Lipidlike compounds are termed lipidoids and have been applied to formulate lipidlike nanoparticles llns 1. Lipid nanoparticles slns and nlcs are regarded as highly promising systems for delivering nucleic acids in gene therapy. Lipidlike materials for lowdose, in vivo gene silencing. Author links open overlay panel xiaoying wang a b 1 yamin li a 1 quanshun li a c caleb i.
In vivo hoxa1 silencing in mammary gland by intraductal delivery of sirna lipidoid nanoparticles. Specifically, they are using nanoparticles to design systems for delivering genes. Here we report a combinatorial library of disulfide bondcontaining cationic lipidoid nanoparticles lnps as carrier systems for intracellular cas9sgrna delivery and subsequent genome editing. Functionalization of the iron oxide nanoparticle surface. Anderson,1,2,3 1david h koch institute for integrative cancer research, massachusetts institute of technology, 77 massachusetts avenue, cambridge, massachusetts 029, united states 2department of. Here we develop a magnetic nucleic acid delivery system composed of iron oxide nanoparticles and cationic lipidlike materials termed lipidoids. Nano 24375101mmedia and were characterized by mass spectrometry and highperformance liquid chromatography. Herein, a new type of noncationic lipidoid nanoparticle lnp is reported for his. They are highly reactive because of their large surface area. Of note, at these high concentrations, the strongest tlr4 activation was noted for l 6, which showed the. A modern formulation approach in drug delivery system s. Lipidoid nanoparticles containing pdl1 sirna delivered in. Engineering of lipidpolymer hybrid nanoparticles with lipidoids as lipid component and plga as polymer component for local delivery of. Lipidoidcoated iron oxide nanoparticles for efficient dna.
Lipidoid iron oxide nanoparticles are a platform for. Particles composed of leading lipidoids show significantly better delivery to ecs than a leading commercially available transfection reagent, lipofectamine 2000. Pdf the antisense technology that emerged with the discovery of rna. Ethanol removal and buffer exchange of sirnacontaining lipidoid nanoparticles was. As a model of potential therapeutic application, nanoparticles composed of the top performing lipidoid, na114, are studied for their ability to deliver sirna targeting anti. Silencing hoxa1 by intraductal injection of sirna lipidoid. They are widely used in medical and laboratory applications and have also been studied for remediation of industrial sites. Nanotechnology, volume 24, number 37, 20 september 20.
Lipid nanoparticles safely and effectively deliver nucleic acids, overcoming a major barrier preventing the development and use of genetic medicines. Metal oxide ceramic nanoparticles can also be used to create thin layers, whether crystalline or amorphous. Rna interference rnai is an evolutionarily conserved mechanism of gene regulation by which small doublestranded rna dsrna moleculestermed small interfering rnas sirnasdegrade complementary messenger rna to silence gene expression. Lipidoid mrna nanoparticles for myocardial delivery in rodents. Lipidoidcoated iron oxide nanoparticles for e cient dna. A novel local anticolorectal cancer drug delivery system. Nanoscale iron particles are submicrometer particles of iron metal.
Lnps maintain potency in a wide range of ph solutions. A novel lipidoidmicrorna formulation promotes calvarial. Galactosylated lipidoid nanoparticles for delivery of. Ceramic nanoparticles, like metallic nanoparticles, can also be formed into coatings and bulk materials at lower temperatures than their non nano counterparts, reducing manufacturing costs. Systemic administration of siprk2 using the lipidoid nanoparticles results in significant reduction of host prk2 in the mouse liver. Lipidoidcoated iron oxide nanoparticles for efficient dna and.
