Graft copolymer polyelectrolyte complexes for drug delivery
Inventors
Assignees
Rutgers State University of New Jersey • United States Department of the Army
Publication Number
US-9789194-B2
Publication Date
2017-10-17
Expiration Date
2028-11-26
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Abstract
Graft copolymer polyelectrolyte complexes are disclosed for the efficient delivery of anionic, cationic or polyelectrolyte therapeutic agents into biological cells, and for maintaining the biological activity of these molecules while in serum and other aqueous environments are provided. Such complexes comprise (1) an anionic graft copolymer containing an anionic polymer backbone, with pendent carboxylic acid groups and pendant chains containing amphipathic or hydrophilic polymers covalently bonded to a portion of the pendant carboxylic acid groups, (2) one or more anionic, cationic or polyelectrolyte therapeutic agents, and (3) optionally a liposome optionally containing an additional therapeutic agent. Also disclosed are functional nanoparticles containing the complexes.
Core Innovation
The invention provides graft copolymer polyelectrolyte complexes designed to facilitate the efficient intracellular delivery of therapeutic agents such as anionic, cationic, or polyelectrolyte molecules into biological cells. These complexes maintain the biological activity of therapeutic molecules in serum and aqueous environments, overcoming challenges in cellular uptake and protection from degradation. The complexes comprise an anionic graft copolymer with a poly(alkylacrylic acid) backbone and polyetheramine pendent chains covalently attached as amides with ethylene oxide repeating units, therapeutic agents, and optionally liposomes containing additional therapeutic agents.
The invention addresses significant barriers in systemic and cellular delivery of antisense therapeutics and other molecules, including poor survival in serum, non-specific accumulation in organs, inefficient cellular uptake, endosomal sequestration, lysosomal degradation, and toxicity associated with viral and non-viral vectors. The graft copolymer complexes offer a synthetic, structurally tunable platform that enhances delivery efficiency, intracellular release, and cytocompatibility. The pendent chains provide steric protection against enzymatic degradation and improve solubility and stability of delivery vectors, contributing to improved antisense oligonucleotide, siRNA, cationic peptide, and antibiotic molecule delivery.
Claims Coverage
The patent includes multiple inventive features centered on the composition, preparation, and therapeutic use of graft copolymer polyelectrolyte complexes.
Graft copolymer composition
Comprises an anionic graft copolymer with a poly(alkylacrylic acid) backbone and polyetheramine pendent chains covalently attached as amides of acrylic acid groups, with pendent chains predominantly of ethylene oxide repeating units and a graft density between about 0.1 and about 25 mole percent.
Incorporation of therapeutic agents
The complex includes one or more anionic, cationic or polyelectrolyte therapeutic agents, optionally combined with a liposome which can carry an additional therapeutic agent.
Backbone polymer identity and graft density
Preference for copolymer backbone comprising poly(propyl acrylic acid) or poly(methacrylic acid), with optional graft densities between about 0.5 and about 5 mole percent to optimize properties.
Functionalization with targeting ligands
Pendent chains can further comprise ligands targeting specific cells, tissues, or surfaces, including microbial biofilms, planktonic microbes, and bone tissue.
Therapeutic agent diversity
Therapeutic agents include cationic peptides (such as KSL-W, colistin, polymyxin B), peptide nucleic acids, aminoglycoside antibiotics (e.g., neomycin, gentamicin, tobramycin), oligonucleotides, nucleic acids, plasmid DNA, ribozymes, and small molecule drugs including anticancer, wound healing, tissue regeneration, antibiotic, imaging agents, fluorescent dyes, and quantum dots.
Functional nanoparticles for delivery
Formation of functional nanoparticles comprising the graft copolymer polyelectrolyte complexes that enable delivery in vitro, ex vivo, or in vivo via oral, enteral, parenteral, or topical administration routes.
Preparation method
A method of preparing the complex by forming aqueous mixtures of graft copolymer, adding polyelectrolytes, optionally adding liposomes with therapeutic agents, and allowing self-assembly in aqueous medium to form nanoparticles.
Therapeutic methods
Methods of treating patients by formulating the complexes with pharmaceutically acceptable carriers and administering an effective amount, targeting conditions such as bacterial infections, cancer, wounds, and tissue regeneration.
The claims comprehensively cover the novel graft copolymer complexes compositions, their methods of synthesis, functionalization with targeting ligands, inclusion of various therapeutic agents, formation into nanoparticles, and their therapeutic administration for diverse medical applications.
Stated Advantages
Improved intracellular delivery of antisense therapeutics, siRNA, cationic peptides, antibiotics and other drugs with enhanced stability and protection in serum environments.
Reduced cytotoxicity compared to conventional non-viral vectors and viral vectors.
Enhanced systemic circulation and tissue targeting via modulation of graft density and ligand functionalization.
Provision of stable, soluble particles that do not aggregate and maintain payload bioactivity.
Flexibility to co-deliver multiple therapeutic agents including liposome-incorporated drugs, imaging agents, and therapeutics for theranostic applications.
Documented Applications
Intracellular delivery of therapeutic cationic peptides, oligonucleotides, nucleic acids including antisense molecules, siRNA, plasmid DNA, ribozymes, and peptide nucleic acids.
Cancer therapy via gene silencing, e.g., silencing anti-apoptotic genes such as Bcl-2 in cancer cells.
Treatment of heterotopic ossification by silencing osteogenic pathway genes such as Runx2 using siRNA delivery.
Delivery of cationic antimicrobial peptides for treatment of microbial infections and biofilm penetration.
Co-delivery of chemotherapeutic drugs with antisense oligonucleotides for cancer treatment.
Targeted delivery of siRNA to bone tissue using alendronate ligand conjugated graft copolymers.
Targeted delivery of siRNA to macrophages via mannose receptor using mannose-functionalized graft copolymers.
In vivo systemic delivery for treatment of diseases including cancer, cardiovascular and chronic wounds such as diabetic ulcers.
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