Lnps are among the most efficacious of existing rna delivery systems. Preparation, characterization, and in vitro evaluation 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. Pdf engineering of small interfering rnaloaded lipidoid. Research aim engineering of lipidpolymer hybrid nanoparticles with lipidoids as lipid component and plga as.
Myocardial delivery of lipidoid nanoparticle carrying. 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. Lipid nanoparticles used in skin care cosmetics processes and associated benefits. A novel local anticolorectal cancer drug delivery system. The mean hydrodynamic size of these nanoparticles was systematically varied and optimized for delivery. Systemic administration of siprk2 using the lipidoid nanoparticles results in significant reduction of host prk2 in the mouse liver. In vivo sirna delivery activity of lipidoid nanoparticles. Syntheticbased nano and microparticles intended for transmucosal drug delivery. Functionalization of the iron oxide nanoparticle surface. Negative lipidoid nanoparticle synthesis the synthesis of 98n1251 was implemented according to the description in 6. Enhanced delivery performances have been achieved using disulfide bondcontaining bioreducible lipidoids. Mcmurry department of mechanical engineering, university of minnesota, minneapolis, mn 55455, usa.
Lipidoidcoated iron oxide nanoparticles for e cient dna. Pdf the antisense technology that emerged with the discovery of rna. Oral delivery, a patientfriendly means of drug delivery, is preferred for local administration of intestinal therapeutics. Genetic medicine has many different applications such as gene editing, rapid vaccine development, immuno.
The role of nanotechnology in the treatment of viral. Lipidlike materials for lowdose, in vivo gene silencing. Pdf lipidoid nanoparticles for sirna delivery to the. Lipidoidcoated iron oxide nanoparticles for efficient dna and. From these experiments, three compounds were identified which facilitated greater than 70% silencing at an sirna dose of 5 ng per well fig.
Of note, at these high concentrations, the strongest tlr4 activation was noted for l 6, which showed the. In order to develop efficacious, degradable nanoparticles for sirna delivery while conducting structurefunction analysis, we first employed. Pdf tunable lipidoidtelodendrimer hybrid nanoparticles. Silencing hoxa1 by intraductal injection of sirna lipidoid. Silencing hoxa1 by intraductal injection of sirna lipidoid nanoparticles editors summary human dcis and mammary tumorigenesis. 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. Lipidoid nanoparticles, which have been previously shown to deliver. The ph of the gi tract ranges from 12 in the stomach to 8 in the large intestine 31. Lipid nanoparticles slns and nlcs are regarded as highly promising systems for delivering nucleic acids in gene therapy. Researchers are using nanotechnology to develop new formulations that can be applied to drugs and gene therapy.
Whereas the diameter of free l8 lipidoid nanoparticles was 277. Engineering of small interfering rnaloaded lipidoid polydllacticcoglycolic acid hybrid nanoparticles for highly efficient and safe gene silencing. Nanoparticle based delivery of nucleotides offers an alternative to viral vectors for gene therapy. 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. Recently, a class of lipidlike materials termed lipidoids have been shown to potently deliver sirna to the liver and immune cells. 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. Introduction to nanoparticle characterization with afm. Herein, a new type of noncationic lipidoid nanoparticle lnp is reported for his. Author links open overlay panel xiaoying wang a b 1 yamin li a 1 quanshun li a c caleb i. Solid lipid nanoparticles possess a solid lipid core matrix that can solubilize lipophilic molecules. Nanoscale iron particles are submicrometer particles of iron metal. Although mrna and sirna have significant therapeutic potential, their simultaneous delivery has not been previously explored. A novel lipidoidmicrorna formulation promotes calvarial. A combinatorial library of lipidlike materials for.
Nano 24375101mmedia and were characterized by mass spectrometry and highperformance liquid chromatography. Engineering of lipidpolymer hybrid nanoparticles with lipidoids as lipid component and plga as polymer component for local delivery of. Lipidoid nanoparticle mediated silencing of mcl1 induces. Synthetic lipidlike molecules lipidoids are superior for intracellular delivery of various bioactive cargos. Both free lipidoid l8 and lmfs formed narrowly distributed nanoparticles. The nanoparticles were fabricated through selfassembly procedures, and their photoresponsive behaviors were examined.
Lipidlike nanoparticles for small interfering rna full paper. Until now, viral systems have been the most effective method for. 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. 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. Introduction to nanoparticle characterization with afm 2 revision. Intracellular delivery and biodistribution study of crispr. Lipidoidcoated iron oxide nanoparticles for efficient dna. 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. Ethanol removal and buffer exchange of sirnacontaining lipidoid nanoparticles was. Preparation and optimization of lipidlike nanoparticles for mrna. 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. The lipid core is stabilized by surfactants emulsifiers. Metal oxide ceramic nanoparticles can also be used to create thin layers, whether crystalline or amorphous.
Recently, increasing attention has been focused on these sln as colloidal drug carriers for incorporating hydrophilic or lipophilic drugs. Darunavir, an antihiv drug having poor solubility in aqueous and lipid medium, illustrates degradation above its melting point, i. 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. Lipid nanoparticle formulations for enhanced codelivery. Information, dna entrapment is low nano particles smaller than 50 nm, whereas sirna entrapment is high. Immunogenicity testing of lipidoids in vitro and in silico cell press. In an in vitro study using polystyrene particles ranging from 0. The aim of this work was to design a system for antisense drug delivery to liver hepatocytes using lipidoid magnetic nanoparticles lnp. Exploring the potential of lipidoid polymer hybrid nanoparticles to deliver oligonucleotides to intracellular pharmacological targets. Lipidoidpolymer hybrid nanoparticles loaded with tnf sirna. Formulation and characterization of solid lipid nanoparticles. Lipidoid nanoparticles containing pdl1 sirna delivered in. 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. Pdf lipidbased nanoparticles for cancer treatment researchgate.