Direct myocardial injection of flnp containing 110. Nanoparticles with high efficacies of targeted gene knockout as well as relatively low cytotoxicities have been identified through in vitro screening. Engineering of small interfering rnaloaded lipidoid polydllacticcoglycolic acid hybrid nanoparticles for highly efficient and safe gene silencing. Studies were conducted using two different mantle cell lymphoma cell lines, a normal jeko1 and an aggressive maver1 line, to assess the ability of lipidoid nanoparticles to be used broadly in the treatment of mantle cell lymphoma. Degradable lipid nanoparticles with predictable in vivo. This study suggests that negative lipidoid nanoparticles with enema delivery costitute, uniquely and appropriately, a local anticolorectal cancer nucleic acid drug delivery platform, and the application of similar modes may be feasible in other therapeutic settings. Syntheticbased nano and microparticles intended for transmucosal drug delivery. These are predominantly due to the particle size which affects bioavailability and circulation time, large surface area to volume ratio enhanced solubility compared to larger particles, tunable surface charge of the particle with the possibility of encapsulation, and large drug payloads that can be accommodated. The mean hydrodynamic size of these nanoparticles was systematically varied and optimized for delivery. Enhanced delivery performances have been achieved using disulfide bondcontaining bioreducible lipidoids. In the present study, we demonstrated that lipidoid polymer hybrid nanoparticle fs14np can efficiently deliver sirna against il1.
Immunogenicity testing of lipidoids in vitro and in silico cell press. Genetic medicine has many different applications such as gene editing, rapid vaccine development, immuno. Lipid nanoparticles are ideal for delivering genes and drugs. Exploring the potential of lipidoid polymer hybrid nanoparticles to deliver oligonucleotides to intracellular pharmacological targets. Bring all stocks of the required components to room temperature lipidoid, dspc, peg, and cholesterol and make sure they are well dissolved prior to use see note 4. Synthetic lipidlike molecules lipidoids are superior for intracellular delivery of various bioactive cargos. Although mrna and sirna have significant therapeutic potential, their simultaneous delivery has not been previously explored. To help make this technology accessible to other investigators, herein we describe lipidbased nanoparticles containing modrna using a custom formulation consisting of an epoxidederived lipidoid mixed in ethanol with the stabilizers dspc, cholesterol and pegdmg, added to modified mrna dissolved in citrate buffer resulting in synthesis of formulated lipid nanoparticles flnps via. Research aim engineering of lipidpolymer hybrid nanoparticles with lipidoids as lipid component and plga as. Formulation and characterization of solid lipid nanoparticles.
Technological developments and in vivo techniques to evaluate their interaction with the skin mariella bleve, franca pavanetto and paola perugini department of drug sciences. Pdf engineering of small interfering rnaloaded lipidoid. Until now, viral systems have been the most effective method for. In vivo sirna delivery activity of lipidoid nanoparticles. Hyaluronic acid modification of rnase a and its intracellular delivery using lipidlike nanoparticles. In an in vitro study using polystyrene particles ranging from 0. The lipid core is stabilized by surfactants emulsifiers. Solid lipid nanoparticles possess a solid lipid core matrix that can solubilize lipophilic molecules. Both free lipidoid l8 and lmfs formed narrowly distributed nanoparticles.
Intracellular delivery and biodistribution study of crispr. Lipidoid nanoparticles, which have been previously shown to deliver. Darunavir, an antihiv drug having poor solubility in aqueous and lipid medium, illustrates degradation above its melting point, i. Active lipidoids are synthesized by conjugating nitrilotriacetic acid with hydrophobic tails and nanoparticles are formulated in the presence of helper lipids through self. The ph of the gi tract ranges from 12 in the stomach to 8 in the large intestine 31. Lipidoid encapsulated nanoparticle lnp formulation is validated as a delivery vehicle to mediate p21 induction and inhibit growth of prostate tumor xenografts grown in nude mice following intratumoral injection. To facilitate the treatment of diseases associated with aberrant gene upregulation and downregulation, we sought to coformulate sirna and mrna in a single lipidoid nanoparticle lnp formulation.
