Novel nanostructured lipid carriers dedicated to nucleic acid delivery for RNAi purposes (original) (raw)
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Recent Patents in Cationic Lipid Carriers for Delivery of Nucleic Acids
Recent Patents on DNA & Gene Sequences, 2011
Gene therapy is a medical technique intended for treatment of disorders caused by defective, missing, or overexpressing genes. Efficient delivery vectors are necessary in order to transport genetic material to the target cells. Such vectors include viral and non-viral carriers. Viral vectors transfect cells efficiently, however risks associated with their use have limited their clinical applications. Nonviral delivery systems are safer, easier to prepare, more versatile and cost effective. However, their transfection efficiency still falls behind that of the viral vectors. Considerable research into nonviral gene delivery has been conducted in the last two decades on synthetic soft materials such as cationic lipids, polymers, surfactants, and dendrimers as prospective nucleotide carriers for gene delivery. So far, cationic lipids are the most widely used constituents of nonviral gene carriers, with multiple strategies employed to improve their in vitro and in vivo transfection. Efforts in synthesizing new cationic lipids were not fully successful in closing the gap between the efficiency of the viral vectors and that of binary cationic lipid/DNA complexes. Current efforts for improving lipofection efficiency are focused on the development of multicomponent carriers including cationic lipids as key constituents. This review summarizes the recent patents on new cationic lipids as well as on multicomponent formulations enhancing their efficiency as nucleotide carriers.
Cationic lipid nanosystems as carriers for nucleic acids
New Biotechnology, 2014
Solid lipid nanoparticles (SLNs) consisting of tristearin or tribehenin, and monoolein aqueous dispersions (MADs) consisting of glyceryl-monoolein have been studied as potential nanocarriers for nucleic acids. The cationic character of nanocarriers was obtained by adding cationic surfactants, such as diisobutylphenoxyethyl-dimethylbenzyl ammonium chloride (DEBDA) or PEG-15 Cocopolyamine (PCPA), to the lipid composition. The products were characterised in terms of size and morphology by Cryo-TEM and PCS. The charge properties were determined by measuring the zeta potential. Our experimental protocol enabled us to obtain homogeneous and stable cationic nanosystems within 3-6 months of production. Assessment of cytotoxicity on HepG2 cells by MTT assays indicated that MAD preparations were less toxic than SLN, and in general PCPA-containing formulations are less cytotoxic than DEBDA-containing ones. The formation of electrostatic complexes with salmon sperm or plasmid DNA, used as model nucleic acids, was evaluated by electrophoresis on agarose gel. The results confirmed that all the formulations studied are able to form the complex. Finally, we investigated the ability of SLN and MAD to deliver DNA into HepG2 cells, and to this purpose we exploited expression plasmids for green fluorescent protein or firefly luciferase. Although with reduced efficiency, the results showed that the produced nanocarriers are able to convey plasmids into cells. The data obtained encourage further study aimed at improving these new formulations and proposing them as novel in vitro transfection reagents with potential application to in vivo delivery of nucleic acids.
Solid lipid nanoparticles as nucleic acid delivery system: Properties and molecular mechanisms
Solid lipid nanoparticles (SLNs) have been proposed in the 1990s as appropriate drug delivery systems, and ever since they have been applied in a wide variety of cosmetic and pharmaceutical applications. In addition, SLNs are considered suitable alternatives as carriers in gene delivery. Although important advances have been made in this particular field, fundamental knowledge of the underlying mechanisms of SLN-mediated gene delivery is conspicuously lacking, an imperative requirement in efforts aimed at further improving their efficiency. Here, we address recent advances in the use of SLNs as platform for delivery of nucleic acids as therapeutic agents. In addition, we will discuss available technology for conveniently producing SLNs. In particular, we will focus on underlying molecular mechanisms by which SLNs and nucleic acids assemble into complexes and how the nucleic acid cargo may be released intracellularly. In discussing underlying mechanisms, we will, when appropriate, refer to analogous studies carried out with systems based on cationic lipids and polymers, that have proven useful in the assessment of structure–function relationships. Finally, we will give suggestions for improving SLN-based gene delivery systems, by pointing to alternative methods for SLNplex assembly, focusing on the realization of a sustained nucleic acid release.
Lipid Nanoparticles for Delivery of Therapeutic RNA Oligonucleotides
Molecular Pharmaceutics, 2019
Gene therapy is an exciting field that has the potential to address emerging scientific and therapeutic tasks. RNA-based gene therapy has made remarkable progress in recent decades. Nevertheless, efficient targeted delivery of RNA therapeutics is still a prerequisite for entering the clinics. In this review, we introduce current delivery methods for RNA gene therapeutics based on lipid nanoparticles (LNP). We focus on the clinical appeal of recent RNA NPs and discuss existing challenges of fabrication and screening LNP candidates for effective translation into drugs of human metabolic diseases and cancer.
