Dendrimer based nanodevices for therapeutic and imaging purposes
Inventors
Rangaramanujam, Kannan • Kannan, Sujatha • Romero, Roberto • Navath, Raghavendra S • Dai, Hui • Menjoge, Anupa R.
Assignees
Wayne State University • US Department of Health and Human Services
Publication Number
US-10561673-B2
Publication Date
2020-02-18
Expiration Date
2030-06-10
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Abstract
A nanodevice composition including N-acetyl cysteine linked to a dendrimer, such as a PAMAM dendrimer or a multiarm PEG polymer, is provided. Also provided is a nanodevice for targeted delivery of a compound to a location in need of treatment. The nanodevice includes a PAMAM dendrimer or multiarm PEG polymer, linked to the compound via a disulfide bond. There is provided a nanodevice composition for localizing and delivering therapeutically active agents, the nanodevice includes a PAMAM dendrimer or multiarm PEG polymer and at least one therapeutically active agent attached to the PAMAM dendrimer or multiarm PEG polymer. A method of site-specific delivery of a therapeutically active agent, by attaching a therapeutically active agent to a PAMAM dendrimer or multiarm PEG polymer using a disulfide bond, administering the PAMAM dendrimer or multiarm PEG polymer to a patient in need of treatment, localizing the dendrimer or multiarm PEG polymer to a site in need of treatment, and releasing the therapeutically active agent at the site in need of treatment.
Core Innovation
The invention provides nanodevice compositions including N-acetyl cysteine linked to a polyamidoamine (PAMAM) dendrimer or a multiarm polyethylene glycol (PEG) polymer. These nanodevices are capable of targeted delivery of therapeutically active agents to sites in need of treatment, with the agents linked to the dendrimer or polymer via disulfide, amide, or ester bonds. The compositions allow for site-specific localization, delivery, and rapid intracellular release of the therapeutic agents under the reduced conditions found in vivo, such as in neuroinflammatory tissues or cells.
The problem addressed is the challenge of effectively delivering bioactive agents, such as antioxidants, antibiotics, and anti-inflammatory drugs, to target cells, particularly in the context of neuroinflammation and maternal-fetal infections. Currently available delivery systems, including viral and non-viral transfection systems, have limitations in safety, efficacy, toxicity, and complexity. Moreover, free drugs like N-acetyl cysteine suffer from poor bioavailability, rapid degradation, and high plasma protein binding, necessitating high doses that cause side effects. There is a need for delivery systems that increase bioavailability, ensure targeted delivery, minimize systemic toxicity, and release drugs rapidly at the site of action.
The nanodevices disclosed use dendritic polymers, particularly PAMAM dendrimers of various generations and multiarm PEG polymers, linked covalently to therapeutically active agents through cleavable bonds, primarily disulfide bonds sensitive to intracellular glutathione levels. These nanodevices can cross biological barriers selectively, such as the blood-brain barrier under diseased conditions, and can accumulate preferentially in activated microglia and astrocytes involved in neuroinflammatory processes. This targeted delivery enhances efficacy by ten to a hundred times compared to free drug, enabling significant dose reduction and reduced side effects. The dendrimers also exhibit selective permeability, not crossing the placenta or amniotic membranes, enabling maternal treatment without fetal exposure.
Claims Coverage
The claims include one independent claim directed to a composition of a polyamidoamine (PAMAM) dendrimer linked to N-acetyl cysteine and various dependent claims specifying details such as dendrimer generation, terminal functional groups, linkers, formulation, dosage, and therapeutic methods. The main inventive features focus on the composition of PAMAM dendrimer-NAC conjugates, the linkage chemistry, and therapeutic applications.
Dendrimer composition linked to N-acetyl cysteine
A composition comprising a polyamidoamine (PAMAM) dendrimer linked to N-acetyl cysteine, optionally via one or more spacers.
Dendrimer generation and terminal groups
The PAMAM dendrimer can be of generation 3 through generation 10, with generation 4 being exemplified, having terminal functional groups selected from carboxylic, amine and hydroxyl groups.
Linkage via specific spacers and disulfide bonds
The dendrimer is linked to N-acetyl cysteine via one or more spacers selected from N-Succinimidyl 3-(2-pyridyldithio)-propionate, glutathione, gamma-aminobutyric acid, and combinations thereof, with disulfide linkages enabling controlled intracellular release.
Therapeutic efficacy and targeting
The composition is in an amount effective to treat inflammation or neuroinflammation, targeting activated microglia and astrocytes of the central nervous system and reducing hydrogen peroxide and/or nitrite levels in these cells.
Treatment of cerebral palsy and white matter injury
The composition is effective to treat and/or prevent cerebral palsy symptoms or white matter injury in the brain.
Formulation and administration routes
The composition can be formulated for parenteral, topical or oral administration and in forms including hydrogels, nanoparticles or microparticles, suspensions, gels, ointments, powders, tablets, capsules, and solutions.
Methods of reducing or preventing inflammation or microbial growth
Methods comprise administering effective amounts of the composition for reducing or preventing inflammation (including chronic inflammation and neuroinflammation) and for preventing microbial growth via vaginal, cervical, or rectal routes.
The claims cover compositions of PAMAM dendrimer linked to N-acetyl cysteine by disulfide or spacer linkages, their therapeutic formulations, and methods for treating neuroinflammation, cerebral palsy, and microbial infections focusing on targeted delivery and enhanced efficacy.
Stated Advantages
The nanodevices deliver therapeutics ten to one hundred times more efficaciously than free drugs.
They enable significant dose reduction of agents, thereby reducing side effects.
They provide rapid intracellular release of drugs at the target site via disulfide linkage cleavage in redox environments.
They achieve selective targeting and delivery to activated microglia and astrocytes in neuroinflammatory conditions.
Their selective permeability prevents crossing into the fetus when administered to pregnant women, enabling maternal treatment without fetal exposure.
The dendrimers improve bioavailability by reducing plasma protein binding of drugs like N-acetyl cysteine.
The compositions can be formulated in various dosage forms and administered by multiple routes.
Documented Applications
Treatment of neuroinflammation, cerebral palsy, white matter injury, and other central nervous system diseases.
Targeted delivery of antioxidants, antibiotics, steroids, NSAIDs, progesterone, and nucleic acid based therapeutics.
Treatment of maternal-fetal infections such as chorioamnionitis, bacterial vaginosis, urinary tract infections, HIV/AIDS, herpes, Group B streptococcus and listeriosis.
Topical or injectable formulations for selective treatment of pregnant women without fetal exposure.
Use as antibacterial and antimicrobial agents, including treatment of infections causing chorioamnionitis.
Use in intracellular drug delivery systems responsive to glutathione levels for controlled drug release.
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