Cross-linked polymer modified nanoparticles
Inventors
Yantasee, Wassana • NGAMCHERDTRAKUL, Worapol • MORRY, Jingga • Castro, David • Gray, Joe
Assignees
Oregon Health and Science University • PDX Pharmaceuticals Inc
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Publication Number
US-11207428-B2
Publication Date
2021-12-28
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 pharmaceutical composition comprising a plurality of multilayer nanoconstructs and an oligonucleotide non-covalently attached to the PEI, all formulated in a pharmaceutically acceptable carrier. Each nanoconstruct comprises about 10% to about 30% by weight cross-linked polyethylenimine (PEI) bound to an exterior surface of a nanoparticle, where the nanoparticle comprises silica, silicon, iron oxide, silver, or a carbon nanotube. Polyethylene glycol (PEG) is bound to the PEI or to the nanoparticle.
The nanoconstructs have a hydrodynamic size Z-average diameter of about 200 nm or less and a polydispersity index (PDI) of no more than about 0.37. The multilayer nanoconstruct concept is described as nanoparticles with an exterior-bound, cross-linked cationic polymer layer, with PEG as a stabilizer to prevent aggregation. The non-covalently attached nucleic acid cargos include oligonucleotides such as siRNA and miRNA, including miRNA mimics and antisense oligomers.
The same platform is described as applicable to therapeutic gene modulators and to labels for imaging and diagnosis. Optional targeting agents include antibodies, scFv, aptamers, peptides, and ligands.
Claims Coverage
The independent claim coverage centers on a pharmaceutical composition comprising multilayer nanoconstructs and an oligonucleotide in a pharmaceutically acceptable carrier. The combined claim features define six inventive features spanning structure, attachment chemistry, and quantitative size and polydispersity limits.
Multilayer nanoconstructs with exterior-bound cross-linked PEI
A plurality of multilayer nanoconstructs comprising about 10% to about 30% by weight cross-linked polyethylenimine (PEI) bound to an exterior surface of a nanoparticle.
Nanoparticles selected from silica, silicon, iron oxide, silver, or carbon nanotube
The nanoparticle comprises silica, silicon, iron oxide, silver, or a carbon nanotube.
PEG bound to PEI or nanoparticle
Polyethylene glycol (PEG) bound to the PEI or to the nanoparticle.
Size and 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.
Non-covalent oligonucleotide attachment to PEI
An oligonucleotide non-covalently attached to the PEI.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprising the plurality of multilayer nanoconstructs and a pharmaceutically acceptable carrier.
Overall, the claims define a pharmaceutical composition built from multilayer nanoconstructs having a specified nanoparticle core, an exterior-bound cross-linked PEI layer, PEG bound to PEI or nanoparticle, a non-covalently attached oligonucleotide, and defined hydrodynamic size and PDI limits, all in a pharmaceutically acceptable carrier.
Stated Advantages
Enhanced hydrodynamic size control.
Improved siRNA protection.
Increased buffering/endosomal escape.
Reduced HER2 protein levels.
Tumor growth inhibition in resistant models.
Improved blood compatibility.
Limited cytokine/endotoxin responses.
Imaging/diagnostic capabilities, including lanthanide/MRI/iron-oxide T2 relaxivity.
Improved breast cancer cell specificity when siPLK1 is delivered with nanoconstructs versus DharmaFECT, including ability to deliver miRNA mimics.
Enhanced tumor cell viability reduction when siRNA is combined with paclitaxel, with best enhancement often via paclitaxel plus siPLK1 and significant synergy for siAKT1/BCL2 and siEPS8L1.
Can deliver other cargoes, including small peptides, trastuzumab, and doxorubicin/paclitaxel with trastuzumab-supplemented delivery, without impairing gene knockdown.
Antioxidant and copper-chelating nanoconstruct behavior including ROS reduction and NOX modulation, and anti-fibrotic marker suppression in a bleomycin fibrosis model.
Anti-metastatic effects with siPLK1 nanoconstructs.
MRI contrast capability, including T2 relaxivity enhancement associated with the described formulations.
Documented Applications
Delivery of siRNA cargoes targeting genes including HER2, AKT1/BCL2, PLK1, and EPS8L1 in multiple cell lines, with reported potency comparisons including siPLK1.
Combination therapy context involving siRNA, including siPLK1, siAKT1/BCL2, and siEPS8L1, combined with paclitaxel to reduce tumor cell viability.
Delivery of miRNA mimics using the nanoconstructs.
Use of nanoconstructs for delivery of other cargoes including small peptides and trastuzumab, and combined doxorubicin/paclitaxel with trastuzumab-supplemented delivery while maintaining gene knockdown.
Assessment of antioxidant and copper-chelating behavior with ROS reduction and NOX modulation and suppression of anti-fibrotic markers in a bleomycin fibrosis model.
Anti-metastatic effects using siPLK1 nanoconstructs.
MRI-related contrast imaging using alternative iron-oxide nanoconstructs, including described T2 relaxivity enhancement.
Luciferase knockdown (siLUC) in the context of the described delivery system.
Delivering therapeutic gene modulators and/or labels for treating and/or diagnosing diseases including cancer, inflammation, and fibrosis.
Tumor imaging using MRI/PET/fluorescence and related label-based imaging.
Applications described in models for drug-resistant cancer, including HER2+ contexts.
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