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Codelivery of doxorubicin and JIP1 siRNA with novel EphA2-targeted PEGylated cationic nanoliposomes to overcome osteosarcoma multidrug resistance

Authors Haghiralsadat F, Amoabediny G, Naderinezhad S, Zandieh-Doulabi B, Forouzanfar T, Helder MN

Received 25 August 2017

Accepted for publication 17 March 2018

Published 3 July 2018 Volume 2018:13 Pages 3853—3866


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Thomas Webster

Fateme Haghiralsadat,1–3 Ghasem Amoabediny,3–5 Samira Naderinezhad,4 Behrouz Zandieh-Doulabi,6 Tymour Forouzanfar,5 Marco N Helder5

1Department of Life Science Engineering, Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran; 2Department of Orthopaedic Surgery, VU University Medical Center, MOVE Research Institute Amsterdam, Amsterdam, the Netherlands; 3Department of Nano Biotechnology, Research Center for New Technologies in Life Science Engineering, 4Department of Biotechnology and Pharmaceutical Engineering, School of Chemical Engineering, College of Engineering, University of Tehran, Tehran, Iran; 5Department of Oral and Maxillofacial Surgery, VU University Medical Center, MOVE Research Institute Amsterdam, 6Department of Oral Cell Biology and Functional Anatomy, Academic Center for Dentistry Amsterdam (ACTA), Vrije Universiteit Amsterdam and University of Amsterdam, MOVE Research Institute, Amsterdam, the Netherlands

Purpose: Osteosarcoma (OS) mostly affects children and young adults, and has only a 20%–30% 5-year survival rate when metastasized. We aimed to create dual-targeted (extracellular against EphA2 and intracellular against JNK-interacting protein 1 [JIP1]), doxorubicin (DOX)-loaded liposomes to treat OS metastatic disease.
Materials and methods: Cationic liposomes contained N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl-sulfate (DOTAP), cholesterol, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and distearoyl-phosphatidylethanolamine–methyl-poly(ethylene glycol) (DSPE–mPEG) conjugate. EphA2 targeting was accomplished by conjugating YSA peptide to DSPE–mPEG. Vesicles were subsequently loaded with DOX and JIP1 siRNA.
Results: Characteristics assessment showed that 1) size of the bilayered particles was 109 nm; 2) DOX loading efficiency was 87%; 3) siRNA could be successfully loaded at a liposome:siRNA ratio of >24:1; and 4) the zeta potential was 18.47 mV. Tumor-mimicking pH conditions exhibited 80% siRNA and 50.7% DOX sustained release from the particles. Stability studies ensured the protection of siRNA against degradation in serum. OS cell lines showed increased and more pericellular/nuclear localizations when using targeted vesicles. Nontargeted and targeted codelivery caused 70.5% and 78.6% cytotoxicity in OS cells, respectively (free DOX: 50%). Targeted codelivery resulted in 42% reduction in the siRNA target, JIP1 mRNA, and 46% decrease in JIP1 levels.
Conclusion: Our dual-targeted, DOX-loaded liposomes enhance toxicity toward OS cells and may be effective for the treatment of metastatic OS.

Keywords: MAP kinase 8 interacting protein 1, MAPK8IP1, functionalization, cationic liposome, intracellular targeting, extracellular targeting

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