The nanoparticles were fabricated through selfassembly procedures, and their photoresponsive behaviors were examined. Introduction to nanoparticle characterization with afm. Shell thickness of the particles decreased with increasing pressure and nozzle diameter. For comparison, we prepared and characterized a reference formulation of tnf sirnaloaded stable nucleic acid lipid particles snalps using lipidoid as the cationic lipid component, and investigated how the particle structure and surface properties of these two systems differentially affected the sirna delivery to activated macrophages in vitro. Recently, we have developed n 1,n 3,n 5tris2aminoethylbenzene1,3,5tricarboxamide tt derived lipidlike compounds, formulated them into tt llns for mrna delivery, and applied an orthogonal array design to facilitate formulation optimization. A combinatorial library of lipidlike materials for. We report highly efficient in vivo delivery of modified mrna modrna to rat and pig myocardium using formulated lipidoid nanoparticles flnp. This treatment significantly suppresses hcv replication in an hcv. Pdf lipidoid nanoparticles for sirna delivery to the. The aim of this work was to design a system for antisense drug delivery to liver hepatocytes using lipidoid magnetic nanoparticles lnp. To examine the role of hepatic myeloid pdl1 expression during viral infection, we determined the magnitude and quality of antiviral immune responses by administering pdl1 shortinterfering rna sirna encapsulated in lipidoid nanoparticles lnp in mice.
Lipidlike nanoparticles for small interfering rna full paper. Lipid nanoparticle formulations for enhanced codelivery. Recently, we showed that encapsulation of sirna in lipidpolymer hybrid nanoparticles lpns, based on. Interference with the assay is a likely explanation for the reduced tlr4 activation observed at high l 5 concentrations above 110 mm lipidoid. In this study, we use potent lipidoid nanoparticles to deliver sirna to silence mcl1 expression. Lipidoidcoated iron oxide nanoparticles for e cient dna and. Researchers are using nanotechnology to develop new formulations that can be applied to drugs and gene therapy. The study reported herein suggests that lipidoidsirna nano particles may provide a vehicle for the delivery of rnai therapeutics to ecs. Pdf tunable lipidoidtelodendrimer hybrid nanoparticles. It can be used as a prefix for any unit to mean a billionth of that unit. Through incorporating stimuliresponsive linkers, lipidoid nanoparticle based delivery systems with triggeredrelease features can be constructed. Recently, a class of lipidlike materials termed lipidoids have been shown to potently deliver sirna to the liver and immune cells. Like nanoparticles for small interfering rna delivery.
Recently, increasing attention has been focused on these sln as colloidal drug carriers for incorporating hydrophilic or lipophilic drugs. A afm capabilities in nanoparticle characterization qualitative analysis using the afm, individual particles and groups of particles can be resolved. Solid lipid nanoparticles sln have emerged as a nextgeneration drug delivery system with potential applications in pharmaceutical field, cosmetics, research, clinical medicine and other allied sciences. Preparation and optimization of lipidlike nanoparticles for. Mcmurry department of mechanical engineering, university of minnesota, minneapolis, mn 55455, usa. Pdf lipidbased nanoparticles for cancer treatment researchgate. Formulation of small activating rna into lipidoid nanoparticles inhibits xenograft prostate tumor growth by inducing p21 expression. A solid lipid nanoparticle is typically spherical with an average diameter between 10 and nanometers. Information, dna entrapment is low nano particles smaller than 50 nm, whereas sirna entrapment is high. Contents of liposomes introduction mechanism of liposome formation. In the presence of oxygen and water, they rapidly oxidize to form free iron ions. From these experiments, three compounds were identified which facilitated greater than 70% silencing at an sirna dose of 5 ng per well fig.
These sirnaloaded lpns are composed of lipidoids and polydllacticcoglycolic acid plga, and we recently. Thus, lipidoidmediated tlr4 activation during sirna delivery may be modulated via. Despite, the drug suffers from poor oral bioavailability 37% owing to less permeability and being polyglycoprotein and cyp3a metabolism substrate. A concern for oral sirna lnp delivery is that lnps may. Exploring the potential of lipidoidpolymer hybrid nanoparticles to. Lipidoids and lipids share many of the physicochemical properties that drive the formation of liposomes for gene delivery. Lipidoidpolymer hybrid nanoparticles loaded with tnf sirna. Silencing hoxa1 by intraductal injection of sirna lipidoid nanoparticles editors summary human dcis and mammary tumorigenesis. Lipidoid nanoparticle mediated silencing of mcl1 induces. Tunable lipidoid telodendrimer hybrid nanoparticles for intracellular protein delivery in brain tumor treatment article pdf available in small 1231 june 2016 with 116 reads. We provide insight into the stepwise creation and analysis of a putative rnaabased therapeutic with antitumor activity. Lipid nanoparticles used in skin care cosmetics processes and associated benefits. Experimental section, nanoparticle characterization, dna transfection, sirna transfection, and dna and sirna entrapment and figures showing synthesis of epoxidederived lipidoid library, invitro screen of lipidoid library, lipid content in supernatant, sirna concentration in supernatant, tem images of iron oxide nanoparticles, entrapment of dna and sirna on the nanoparticle.
