Manganese ion coated nanoparticles for delivery of compositions into the central nervous system by nasal insufflation
Inventors
Sanchez-Ramos, Juan • Sava, Vasyl • Song, Shijie • Mohapatra, Shyam S. • Mohapatra, Subhra
Assignees
Office of General Counsel of VA • University of South Florida St Petersburg
Publication Number
US-9938526-B2
Publication Date
2018-04-10
Expiration Date
2032-09-14
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Abstract
The compositions and methods of the disclosure particularly target the divalent metal transporter expressed on olfactory nerve terminals to transport divalent cation-coated or cation-containing nanoparticles to all regions of brain. It has been found that such divalent cation-containing nanoparticles, including those nanoparticles comprising manganese have affinity for the metal transport receptor proteins. Although this receptor has particular affinity for manganese, it is contemplated that other divalent ions, including magnesium, calcium, and the like may also be bound to such receptors leading to transport of the nanoparticles into the intracellular cytoplasm. Nanoparticles have been developed, therefore, as vehicles for parenteral delivery of genes, proteins and drugs. The present disclosure encompasses embodiments of nanoparticle-based compositions and methods for the use thereof for the delivery of genes, oligonucleotides, including but not limited to small interfering RNA, and other small molecule drugs, into the brain by nasal insufflation.
Core Innovation
The invention relates to compositions and methods for delivering therapeutic agents to the central nervous system (CNS) via the olfactory nerve by administering nanoparticle delivery vehicles to the nasal epithelium. These nanoparticles comprise a core made of chitosan or derivatives thereof, cross-linked by chelators and bonded with divalent metal ions, particularly manganese, which have binding affinity for divalent metal transporters expressed on olfactory nerve terminals.
The problem addressed is the difficulty in delivering therapeutic genes, nucleic acids, proteins, or drugs into the brain without invasive neurosurgical procedures or risky viral vectors. Current methods relying on injections or viral carriers pose challenges especially for chronic or widespread CNS diseases. Additionally, the blood-brain barrier limits delivery of many agents, and there is a need for safe, efficient, and non-invasive delivery vehicles that can target the CNS effectively.
The disclosed nanoparticles exploit the natural capacity of manganese and other divalent metals to be transported into the brain through olfactory neurons. Manganese-coated or containing nanoparticles bind to divalent metal transport receptors on olfactory nerve terminals, facilitating uptake and intracellular transport to the olfactory bulb and other brain regions. The nanoparticles can carry therapeutic agents such as nucleic acids including siRNA, gene vectors, proteins, or small molecule drugs, and enable delivery throughout the brain by trans-synaptic transport, bypassing the blood-brain barrier.
Claims Coverage
The patent contains three independent claims encompassing methods, nanoparticle delivery vehicles, and pharmaceutical compositions related to divalent metal-coated chitosan nanoparticles for CNS delivery.
Method of delivering agents via olfactory nerve using manganese-cross-linked chitosan nanoparticles
Administering to nasal epithelium a composition comprising nanoparticles having a core of cross-linked chitosan or thiolated chitosan molecules bonded with manganese ions, where the core carries a pharmaceutically acceptable agent. The manganese selectively binds to divalent metal transporters on olfactory nerve cells, is internalized, and transports to the olfactory bulb of the CNS.
Cross-linking chitosan molecules with specific chelators binding manganese ions
The chitosan or thiolated chitosan molecules in the nanoparticle core are cross-linked by chelators selected from L-(+)-Tartaric acid, ethylenediamine-N,N;,N;-triacetic acid, protoporphyrin IX, nitrilotriacetic acid, mercaptosuccinic acid, and ethylenediaminetetraacetic acid, which chelate manganese ions within the nanoparticle structure.
Use of nucleic acids as therapeutic agents attached to manganese-chitosan nanoparticle cores
The nanoparticle cores have nucleic acid molecules, including siRNA, bonded to the cross-linked chitosan or thiolated chitosan molecules, enabling delivery of nucleic acid therapies to recipient CNS cells.
Imaging detection of nanoparticle distribution in CNS
Including a step of detecting the nanoparticle delivery vehicle in the recipient subject to form images showing distribution of the nanoparticles within CNS tissue.
The independent claims cover a method for nasal administration of manganese-chelated, chitosan-based nanoparticles carrying therapeutic agents, the nanoparticle formulations with manganese cross-linked by specific chelators and carrying nucleic acids, and the imaging detection of such nanoparticles after delivery to the CNS.
Stated Advantages
The method enables non-invasive delivery of therapeutic genes, siRNA, proteins, and drugs to the brain by nasal administration without requiring neurosurgical intervention or viral vectors.
The nanoparticles bypass the blood-brain barrier by utilizing the olfactory nerve pathway for CNS targeting.
Manganese-containing nanoparticles can be detected via MRI imaging to monitor nanoparticle distribution in vivo.
The use of chitosan and its derivatives confers low toxicity, low immunogenicity, and high biocompatibility for gene delivery.
Documented Applications
Delivery of therapeutic agents such as nucleic acids including siRNA, genes, proteins, peptides, and small molecule drugs into the brain by nasal insufflation.
Non-invasive gene therapy for diseases affecting the CNS like Huntington's disease without requiring multiple brain injections.
Use of manganese-containing nanoparticles as MRI contrast agents for imaging distribution within the brain.
Delivery of gene-silencing RNA for modulation of gene expression in brain tissue via olfactory nerve transport.
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