.
Morss Clyne, Alisa
Granot, Zvi
Golomb, Gershon
author_facet Ben-David-Naim, Meital
Dagan, Arie
Grad, Etty
Aizik, Gil
Nordling-David, Mirjam M.
Morss Clyne, Alisa
Granot, Zvi
Golomb, Gershon
author_sort Ben-David-Naim, Meital
collection PubMed
description Non-viral, polymeric-based, siRNA nanoparticles (NPs) have been proposed as promising gene delivery systems. Encapsulating siRNA in targeted NPs could confer improved biological stability, extended half-life, enhanced permeability, effective tumor accumulation, and therapy. In this work, a peptide derived from apolipoprotein B100 (ApoB-P), the protein moiety of low-density lipoprotein, was used to target siRNA-loaded PEGylated NPs to the extracellular matrix/proteoglycans (ECM/PGs) of a mammary carcinoma tumor. siRNA against osteopontin (siOPN), a protein involved in breast cancer development and progression, was encapsulated into PEGylated poly(d,l-lactic-co-glycolic acid) (PLGA) NPs using the double emulsion solvent diffusion technique. The NPs obtained possessed desired physicochemical properties including ~200 nm size, a neutral surface charge, and high siOPN loading of ~5 µg/mg. ApoB-P-targeted NPs exhibited both enhanced binding to isolated ECM and internalization by MDA-MB-231 human mammary carcinoma cells, in comparison to non-targeted NPs. Increased accumulation of the targeted NPs was achieved in the primary mammary tumor of mice xenografted with MDA-MB-231 mammary carcinoma cells as well as in the lungs, one of the main sites affected by metastases. siOPN NPs treatment resulted in significant inhibition of tumor growth (similar bioactivity of both formulations), accompanied with significant reduction of OPN mRNA levels (~40% knockdown of mRNA levels). We demonstrated that targeted NPs possessed enhanced tumor accumulation with increased therapeutic potential in mice models of mammary carcinoma.
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spelling pubmed-65210502019-05-31 Targeted siRNA Nanoparticles for Mammary Carcinoma Therapy Ben-David-Naim, Meital Dagan, Arie Grad, Etty Aizik, Gil Nordling-David, Mirjam M. Morss Clyne, Alisa Granot, Zvi Golomb, Gershon Cancers (Basel) Article Non-viral, polymeric-based, siRNA nanoparticles (NPs) have been proposed as promising gene delivery systems. Encapsulating siRNA in targeted NPs could confer improved biological stability, extended half-life, enhanced permeability, effective tumor accumulation, and therapy. In this work, a peptide derived from apolipoprotein B100 (ApoB-P), the protein moiety of low-density lipoprotein, was used to target siRNA-loaded PEGylated NPs to the extracellular matrix/proteoglycans (ECM/PGs) of a mammary carcinoma tumor. siRNA against osteopontin (siOPN), a protein involved in breast cancer development and progression, was encapsulated into PEGylated poly(d,l-lactic-co-glycolic acid) (PLGA) NPs using the double emulsion solvent diffusion technique. The NPs obtained possessed desired physicochemical properties including ~200 nm size, a neutral surface charge, and high siOPN loading of ~5 µg/mg. ApoB-P-targeted NPs exhibited both enhanced binding to isolated ECM and internalization by MDA-MB-231 human mammary carcinoma cells, in comparison to non-targeted NPs. Increased accumulation of the targeted NPs was achieved in the primary mammary tumor of mice xenografted with MDA-MB-231 mammary carcinoma cells as well as in the lungs, one of the main sites affected by metastases. siOPN NPs treatment resulted in significant inhibition of tumor growth (similar bioactivity of both formulations), accompanied with significant reduction of OPN mRNA levels (~40% knockdown of mRNA levels). We demonstrated that targeted NPs possessed enhanced tumor accumulation with increased therapeutic potential in mice models of mammary carcinoma. MDPI 2019-03-29 /pmc/articles/PMC6521050/ /pubmed/30934857 http://dx.doi.org/10.3390/cancers11040442 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ben-David-Naim, Meital
Dagan, Arie
Grad, Etty
Aizik, Gil
Nordling-David, Mirjam M.
Morss Clyne, Alisa
Granot, Zvi
Golomb, Gershon
Targeted siRNA Nanoparticles for Mammary Carcinoma Therapy
title Targeted siRNA Nanoparticles for Mammary Carcinoma Therapy
title_full Targeted siRNA Nanoparticles for Mammary Carcinoma Therapy
title_fullStr Targeted siRNA Nanoparticles for Mammary Carcinoma Therapy
title_full_unstemmed Targeted siRNA Nanoparticles for Mammary Carcinoma Therapy
title_short Targeted siRNA Nanoparticles for Mammary Carcinoma Therapy
title_sort targeted sirna nanoparticles for mammary carcinoma therapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521050/
https://www.ncbi.nlm.nih.gov/pubmed/30934857
http://dx.doi.org/10.3390/cancers11040442
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