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      International Journal of Nanomedicine (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the application of nanotechnology in diagnostics, therapeutics, and drug delivery systems throughout the biomedical field. Sign up for email alerts here.

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      Is Open Access

      Brain Targeted Gold Liposomes Improve RNAi Delivery for Glioblastoma

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          Abstract

          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.

          Most cited references82

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          Analysis of nanoparticle delivery to tumours

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            DLS and zeta potential - What they are and what they are not?

            Adequate characterization of NPs (nanoparticles) is of paramount importance to develop well defined nanoformulations of therapeutic relevance. Determination of particle size and surface charge of NPs are indispensable for proper characterization of NPs. DLS (dynamic light scattering) and ZP (zeta potential) measurements have gained popularity as simple, easy and reproducible tools to ascertain particle size and surface charge. Unfortunately, on practical grounds plenty of challenges exist regarding these two techniques including inadequate understanding of the operating principles and dealing with critical issues like sample preparation and interpretation of the data. As both DLS and ZP have emerged from the realms of physical colloid chemistry - it is difficult for researchers engaged in nanomedicine research to master these two techniques. Additionally, there is little literature available in drug delivery research which offers a simple, concise account on these techniques. This review tries to address this issue while providing the fundamental principles of these techniques, summarizing the core mathematical principles and offering practical guidelines on tackling commonly encountered problems while running DLS and ZP measurements. Finally, the review tries to analyze the relevance of these two techniques from translatory perspective.
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              Gold nanoparticles for biology and medicine.

              Gold colloids have fascinated scientists for over a century and are now heavily utilized in chemistry, biology, engineering, and medicine. Today these materials can be synthesized reproducibly, modified with seemingly limitless chemical functional groups, and, in certain cases, characterized with atomic-level precision. This Review highlights recent advances in the synthesis, bioconjugation, and cellular uses of gold nanoconjugates. There are now many examples of highly sensitive and selective assays based upon gold nanoconjugates. In recent years, focus has turned to therapeutic possibilities for such materials. Structures which behave as gene-regulating agents, drug carriers, imaging agents, and photoresponsive therapeutics have been developed and studied in the context of cells and many debilitating diseases. These structures are not simply chosen as alternatives to molecule-based systems, but rather for their new physical and chemical properties, which confer substantive advantages in cellular and medical applications.
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                Author and article information

                Journal
                Int J Nanomedicine
                Int J Nanomedicine
                IJN
                intjnano
                International Journal of Nanomedicine
                Dove
                1176-9114
                1178-2013
                23 April 2020
                2020
                : 15
                : 2809-2828
                Affiliations
                [1 ]Department of Physiology, University of Puerto Rico , San Juan, Puerto Rico
                [2 ]Comprehensive Cancer Center, University of Puerto Rico , San Juan, Puerto Rico
                [3 ]Department of Neurosurgery, University of Puerto Rico , San Juan, Puerto Rico
                [4 ]Department of Biology, University of Puerto Rico , San Juan, Puerto Rico
                [5 ]Department of Biochemistry, University of Puerto Rico , San Juan, Puerto Rico
                [6 ]Department of Chemistry, University of Puerto Rico , San Juan, Puerto Rico
                Author notes
                Correspondence: Pablo E Vivas-Mejía Comprehensive Cancer Center, University of Puerto Rico, Medical Sciences Campus , San Juan00935, Puerto RicoTel +1787 772 8300, ext 1114Fax +1787 758 2557 Email pablo.vivas@upr.edu
                Author information
                http://orcid.org/0000-0001-5705-7663
                http://orcid.org/0000-0001-8971-4314
                Article
                241055
                10.2147/IJN.S241055
                7185647
                32368056
                da498fc4-f0c9-4528-9ab9-a702b18a0a44
                © 2020 Grafals-Ruiz et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 04 December 2019
                : 27 March 2020
                Page count
                Figures: 8, Tables: 2, References: 106, Pages: 20
                Categories
                Original Research

                Molecular medicine
                glioblastoma,gbm,central nervous system,cns,micrornas,rna interference,spherical nucleic acids,liposomes

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