Injectable dendrimer hydrogel nanoparticles
Inventors
Rangaramanujam, Kannan • Kannan, Sujatha • Romero, Roberto • Navath, Raghavendra • Menjoge, Anupa
Assignees
Wayne State University • US Department of Health and Human Services
Publication Number
US-11446238-B2
Publication Date
2022-09-20
Expiration Date
2031-03-31
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Abstract
Injectable hydrogels 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 are formed by reaction of the PAMAM dendrimer with asymmetrical end groups with 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 is formed as small crosslinked particles in the size range 25 nm to 10 μm and is suitable for injectable delivery of hydrogel or ocular delivery for the purpose of therapeutic treatment and imaging.
Core Innovation
The invention provides biocompatible, injectable nanosized hydrogel particles formed as crosslinked nanobeads or particles ranging from 5 nm to 10 μm in size, comprising poly(amidoamine) (PAMAM) dendrimers modified with asymmetrical peripheral end groups. One terminal group of the dendrimer is involved in hydrogel formation while the other is available for conjugation with drugs or imaging agents. The asymmetrical terminal groups are achieved by modifying symmetrical terminal groups of PAMAM dendrimers (Generation 2 and above) using amino acids or their derivatives, enabling chemoselective attachment of multiple functional moieties with reduced synthetic complexity.
The hydrogels are formed by reacting the asymmetrically terminated PAMAM dendrimers with linear, branched, hyperbranched, or star-shaped polymers having functionalized terminal groups, such as polyethylene glycol (PEG). The hydrogel particles provide biodegradability and sustained release of therapeutic agents via a dual mechanism: enzymatic or pH-mediated degradation of the chemical bond tethering the drug to the dendrimer, and diffusion of the free drug from the gel network. This dual mechanism enables controlled delivery with reduced burst release and lower carrier load.
The problem addressed is the difficulty in appending multiple functional moieties, such as drugs and imaging agents, onto dendrimers with symmetrical end groups due to uniform reactivity, requiring multiple synthetic steps involving protection, deprotection, and specific linkers. Furthermore, cationic dendrimers face cytotoxicity issues, and existing methods to reduce toxicity often compromise efficacy. There is a need for dendrimers with orthogonal, chemoselective terminal groups that allow conjugation of diverse functional groups in minimal synthetic steps under mild conditions while maintaining biocompatibility.
The invention overcomes these limitations by providing a simple one-step method to convert symmetrical PAMAM dendrimer end groups into two distinct reactive terminal groups via amino acid modification, yielding hetero-bifunctional dendrimers with high density (>110 groups) of orthogonal peripheral end groups. These dendrimers enable sequential conjugation of drugs, imaging agents, and formation of hydrogels without protection/deprotection steps. The resulting nanosized injectable hydrogels have enhanced efficacy for targeted delivery, including intraocular applications for treatment of neuroinflammation and inflammation, with controlled size for tissue targeting and improved biocompatibility.
Claims Coverage
The patent claims provide six main inventive features relating to compositions of PAMAM dendrimers with amino acid linkers, functionalization, hydrogel formation, drug and imaging conjugation, and methods of treating inflammation and microbial growth.
PAMAM dendrimer with orthogonally conjugated amino acid linkers
A composition comprising a PAMAM dendrimer having at least 59% of terminal functional groups conjugated to amino acid linkers, whereby the amino acid linkers are covalently bound to two different chemically reactive groups, yielding dendrimers with at least two distinct reactive peripheral groups.
Functionalization with polymers, drugs, imaging agents, and targeting moieties
Each of the two chemically reactive groups on the dendrimer is conjugated to functional moieties such as polymers (linear, branched, star-shaped, e.g., PEG), drugs, imaging agents, or targeting ligands, optionally via spacers.
Hydrogel formation via crosslinking with functionalized PEG polymers
Hydrogels formed by crosslinking PAMAM dendrimers bearing asymmetrical terminal groups with functionalized polyethylene glycol polymers (5 kDa to 80 kDa), including specific PEG types such as 8-arm-PEG with thiol terminations, methoxy-PEG with thiol termination, or pyridyldithio-propionate PEG derivatives.
Use of bifunctional spacers for attaching functional moieties
Inclusion of one or more spacers selected from a defined group (maleimide-PEG-maleimide, succinimidyl-carboxyl-methyl ester-PEG, acrylate-PEG, ortho-pyridyldisulfide-PEG, thiol-PEG, nitrophenyl carbonate-PEG, isocyanate-PEG, 1,6-hexane-bis-vinylsulfone) for conjugation of functional groups to the dendrimer.
Conjugation of a wide range of drugs and imaging agents
The composition comprises drugs including macrolide antibiotics, tetracyclines, fluoroquinolones, cephalosporins, non-steroidal anti-inflammatories, analgesics, corticosteroids, antibodies, vitamins, growth factors, neurostimulants, neuroprotectants, and pharmaceutically acceptable salts thereof, as well as imaging agents such as fluorescent dyes, radiolabeled dyes, and magnetic resonance imaging agents.
Methods of reducing inflammation and microbial growth
Methods involving administration of the compositions for reducing or preventing inflammation (including neuroinflammation by intraocular injection) and microbial growth via routes including vaginal, cervical, or rectal administration, wherein drugs are conjugated selectively to the chemically reactive groups of the dendrimer.
The claims cover compositions of PAMAM dendrimers modified with amino acid linkers providing orthogonal chemically reactive terminal groups that enable conjugation with a variety of functional moieties, including polymers for hydrogel formation, drugs, and imaging agents. They encompass hydrogels formed by crosslinking with functionalized PEG polymers, use of bifunctional spacers, a wide range of therapeutic and diagnostic agents, and methods for treating inflammation and microbial infections with administration via targeted routes.
Stated Advantages
Significant reduction in synthetic steps to create dendrimers with orthogonal functional end groups, eliminating need for protection/deprotection or spacer/linker attachment.
Ability to conjugate multiple drugs and imaging agents in immediate succession to different terminal groups of the dendrimer.
Sustained and controlled drug release from hydrogels via dual mechanism: covalent bond degradation and diffusion.
Improved biocompatibility and reduced cytotoxicity due to modification of dendrimer surfaces with biocompatible amino acids.
Injectable nanosized hydrogels with controlled particle size optimized for targeted delivery to specific tissues or organs.
Hydrogels suitable for intraocular and localized delivery with site-specific residence and efficacy in treating neuroinflammation and inflammation.
Hydrogels permit high drug payload on one terminal group while the other terminal group forms the hydrogel, reducing burst release and carrier amount.
The compositions allow multifunctionality acting as nanodevices performing targeting, localization, imaging, and sustained drug delivery.
Documented Applications
Injectable delivery of therapeutic agents for treatment of diseases or disease states.
Ocular delivery for therapeutic treatment and imaging, specifically for treating neuroinflammation and inflammation in the eye.
Intravaginal drug delivery for treatment of ascending genital infections during pregnancy to provide sustained localized delivery of antibiotics.
Topical microbicide formulations for vaginal or rectal application to treat microbial infections.
Diagnostic and imaging purposes using dendrimer conjugated imaging agents in biomedical applications.
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