Degradable lipid nanoparticles with predictable in vivo sirna. Ribonucleoprotein loaded bioreducible lipidoid nanoparticles yamin lia, justin bolingera, yingjie yua, zachary glassa, nicola shia, liu yanga, ming wangb, qiaobing xua adepartment of biomedical engineering, tufts university, medford, maacademy02155, usa bbeijing national laboratory for molecular sciences, key laboratory of analytical. Similarly, 300 nm sized plga particles also showed higher internalization and activation of dcs in comparison to 17, 7 and 1. In order to develop efficacious, degradable nanoparticles for sirna delivery while conducting. Lnps are among the most efficacious of existing rna delivery systems. Measurement of inherent material density of nanoparticle agglomerates kihong park, david b. Jun 27, 2014 lipidoid synthesis and nanoparticle formulation. Here, we seek to establish the utility of lipidoid nanoparticles lnps in the context of sirna delivery to the intestinal epithelium. In this study, we tested a novel strategy for controlling pdl1 expression through delivery of pdl1 sirna encapsulated in a cationic lipidoid nanoparticle lnp as the vehicle targeting myeloid cells. Negative lipidoid nanoparticle synthesis the synthesis of 98n1251 was implemented according to the description in 6. Measurement of inherent material density of nanoparticle. Oral delivery, a patientfriendly means of drug delivery, is preferred for local administration of intestinal therapeutics. Here we describe the use of lipidoid nanoparticles for delivery of modified mrna modrna to the myocardium in vivo, with a focus on rodent models that.
Pdf applications of lipidic and polymeric nanoparticles for sirna. Notably, the synthesis reaction for generating a lipidoid library proceeds in the absence of solvent or catalysts, and thereby eliminates the purification or concentration steps akinc et al. Lipidoidcoated iron oxide nanoparticles for efficient dna and sirna delivery article in nano letters 3 february 20 with 71 reads how we measure reads. Lipid nanoparticles used in skin care cosmetics processes. Myocardial delivery of lipidoid nanoparticle carrying. Lipidoid from the greek which means lipidlike nanoparticles are a. Lipid nanoparticle formulations for enhanced codelivery of. Melting point of fhso decreased from 69 c to 57 c above 120 bar in co 2, and onset melting temperature of the particles was 50 c due to nanosize. Dear colleagues, among the many strategies pursued to enhance the efficacy of subunit vaccines in recent years, the use of synthetic or biologicallyderived nanoparticles as a platform for vaccine delivery is an approach which has both demonstrated clinical success and has much potential for further development. The role of nanotechnology in the treatment of viral. Formation of bioactivecarrier hollow solid lipid micro and. Nanoparticle based delivery of nucleotides offers an alternative to viral vectors for gene therapy.
Lipid nanoparticles lnps are the most clinically advanced nonviral gene delivery system. Lipidoid nanoparticles for sirna delivery to the intestinal epithelium. In particular, the formulations described here may provide a vehicle for the treatment of ischemicdiseases such as myocardial, hindlimb, or cerebral ischemia. Lightregulated cargo release and following functionality restoration indicated the potential of the newly developed lipidoid nanoparticles for spatiotemporal delivery. Preparation and optimization of lipidlike nanoparticles for mrna. Lipidlike nanoparticles llns have shown great promise for nucleic acid delivery. Transmucosal routes of drug delivery include transport across the nasal, rectal, vaginal, ocular and oral cavity mucous membranes, and offer distinct advantages over oral administration for systemic drug delivery. Preparation, characterization, and in vitro evaluation of. The safe, targeted and effective delivery of gene therapeutics remains a significant barrier to their broad clinical application. Introduction to nanoparticle characterization with afm 2 revision. Coated nanoparticles are capable of delivering dna and sirna to cells in culture.
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