Degradable lipid nanoparticles with predictable in vivo. 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. Lipid nanoparticles are ideal for delivering genes and drugs. Interference with the assay is a likely explanation for the reduced tlr4 activation observed at high l 5 concentrations above 110 mm lipidoid. Here we report a combinatorial library of disulfide bondcontaining cationic lipidoid nanoparticles lnps as carrier systems for intracellular cas9sgrna delivery and subsequent genome editing. Direct myocardial injection of flnp containing 110. 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.
They are widely used in medical and laboratory applications and have also been studied for remediation of industrial sites. Similarly, 300 nm sized plga particles also showed higher internalization and activation of dcs in comparison to 17, 7 and 1. The safe, targeted and effective delivery of gene therapeutics remains a significant barrier to their broad clinical application. 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. 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. Technological developments and in vivo techniques to evaluate their interaction with the skin mariella bleve, franca pavanetto and paola perugini department of drug sciences. Preparation and optimization of lipidlike nanoparticles for. 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.
Lnps maintain potency in a wide range of ph solutions. Like nanoparticles for small interfering rna delivery. Lipidoidcoated iron oxide nanoparticles for efficient dna and sirna delivery article in nano letters 3 february 20 with 71 reads how we measure reads. Here we develop a magnetic nucleic acid delivery system composed of iron oxide nanoparticles and cationic lipidlike materials termed lipidoids. Here, we seek to establish the utility of lipidoid nanoparticles lnps in the context of sirna delivery to the intestinal epithelium. 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. It can be used as a prefix for any unit to mean a billionth of that unit.
Hyaluronic acid modification of rnase a and its intracellular delivery using lipidlike nanoparticles. 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. Shell thickness of the particles decreased with increasing pressure and nozzle diameter. Nanoparticles with high efficacies of targeted gene knockout as well as relatively low cytotoxicities have been identified through in vitro screening. Lipid nanoparticle formulations for enhanced codelivery of. Lipidoid iron oxide nanoparticles are a platform for.
Lipid nanoparticles safely and effectively deliver nucleic acids, overcoming a major barrier preventing the development and use of genetic medicines. 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. Recently, we showed that encapsulation of sirna in lipidpolymer hybrid nanoparticles lpns, based on. Lipidoid mrna nanoparticles for myocardial delivery in rodents. A solid lipid nanoparticle is typically spherical with an average diameter between 10 and nanometers. In vivo hoxa1 silencing in mammary gland by intraductal delivery of sirna lipidoid nanoparticles.
Degradable lipid nanoparticles with predictable in vivo sirna. Lipidoid nanoparticles for sirna delivery to the intestinal. Galactosylated lipidoid nanoparticles for delivery of. Particles composed of leading lipidoids show significantly better delivery to ecs than a leading commercially available transfection reagent, lipofectamine 2000. The study reported herein suggests that lipidoidsirna nano particles may provide a vehicle for the delivery of rnai therapeutics to ecs. Lipidlike compounds are termed lipidoids and have been applied to formulate lipidlike nanoparticles llns 1. Lipidoidcoated iron oxide nanoparticles for e cient dna and.
Contents of liposomes introduction mechanism of liposome formation. Coated nanoparticles are capable of delivering dna and sirna to cells in culture. 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. They are highly reactive because of their large surface area. Pdf applications of lipidic and polymeric nanoparticles for sirna. Specifically, they are using nanoparticles to design systems for delivering genes. 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. 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. Formulation of small activating rna into lipidoid nanoparticles inhibits xenograft prostate tumor growth by inducing p21 expression. In this study, we use potent lipidoid nanoparticles to deliver sirna to silence mcl1 expression. 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. Active lipidoids are synthesized by conjugating nitrilotriacetic acid with hydrophobic tails and nanoparticles are formulated in the presence of helper lipids through self.
Lipid nanoparticles lnps are the most clinically advanced nonviral gene delivery system. A modern formulation approach in drug delivery system s. Measurement of inherent material density of nanoparticle. Lipidoids and lipids share many of the physicochemical properties that drive the formation of liposomes for gene delivery. This provides the potential for other antiinflammatory treatments.
Immunogenicity testing of lipidoids in vitro and in silico. In the present study, we demonstrated that lipidoid polymer hybrid nanoparticle fs14np can efficiently deliver sirna against il1. In particular, the formulations described here may provide a vehicle for the treatment of ischemicdiseases such as myocardial, hindlimb, or cerebral ischemia. In order to develop efficacious, degradable nanoparticles for sirna delivery while conducting. Jun 27, 2014 lipidoid synthesis and nanoparticle formulation. To explore whether hoxa1 represents a feasible target for treating the early stages of breast cancer progression, we formulated hoxa1 and control, nontargeting sirnas sints with lipidoid nanoparticles 16, 31. 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. Exploring the potential of lipidoidpolymer hybrid nanoparticles to.
Tunable lipidoid telodendrimer hybrid nanoparticles for intracellular protein delivery in brain tumor treatment article pdf available in small 1231 june 2016 with 116 reads. Lightregulated cargo release and following functionality restoration indicated the potential of the newly developed lipidoid nanoparticles for spatiotemporal delivery. Lipid nanoparticles used in skin care cosmetics processes. Formation of bioactivecarrier hollow solid lipid micro and. We provide insight into the stepwise creation and analysis of a putative rnaabased therapeutic with antitumor activity. Lipidoid from the greek which means lipidlike nanoparticles are a. Nanotechnology, volume 24, number 37, 20 september 20.