Graft copolymer polyelectrolyte complexes for drug delivery
Inventors
Assignees
Rutgers State University of New Jersey • United States Department of the Army
Publication Number
US-9271933-B2
Publication Date
2016-03-01
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 for the efficient intracellular delivery of anionic, cationic, or polyelectrolyte therapeutic agents into biological cells, while maintaining their biological activity in serum and aqueous environments. These complexes comprise an anionic graft copolymer with a poly(alkyl acrylic acid) backbone bearing pendant carboxylic acid groups covalently bonded to polyetheramine pendent chains predominantly composed of ethylene oxide repeating units, therapeutic agents (either anionic, cationic, or polyelectrolytes), and optionally liposomes which may themselves contain additional therapeutic agents. The complexes self-assemble into nanoparticles with sizes ranging from about 25 to 300 nm and exhibit stability in physiological conditions.
The problem addressed by the invention arises from challenges in intracellular delivery of therapeutic molecules such as antisense oligonucleotides, siRNAs, cationic peptides, and antibiotics. Barriers at the systemic level include susceptibility to interactions with serum proteins and off-target organ accumulation, while cellular challenges include inefficiency of cell entry, endosomal sequestration leading to degradation, and poor release into the cytoplasm. While viral vectors show delivery efficiency, safety concerns remain, and existing non-viral vectors tend to show low efficiency and high cytotoxicity. Therefore, there is a continuing need for improved materials and methods to enhance intracellular delivery and maintain therapeutic activity in biological environments.
The invention proposes that the graft density of the anionic graft copolymer controls charge density and biological interactions such as membrane penetration, endosomal escape, and cytotoxicity. Covalently grafted hydrophilic or amphipathic chains provide protection of therapeutic molecules from hydrolytic degradation and protein binding. The graft copolymer complexes, optionally containing liposomes, enable co-delivery of polyelectrolyte therapeutics and other agents such as anticancer drugs or imaging agents. The polymers are synthetically tunable with graft densities between about 0.1 and 25 mole percent and allow for formation of stable nanoparticles for in vitro, ex vivo, or in vivo delivery via multiple administration routes.
Claims Coverage
The patent includes multiple independent claims covering the composition, preparation, and use of graft copolymer polyelectrolyte complexes with therapeutic agents. Four main inventive features are identified spanning composition, functional nanoparticles, methods of formulation and administration, and preparation methods.
Composition of graft copolymer polyelectrolyte complex
The complex comprises an anionic graft copolymer having a poly(alkyl acrylic acid) backbone and polyetheramine pendent chains covalently attached as amides of acrylic acid groups, with the pendent chains predominantly comprising ethylene oxide repeating units. The copolymer has a graft density between about 0.1 and about 25 mole percent. The complex further comprises one or more anionic, cationic or polyelectrolyte therapeutic agents and optionally a liposome which may contain a further therapeutic agent.
Functional nanoparticles providing in vivo delivery
Nanoparticles comprising the graft copolymer polyelectrolyte complex are designed to provide in vivo delivery of the therapeutic agents, facilitating their administration and bioavailability.
Methods of treatment with graft copolymer complexes
Methods involving formulating the graft copolymer complex with pharmaceutically acceptable carriers to create pharmaceutical compositions, followed by administration to patients in therapeutically effective amounts via oral, enteral, parenteral, or topical routes for treating diseases with therapeutic agents including antibacterial, anticancer, wound treatment, and tissue regeneration agents.
Methods of preparing graft copolymer-polyelectrolyte complexes
The method includes providing an aqueous mixture of the anionic graft copolymer as defined, adding one or more polyelectrolytes to form a mixture, optionally adding a liposome with a therapeutic agent, and allowing self-assembly in aqueous media to form the polyelectrolyte complex and nanoparticles.
The claims cover the composition of graft copolymer polyelectrolyte complexes with specific backbone and pendent chain features, the formation of functional nanoparticles for therapeutic delivery, methods for treatment using these complexes encompassing various therapeutic agents and administration routes, and methods of synthesis that facilitate self-assembly into nanoparticles.
Stated Advantages
The graft copolymer complexes improve cellular uptake and intracellular delivery efficiency of therapeutic agents such as antisense oligonucleotides and siRNA in serum-containing media.
The copolymers protect therapeutic cationic peptides from rapid biodegradation in vivo by forming stable complexes that confer steric hindrance and enhance biological activity.
The polymer graft density controls membrane interaction properties to facilitate endosomal escape while minimizing cytotoxicity and hemolytic activity.
The complexes form stable nanoparticles with size distribution suitable for biological delivery, maintaining solubility in physiological conditions and avoiding aggregation.
The polymers enable co-delivery of multiple therapeutic agents, including nucleic acids and small molecule drugs, as well as imaging agents for theranostic applications.
The delivery system allows for delivery via various administration routes (oral, enteral, parenteral, topical) and provides controlled release of encapsulated agents.
Documented Applications
Intracellular delivery of antisense oligonucleotides, siRNAs, and other nucleic acid therapeutics for gene silencing in human or animal diseases, including cancer and heterotopic ossification.
Delivery of cationic peptides such as antimicrobial peptides to treat microbial infections and cancers through protection against enzymatic degradation and efficient delivery.
Co-delivery of polyelectrolyte therapeutic agents and other drugs, such as anticancer agents, local anesthetics, wound healing agents, and imaging agents like fluorescent dyes and quantum dots.
In vivo use for treatment of diseases responsive to gene silencing, including autoimmune and cardiovascular diseases, wound healing, viral infections, and cancer.
Delivery of siRNA targeting oncogenes (e.g., BCL-2) for cancer therapy and siRNA targeting genes such as Runx2 to inhibit osteogenesis in heterotopic ossification models.
Use in theranostic applications wherein imaging agents and therapeutic compounds are co-delivered to monitor treatment efficacy and localization.
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