Hyperbranched polyglycerol-coated particles and methods of making and using thereof
Inventors
Deng, Yang • Ediriwickrema, Asiri • Saltzman, W. Mark
Assignees
Publication Number
US-12233140-B2
Publication Date
2025-02-25
Expiration Date
2035-05-11
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Abstract
Core-shell particles and methods of making and using thereof are described herein. The core is formed of or contains one or more hydrophobic materials or more hydrophobic materials. The shell is formed of or contains hyperbranched polyglycerol (HPG). The HPG coating can be modified to adjust the properties of the particles. Unmodified HPG coatings impart stealth properties to the particles which resist non-specific protein absorption and increase circulation in the blood. The hydroxyl groups on the HPG coating can be chemically modified to form functional groups that react with functional groups and adhere the particles to tissue, cells, or extracellular materials, such as proteins.
Core Innovation
The invention describes core-shell particles, such as microparticles and nanoparticles, composed of a core formed from one or more hydrophobic materials and a shell containing hyperbranched polyglycerol (HPG). The HPG coating is covalently bound to the core, and the resulting structure can be tuned to exhibit stealth or adhesive properties. The stealth properties are achieved with unmodified HPG coatings, which resist non-specific protein absorption and increase circulation time in the blood.
The HPG coatings can be chemically modified by converting surface hydroxyl groups into reactive functional groups such as aldehydes, amines, or oximes. These modifications impart bioadhesive properties to the particles, enabling adhesion to tissue, cells, or extracellular materials. The particles may also be further functionalized with targeting moieties, which can be attached either before or after particle formation.
The problem addressed by this invention is the limitation of surface coatings, specifically polyethylene glycol (PEG), in preventing rapid clearance and non-specific protein adsorption of nanoparticles in vivo, which hinders efficient delivery of therapeutic agents. The disclosed particles overcome the limitations associated with PEG coatings by providing a tunable platform for both stealth and adhesive functionalities, and the ability to incorporate targeting ligands and therapeutic, diagnostic, prophylactic agents, or nutraceuticals.
Claims Coverage
The independent claims present several inventive features centered on hyperbranched polyglycerol-coated particles with tunable functionalities for nucleic acid and peptide delivery.
Particles with a core-shell structure and covalently bound hyperbranched polyglycerol shell
Particles are described that comprise: - A core containing one or more polymers that are more hydrophobic than hyperbranched polyglycerol. - A shell comprising hyperbranched polyglycerol, which is covalently bound to the core polymer(s). - The shell can be further modified so that surface hydroxyl groups are converted into reactive functional groups such as aldehydes, amines, oximes, or O-substituted oximes. - Optionally, the surface of the particles can be further modified by attachment of polyethylene glycol.
Integration of nucleic acids, peptides, or their combination in core-shell particles
The particles are formulated to contain one or more nucleic acids, one or more peptides, or a combination thereof, either dispersed within the core, associated with the surface, or both. This enables encapsulation or surface association of bioactive molecules for delivery applications.
In summary, the inventive features focus on the design of core-shell particles with a covalently attached hyperbranched polyglycerol shell, modifiable surface chemistry, and encapsulation or association of nucleic acids and/or peptides, optionally including surface PEG modification.
Stated Advantages
Unmodified HPG coatings impart stealth properties to particles, resisting non-specific protein absorption and increasing blood circulation time.
Hyperbranched polyglycerol allows for a much higher density of functional groups or targeting moieties than polyethylene glycol coatings.
Chemical modification of HPG coatings enables tunable surface properties, providing either stealth or bioadhesive (sticky) particles for controlled interaction with biological materials.
HPG coatings on particles demonstrate improved stability in suspension and enhanced tumor accumulation and penetration compared to PEG-coated particles.
Particles can be loaded with a wide variety of therapeutic, diagnostic, prophylactic agents, and nutraceuticals, and their release can be controlled over time.
Bioadhesive particles maintain prolonged retention at administration sites, such as the peritoneal cavity, enhancing local drug bioavailability and effectiveness.
Blank HPG-coated particles (without drugs) display no toxicity to a variety of cell lines and animal models, supporting their safety profile.
Documented Applications
Drug delivery of therapeutic, diagnostic, prophylactic agents, or nutraceuticals, including systemic and local administration routes such as intravenous, intraperitoneal, oral, nasal, pulmonary, mucosal, subcutaneous, and intramuscular.
Treatment and prevention of restenosis following angioplasty or stent placement, by delivering anti-proliferative and anti-inflammatory agents to vascular tissues.
Cancer therapy and tumor targeting, including administration of nanoparticles for enhanced tumor accumulation, improved chemotherapy delivery, and treatment of a wide range of cancers and tumors.
Local and systemic administration for the treatment of peritoneal and ovarian cancers, with emphasis on extended retention and local delivery in the peritoneal cavity.
Delivery of anti-angiogenic agents, diagnostics, and therapeutic compounds for eye diseases such as macular degeneration, using particles administered intravitreally or subretinally.
Vaccination and immune modulation, including DNA- or peptide-based vaccine delivery to targeted tissues or immune cells.
Tissue engineering matrices and wound healing dressings, providing adhered delivery of growth factors, antibiotics, or other modulatory compounds to matrices, grafts, or implants.
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