Engineering synthethic brain penetrating gene vectors
First Claim
1. A nanoparticle formulation for delivery of nucleic acid to tissue including brain, comprisingnucleic acids;
- a first hydrophilic cationic polymer; and
a second hydrophilic, neutrally charged linear or branched polymer selected from the group consisting of polyethylene glycol, polyethylene oxide, and copolymers thereof,wherein at least about 90% of the first hydrophilic cationic polymer is conjugated to the second hydrophilic, neutrally charged linear or branched polymer,wherein the nucleic acid is encapsulated within the nanoparticle or associated with the surface of the nanoparticle and wherein the nanoparticle is coated with the second hydrophilic, neutrally charged linear or branched polymer at a density that imparts a near neutral charge and enhances the diffusivity through the tissue.
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Abstract
A synthetic gene delivery platform with a dense surface coating of hydrophilic and neutrally charged PEG, capable of rapid diffusion and widespread distribution in brain tissue, and highly effective gene delivery to target cells therein has been developed. Nanoparticles including nucleic acids, are formed of a blend of biocompatible hydrophilic cationic polymers and they hydrophilic cationic polymer conjugated to hydrophilic neutrally charged polymers such as polyethylene glycol. The nanoparticles are coated with polyethylene glycol at a density that imparts a near neutral charge and optimizes rapid diffusion through the brain parenchyma. Methods of treating a disease or disorder of the brain including administering a therapeutically effective amount of nanoparticles densely coated with polyethylene glycol are also provided.
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Citations
24 Claims
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1. A nanoparticle formulation for delivery of nucleic acid to tissue including brain, comprising
nucleic acids; -
a first hydrophilic cationic polymer; and a second hydrophilic, neutrally charged linear or branched polymer selected from the group consisting of polyethylene glycol, polyethylene oxide, and copolymers thereof, wherein at least about 90% of the first hydrophilic cationic polymer is conjugated to the second hydrophilic, neutrally charged linear or branched polymer, wherein the nucleic acid is encapsulated within the nanoparticle or associated with the surface of the nanoparticle and wherein the nanoparticle is coated with the second hydrophilic, neutrally charged linear or branched polymer at a density that imparts a near neutral charge and enhances the diffusivity through the tissue. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20)
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21. A method for treating one or more symptoms of a disease or disorder of the brain, comprising administering directly to the brain a formulation comprising
a therapeutically effective amount of a nanoparticle formulation comprising nucleic acids; -
a first hydrophilic cationic polymer; and a second hydrophilic, neutrally charged linear or branched polymer selected from the group consisting of polyethylene glycol, polyethylene oxide, and copolymers thereof, wherein between 90% and 75% of the first hydrophilic cationic polymer is conjugated to the second hydrophilic, neutrally charged linear or branched polymer or wherein at least 50% of the first hydrophilic cationic polymer is conjugated to the second hydrophilic, neutrally charged branched polymer, wherein the nucleic acid is encapsulated within the nanoparticle or associated with the surface of the nanoparticle, and wherein the nanoparticle is coated with the second hydrophilic, neutrally charged linear or branched polymer at a density that imparts a near neutral charge and enhances the diffusivity through the tissue. - View Dependent Claims (22, 23, 24)
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Specification