Cross-linked polymer modified nanoparticles
Inventors
Yantasee, Wassana • NGAMCHERDTRAKUL, Worapol • MORRY, Jingga • Castro, David • Gray, Joe William
Assignees
Oregon Health and Science University • PDX Pharmaceuticals Inc
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Publication Number
US-11305024-B2
Publication Date
2022-04-19
Expiration Date
Abstract
Disclosed herein are nanoconstructs comprising a nanoparticle, coated with additional agents such as cationic polymers, stabilizers, targeting molecules, labels, oligonucleotides and small molecules. These constructs may be used to deliver compounds to treat solid tumors and to diagnose cancer and other diseases. Further disclosed are methods of making such compounds and use of such compounds to treat or diagnose human disease.
Core Innovation
The invention provides a composition comprising a plurality of multilayer nanoconstructs. Each nanoconstruct includes about 10% to about 30% by weight cross-linked polyethylenimine (PEI) bound to an exterior surface of a silica nanoparticle, a silicon nanoparticle, an iron oxide nanoparticle, a silver nanoparticle, or a carbon nanotube. The nanoconstructs further include polyethylene glycol (PEG) bound to the PEI or to the nanoparticle, and an oligonucleotide non-covalently attached to the PEI.
The nanoconstructs are constrained to have a hydrodynamic size Z-average diameter of about 200 nm or less, and the plurality of nanoconstructs has a polydispersity index (PDI) of no more than about 0.37. The disclosed multilayer architecture and the non-covalent attachment of the oligonucleotide to cross-linked PEI, combined with PEG surface presentation, are used to support oligonucleotide silencing efficacy reported across batches.
The partial content describes silencing efficacy, including luciferase knockdown, and delivery of siRNA, as well as evaluation of cargo combinations and contrast/cargo capacity, including iron-oxide nanoconstructs for MRI T2 relaxivity and lanthanide/fluorescent dye loading. The disclosed content also describes siRNA targeting beyond HER2, dual targeting, miRNA mimic delivery, and siRNA combined with chemotherapeutics.
Claims Coverage
Independent claim clm-00001 defines the core composition, specifying multilayer nanoconstruct structure, PEG/PEI/nanoparticle relationships, oligonucleotide non-covalent attachment, and constraints on hydrodynamic size and PDI. The partial content also indicates dependent claim refinements that narrow dispersity/size and add optional components such as cleavable crosslinkers and labels, plus an additional independent claim (clm-00024) directed to delivery to a site by administering the composition.
Multilayer nanoconstruct composition with cross-linked PEI exterior binding
A plurality of multilayer nanoconstructs each comprising about 10% to about 30% by weight cross-linked polyethylenimine (PEI) bound to an exterior surface of a silica nanoparticle, a silicon nanoparticle, an iron oxide nanoparticle, a silver nanoparticle, or a carbon nanotube.
PEG coating on PEI or nanoparticle with oligonucleotide non-covalent attachment
polyethylene glycol (PEG) bound to the PEI or to the nanoparticle; wherein an oligonucleotide is non-covalently attached to the PEI.
Small hydrodynamic size and low polydispersity constraints
the nanoconstructs have a hydrodynamic size Z-average diameter of about 200 nm or less; and the plurality of nanoconstructs have a polydispersity index (PDI) of no more than about 0.37.
Delivery by administering the composition to a subject site
A method for delivering an oligonucleotide to a site in a human or other mammalian subject by administering an effective amount of the composition of claim 1 under conditions that deliver the nanoconstruct to the site.
The claim set coverage centers on a defined multilayer nanoconstruct architecture (cross-linked PEI bound to an exterior nanoparticle surface), PEG positioning (bound to PEI or nanoparticle), and non-covalent oligonucleotide attachment, with explicit limits on hydrodynamic Z-average diameter and PDI. An additional independent-method style feature is delivering the oligonucleotide to a site in a human or other mammalian subject by administering an effective amount of the composition under conditions that deliver the nanoconstruct to the site.
Stated Advantages
Improved buffering capacity and endosomal escape via PEI cross-linking.
Oligonucleotide silencing efficacy reported across batches.
Luciferase knockdown.
Enhanced gene-silencing and tumor targeting (including HER2-targeted siHER2).
Serum protection.
Reduced aggregation.
Blood compatibility and low cytokine/endotoxin response.
Tumor-growth inhibition.
In vivo tumor growth inhibition, including in trastuzumab-resistant models.
Iron-oxide variants as MRI contrast agents with increased relaxivity.
Reductions in reactive oxygen species and NOX-related effects.
Additional therapeutic roles described for antioxidant/ROS/NOX4 modulation for fibrosis/inflammation.
Documented Applications
siRNA delivery.
siRNA targeting beyond HER2.
Dual targeting.
miRNA mimic delivery.
siRNA combined with chemotherapeutics.
Tumor diagnosis/imaging using labeled constructs, including imaging modalities associated with labels such as fluorescent dyes, PET tracers, and MRI contrast agents such as gadolinium.
Iron-oxide nanoconstructs for MRI T2 relaxivity.
Lanthanide/fluorescent dye loading.
Delivery of oligonucleotides to mammalian sites/cells/tumors by administering an effective amount of the composition to deliver nanoconstructs to a site.
Therapeutic use described as reducing reactive oxygen species and modulating NOX4-related effects associated with fibrosis/inflammation biomarkers.
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