Brain Targeted Gold Liposomes Improve RNAi Delivery for Glioblastoma
Received 4 December 2019
Accepted for publication 27 March 2020
Published 23 April 2020 Volume 2020:15 Pages 2809—2828
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 4
Editor who approved publication: Dr Thomas J Webster
Nilmary Grafals-Ruiz,1,2 Christian I Rios-Vicil,2,3 Eunice L Lozada-Delgado,2,4 Blanca I Quiñones-Díaz,2,5 Ricardo A Noriega-Rivera,2,5 Gabriel Martínez-Zayas,2,6 Yasmarie Santana-Rivera,2 Ginette S Santiago-Sánchez,2,5 Fatma Valiyeva,2 Pablo E Vivas-Mejía2,5
1Department of Physiology, University of Puerto Rico, San Juan, Puerto Rico; 2Comprehensive Cancer Center, University of Puerto Rico, San Juan, Puerto Rico; 3Department of Neurosurgery, University of Puerto Rico, San Juan, Puerto Rico; 4Department of Biology, University of Puerto Rico, San Juan, Puerto Rico; 5Department of Biochemistry, University of Puerto Rico, San Juan, Puerto Rico; 6Department of Chemistry, University of Puerto Rico, San Juan, Puerto Rico
Correspondence: Pablo E Vivas-Mejía
Comprehensive Cancer Center, University of Puerto Rico, Medical Sciences Campus, San Juan 00935, Puerto Rico
Tel +1787 772 8300, ext 1114
Fax +1787 758 2557
Introduction: Glioblastoma (GBM) is the most common and lethal of the central nervous system (CNS) malignancies. The initiation, progression, and infiltration ability of GBMs are attributed in part to the dysregulation of microRNAs (miRNAs). Thus, targeting dysregulated miRNAs with RNA oligonucleotides (RNA interference, RNAi) has been proposed for GBM treatment. Despite promising results in the laboratory, RNA oligonucleotides have clinical limitations that include poor RNA stability and off-target effects. RNAi therapies against GBM confront an additional obstacle, as they need to cross the blood-brain barrier (BBB).
Methods: Here, we developed gold-liposome nanoparticles conjugated with the brain targeting peptides apolipoprotein E (ApoE) and rabies virus glycoprotein (RVG). First, we functionalized gold nanoparticles with oligonucleotide miRNA inhibitors (OMIs), creating spherical nucleic acids (SNAs). Next, we encapsulated SNAs into ApoE, or RVG-conjugated liposomes, to obtain SNA-Liposome-ApoE and SNA-Liposome-RVG, respectively. We characterized each nanoparticle in terms of their size, charge, encapsulation efficiency, and delivery efficiency into U87 GBM cells in vitro. Then, they were administered intravenously (iv) in GBM syngeneic mice to evaluate their delivery efficiency to brain tumor tissue.
Results: SNA-Liposomes of about 30– 50 nm in diameter internalized U87 GBM cells and inhibited the expression of miRNA-92b, an aberrantly overexpressed miRNA in GBM cell lines and GBM tumors. Conjugating SNA-Liposomes with ApoE or RVG peptides increased their systemic delivery to the brain tumors of GBM syngeneic mice. SNA-Liposome-ApoE demonstrated to accumulate at higher extension in brain tumor tissues, when compared with non-treated controls, SNA-Liposomes, or SNA-Liposome-RVG.
Discussion: SNA-Liposome-ApoE has the potential to advance the translation of miRNA-based therapies for GBM as well as other CNS disorders.
Keywords: glioblastoma, GBM, central nervous system, CNS, microRNAs, RNA interference, spherical nucleic acids, liposomes
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