<p>Brain Targeted Gold Liposomes Improve RNAi Delivery for Glioblastoma</p>

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 miRNAbased therapies for GBM as well as other CNS disorders.

Noncoding RNA therapeutics — challenges and potential solutions

“…Systemic administration of miR-182 mimic-coated SNAs showed successful delivery to tumour in a murine glioblastoma model 231 . SNAs may also be combined with liposomal delivery, for instance, anti-miR-92b-loaded SNAs in apolipoprotein E (ApoE)-coated liposomes successfully crossed the blood–brain barrier in a murine glioblastoma model and reduced tumour cell viability 232 . Their clinical safety was proved in a phase 0 clinical trial in which SNAs coated with siRNAs targeting the Bcl2Like12 oncogene were systemically administered to patients with glioblastoma (NCT03020017) 233 .…”

Targeting Non-coding RNA for Glioblastoma Therapy: The Challenge of Overcomes the Blood-Brain Barrier

“…Liposomes increase the distribution of delivered agents, reduce toxicity, and extend half-life. Liposomes can be customized based on the feasibility of the target cell or tissue by modifying their surfaces with a variety of functional moieties ( 17 , 105 , 106 ). For in vivo applications, PEGylation (mostly with PEG-2000) on the liposome surface is commonly used ( 107 ).…”

“…Early studies by Kumur et al showed that RVG peptide significantly increased oligonucleotide delivery (siRNA) to brain ( p = 0.001) in comparison to other organs (liver and spleen), making it an excellent candidate to improve RNA delivery to brain tumors ( 212 ). In a recent study, our research team compared the accumulation levels of RVG- and ApoE-decorated liposomal nanoparticles (with AuNPs-OMI inside liposomes) in orthotopic GBM mouse models ( 106 ). We showed that ApoE decorated NPs accumulate to a higher degree in GBM cells compared with RVG-decorated NPs ( 106 ).…”

An update of advanced nanoplatforms for glioblastoma multiforme management

“…It is described that positive charged NPs are rapidly recognized by the immune system. On the other hand, negatively charged NPs cannot interact so easily with cell membranes, therefore decreasing their internalization efficacy but they are more biocompatible (Grafals-Ruiz et al, 2020[ 52 ]).…”

“…Liposomes and polymeric NPs have also been extensively explored for drug delivery to GBM, and this is their main application in clinical trials (Grafals-Ruiz et al, 2020[ 52 ]). Examples of such liposomal formulations include liposomal Ara-C (DepoCyt) (NCT01044966) and liposomal irinotecan (NCT02022644).…”