Lipid-Based Nanocarriers for RNA Delivery
RNA-interference (RNAi) agents such as small-interfering RNA (siRNA) and micro-RNA (miRNA) have strong potential as therapeutic agents for the treatment of a broad range of diseases such as malignancies, infections, autoimmune diseases and neurological diseases that are associated with undesirable gene expression. In recent years, several clinical trials of RNAi therapeutics especially siRNAs have been conducted with limited success so far. For systemic administration of these poorly permeable and easily degradable macromolecules, it is obvious that a safe and efficient delivery platform is highly desirable. Because of high biocompatibility, biodegradability and solid track record for clinical use, nanocarriers made of lipids and/or phospholipids have been commonly employed to facilitate RNA delivery. In this article, the key features of the major sub-classes of lipid-based nanocarriers, e.g. liposomes, lipid nanoparticles and lipid nanoemulsions, will be reviewed. Focus of the discussion is on the various challenges researchers face when developing lipid-based RNA nanocarriers, such as the toxicity of cationic lipids and issues related to PEGylated lipids, as well as the strategies employed in tackling these challenges. It is hoped that by understanding more about the pros and cons of these most frequently used RNA delivery systems, the pharmaceutical scientists, biomedical researchers and clinicians will be more successful in overcoming some of the obstacles that currently limit the clinical translation of RNAi therapy.
Lipid Delivery Systems for Nucleic-Acid-Based-Drugs: From Production to Clinical Applications
Pharmaceutics, 2019
In the last years the rapid development of Nucleic Acid Based Drugs (NABDs) to be used in gene therapy has had a great impact in the medical field, holding enormous promise, becoming “the latest generation medicine” with the first ever siRNA-lipid based formulation approved by the United States Food and Drug Administration (FDA) for human use, and currently on the market under the trade name Onpattro™. The growth of such powerful biologic therapeutics has gone hand in hand with the progress in delivery systems technology, which is absolutely required to improve their safety and effectiveness. Lipid carrier systems, particularly liposomes, have been proven to be the most suitable vehicles meeting NABDs requirements in the medical healthcare framework, limiting their toxicity, and ensuring their delivery and expression into the target tissues. In this review, after a description of the several kinds of liposomes structures and formulations used for in vitro or in vivo NABDs delivery, ...
Multicomponent Lipid Nanoparticles for RNA Transfection
Pharmaceutics
Despite the wide variety of available cationic lipid platforms for the delivery of nucleic acids into cells, the optimization of their composition has not lost its relevance. The purpose of this work was to develop multi-component cationic lipid nanoparticles (LNPs) with or without a hydrophobic core from natural lipids in order to evaluate the efficiency of LNPs with the widely used cationic lipoid DOTAP (1,2-dioleoyloxy-3-[trimethylammonium]-propane) and the previously unstudied oleoylcholine (Ol-Ch), as well as the ability of LNPs containing GM3 gangliosides to transfect cells with mRNA and siRNA. LNPs containing cationic lipids, phospholipids and cholesterol, and surfactants were prepared according to a three-stage procedure. The average size of the resulting LNPs was 176 nm (PDI 0.18). LNPs with DOTAP mesylate were more effective than those with Ol-Ch. Core LNPs demonstrated low transfection activity compared with bilayer LNPs. The type of phospholipid in LNPs was significant f...
Lipid and polymeric carrier-mediated nucleic acid delivery
Expert Opinion on Drug Delivery, 2010
Importance of the field-Nucleic acids such as plasmid DNA, antisense oligonucleotide, and RNA interference (RNAi) molecules, have a great potential to be used as therapeutics for the treatment of various genetic and acquired diseases. To design a successful nucleic acid delivery system, the pharmacological effect of nucleic acids, the physiological condition of the subjects or sites, and the physicochemical properties of nucleic acid and carriers have to be thoroughly examined. Areas covered in this review-The commonly used lipids, polymers and corresponding delivery systems are reviewed in terms of their characteristics, applications, advantages and limitations. What the reader will gain-This article aims to provide an overview of biological barriers and strategies to overcome these barriers by properly designing effective synthetic carriers for nucleic acid delivery. Take home message-A thorough understanding of biological barriers and the structure-activity relationship of lipid and polymeric carriers is the key for effective nucleic acid therapy.
Molecular Therapy, 2013
In recent years, RNA interference (RNAi) therapeutics, most notably with lipid nanoparticle-based delivery systems, have advanced into human clinical trials. The results from these early clinical trials suggest that lipid nanoparticles (LNPs), and the novel ionizable lipids that comprise them, will be important materials in this emerging field of medicine. A persistent theme in the use of materials for biomedical applications has been the incorporation of biodegradability as a means to improve biocompatibility and/or to facilitate elimination. Therefore, the aim of this work was to further advance the LNP platform through the development of novel, next-generation lipids that combine the excellent potency of the most advanced lipids currently available with biodegradable functionality. As a representative example of this novel class of biodegradable lipids, the lipid evaluated in this work displays rapid elimination from plasma and tissues, substantially improved tolerability in preclinical studies, while maintaining in vivo potency on par with that of the most advanced lipids currently available.