Injectable dendrimer hydrogel nanoparticles
Inventors
Rangaramanujam, Kannan • Kannan, Sujatha • Romero, Roberto • Navath, Raghavendra • Menjoge, Anupa
Assignees
Wayne State University • National Institutes of Health NIH • US Department of Health and Human Services
Publication Number
US-9526794-B2
Publication Date
2016-12-27
Expiration Date
2031-03-31
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Abstract
The invention discloses injectable hydrogels which are in the form of crosslinked nano beads or particle in the size range 5 nm to 10 μm, comprising PAMAM dendrimer with asymmetrical peripheral end groups such that one of the terminal groups is involved in formation of hydrogel and the other in involved in the conjugation of drugs or imaging agents and their methods of preparation. The said gel is formed by reaction of the PAMAM dendrimer with asymmetrical end groups with other polymer wherein the other polymer is selected from the group of linear, branched, hyperbranched or star shaped polymers with functionalized terminal groups. The PAMAM dendrimer with asymmetrical terminal groups consists of a Generation 2 and above PAMAM dendrimer with symmetrical end groups modified using the amino acids or their modified forms. The gel disclosed in the present invention is formed as small crosslinked particles in the size range 25 nm to 10 μm and is suitable for injectable delivery of hydrogel to any of the body orifices, tissues by intramuscular or subcutaneous route and ocular delivery for the purpose of therapeutic treatment and imaging.
Core Innovation
The present invention discloses injectable hydrogels in the form of crosslinked nano beads or particles ranging in size from 5 nm to 10 μm. These hydrogels comprise PAMAM dendrimers with asymmetrical peripheral end groups, such that one of the terminal groups is involved in hydrogel formation and the other is available for conjugation with drugs or imaging agents. The gels are formed by reacting asymmetrically end-capped PAMAM dendrimers with other polymers selected from linear, branched, hyperbranched, or star-shaped polymers bearing functionalized terminal groups.
The invention addresses the need for dendrimers with multiple functional group presentations at their surface, overcoming the difficulty of attaching diverse drugs or imaging agents to the typically symmetric dendrimer end groups that have the same reactivity. The functionalization of these dendrimers aims to reduce cytotoxicity, enable targeted drug delivery, form hydrogels, increase plasma residence time, and improve imaging capabilities, all while simplifying synthesis to involve fewer reaction steps and high yields under mild conditions.
The hydrogels disclosed provide sustained drug release by covalently attaching drugs to one terminal end group of the asymmetric PAMAM dendrimer, with the other terminal utilized for gel formation. This dual-functional design allows drug release via degradation of the chemical bond linking the drug and by diffusion, providing improved sustained release over conventional hydrogels where the drug is passively entrapped. The biocompatible nanosized hydrogels allow control of particle size for targeted delivery through intramuscular, subcutaneous, ocular, or other body routes.
Claims Coverage
The patent includes multiple independent claims covering the injectable hydrogel nanoparticle comprising PAMAM dendrimers with specific amino acid linkers, the nature of the crosslinkable polymer, and the drug and imaging agent conjugation.
Injectable hydrogel nanoparticle with PAMAM dendrimers having amino acid linkers
The hydrogel nanoparticle comprises poly(amidoamine) (PAMAM) dendrimers with end groups covalently bound to amino acid linkers selected from serine, aspartic acid, cysteine, glutamic acid, threonine, and tyrosine. Each amino acid linker is covalently bound by one functional group to a crosslinkable polymer and by another distinct functional group to a drug or imaging agent, forming the nanoparticle by crosslinking the polymer.
Use of protected amino acid forms prior to conjugation
The amino acid linker can be in protected form, including various tert-butylcarbonyl, fluorenylmethoxycarbonyl, methylester, and dithiopyridine derivatives, covalently bound prior to attachment of the crosslinkable polymer and drug or imaging agent.
Selection of crosslinkable polymers for hydrogel formation
The crosslinkable polymer forming the hydrogel is selected from linear, branched, or star-shaped polymers, including functionalized polyethylene glycol (PEG) polymers of size between 5 kDa and 80 kDa, preferably 20-40 kDa.
Nanoparticle size and administration routes
The hydrogel nanoparticle has a diameter between 5 nm and 10 μm and is formulated for administration via intravenous, topical, intravitreal, intramuscular, or subcutaneous routes.
Selection of drugs conjugated to hydrogel
The drug conjugated to the hydrogel nanoparticle is selected from macrolide antibiotics, tetracyclines, fluoroquinolones, cephalosporins, non-steroidal anti-inflammatory and analgesic drugs, and corticosteroids, including examples such as erythromycin, azithromycin, rapamycin, clarithromycin, minocycline, doxycycline, ciprofloxacin, enrofloxacin, ofloxacin, gatifloxacin, levofloxacin, norfloxacin, cefuroxime, cefaclor, cephalexin, cephadroxil, cepfodoxime proxetil, N-acetyl cysteine, ibuprofen, aspirin, acetaminophen, diclofenac sodium, fluocinolone acetonide, and methylprednisolone.
The independent claims cover the inventive aspects of injectable hydrogels comprising PAMAM dendrimers with orthogonal amino acid linker functionalities that enable simultaneous drug or imaging agent conjugation and polymer crosslinking. They specify protected amino acid forms, the types and sizes of crosslinkable polymers, nanoparticle size ranges, administration routes, and the classes of drugs conjugated. These features collectively enable injectable, nanosized hydrogels suitable for sustained drug delivery and imaging.
Stated Advantages
Sustained release of therapeutic agents due to covalent attachment of drugs, preventing burst release encountered in conventional hydrogels.
Biocompatibility of injectable nanosized hydrogels formed from PAMAM dendrimers with amino acid modifications.
Ability to conjugate multiple functional groups such as different drugs and imaging agents in immediate succession without requiring protective/deprotection steps or additional linkers, simplifying synthesis and purification.
Controlled nanoparticle size enabling targeted delivery and optimized biodistribution to specific tissues or organs.
In-situ gel formation capabilities facilitating injectable delivery and prolonged residence time in targeted sites such as ocular or vaginal tissues.
Reduced cytotoxicity of dendrimer carriers due to surface modification with biocompatible amino acids.
Dual antibacterial mechanism in hydrogels delivering antibiotics and releasing dendrimer species with intrinsic antibacterial activity.
Documented Applications
Injectable delivery of hydrogels for therapeutic treatment and imaging to body orifices and tissues by intramuscular or subcutaneous routes and ocular delivery.
Treatment of neuroinflammation, inflammation, and ocular diseases via intraocular delivery confining residence in organs such as the vitreous chamber.
Sustained intravaginal delivery of antibacterial agents, particularly amoxicillin, to treat ascending genital infections during pregnancy.
Local intravaginal and intracervical drug delivery to pregnant women to prevent infections affecting fetal membranes without transfer to the fetus.
Hydrogels used for molecularly engineered scaffolds, controlled drug release, cellular delivery, tissue engineering, and wound dressings due to their resemblance to native extracellular matrix.
Use as topical microbicides for intravaginal delivery including for treatment of bacterial vaginosis and other infections.
Diagnostic and imaging purposes by conjugating imaging agents to dendrimer hydrogels.
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