Dendrimer based nanodevices for therapeutic and imaging purposes
Inventors
Kannan, Rangaramanujam M. • Kannan, Sujatha • Romero, Roberto • Navath, Raghavendra S.
Assignees
Wayne State University • US Department of Health and Human Services
Publication Number
US-8889101-B2
Publication Date
2014-11-18
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 comprising N-acetyl cysteine linked to dendrimers such as PAMAM dendrimers or multiarm PEG polymers through disulfide bonds. These nanodevices are designed for targeted delivery and rapid release of therapeutically active agents at sites in need of treatment, including neuroinflammation and maternal-fetal infections. The nanodevices enable site-specific delivery by attaching therapeutically active agents to PAMAM dendrimers or multiarm PEG polymers using disulfide bonds, which are cleavable under intracellular reducing conditions like elevated glutathione levels. This enhances intracellular delivery and bioavailability of therapeutic agents while minimizing systemic side effects.
The problem addressed by the invention arises from limitations of existing delivery systems for bioactive agents, such as low efficiency, cytotoxicity, poor bioavailability, and safety concerns associated with viral and nonviral transfection systems. Antioxidants like N-acetyl cysteine suffer from low bioavailability due to rapid degradation, first-pass metabolism, and high plasma protein binding, limiting their beneficial effects against conditions such as neuroinflammation in maternal-fetal medicine. Current dendrimer-based delivery attempts often show slow drug release due to hydrolytically stable linkages like amide or ester bonds. Thus, there is a need for an effective delivery system that enables rapid intracellular release, improved targeting, and enhanced efficacy of therapeutics, particularly in the treatment of central nervous system disorders and maternal-fetal infections.
This invention overcomes prior limitations by providing dendrimer or multiarm PEG polymer nanodevices linked to therapeutically active agents via disulfide bonds that exploit intracellular reducing environments for rapid drug release. The nanodevices preferentially cross the blood-brain barrier under diseased conditions, selectively targeting activated microglia and astrocytes implicated in neuroinflammatory diseases like cerebral palsy. The compositions exhibit selective permeability, not crossing the placenta or amniotic membranes appreciably, thus allowing maternal treatment without fetal exposure or vice versa. The approach allows significant reductions in therapeutic dosage due to enhanced bioavailability and targeted intracellular delivery, resulting in reduced side effects and improved therapeutic outcomes.
Claims Coverage
The patent discloses 20 main inventive features related to nanodevice compositions based on dendrimers for targeted drug delivery, drug release, and treatment of neuroinflammation and maternal-fetal infections.
Nanodevice composition comprising N-acetyl cysteine linked to PAMAM dendrimer via disulfide bonds
A nanodevice comprising N-acetyl cysteine covalently attached to a PAMAM dendrimer through disulfide bonds to enable intracellular release.
PAMAM dendrimer selection for nanodevice composition
The PAMAM dendrimer used is selected from G4-PAMAM-NH2, G4-PAMAM-COOH, and G4-PAMAM-OH variants.
Spacer-mediated linkage between N-acetyl cysteine and PAMAM dendrimer
Use of one or more spacer compounds such as SPDP, Glutathione (GSH), Gamma-aminobutyric acid (GABA), or combinations thereof to link N-acetyl cysteine to the PAMAM dendrimer.
Nanodevice for targeted delivery comprising PAMAM dendrimer linked to compound via disulfide bond
A nanodevice comprising a PAMAM dendrimer linked through a disulfide bond to a compound for targeted delivery to a site in need of treatment.
Inclusion of anti-inflammatory agents as delivered compounds
The compound linked to PAMAM dendrimer can be an anti-inflammatory agent.
Nanodevice PAMAM dendrimer selection for targeted delivery
The PAMAM dendrimer in the nanodevice is selected from G4-PAMAM-NH2, G4-PAMAM-COOH, and G4-PAMAM-OH.
Spacer compounds between N-acetyl cysteine and PAMAM dendrimer in nanodevice
The nanodevice further includes spacer compounds between N-acetyl cysteine and PAMAM dendrimer, including SPDP, GSH, GABA, or combinations thereof.
Targeting and rapid release capabilities of nanodevice
The nanodevice is capable of targeting and/or rapidly releasing therapeutically active agents intracellularly or in interstitial spaces at the site of action or absorption.
Selective localization and targeting of microglia and astrocytes
The nanodevice provides therapeutically active agents capable of localizing and targeting microglia and astrocytes in neuroinflammatory conditions.
Nanodevice delivery across the blood-brain barrier
The nanodevice is capable of delivering drugs that penetrate the blood-brain barrier, selectively under diseased conditions.
Treatment of cerebral palsy via nanodevice composition
The nanodevice delivers drugs effective for treating cerebral palsy.
Treatment of neuroinflammation via nanodevice composition
The nanodevice delivers drugs for treating neuroinflammation.
Nanodevice composition with therapeutically active agent attached via disulfide bonds
A composition comprising a PAMAM dendrimer with at least one therapeutically active agent attached via disulfide bonds, the agent including N-acetyl cysteine.
PAMAM dendrimer types for therapeutically active agent nanodevice
The PAMAM dendrimer is selected from G4-PAMAM-NH2, G4-PAMAM-COOH, and G4-PAMAM-OH for the therapeutically active agent nanodevice.
Nanodevice composition using one or more specific spacer compounds
The therapeutically active agent is attached to the dendrimer via spacers such as SPDP, GSH, GABA, amino acids, or their combinations.
Modes of administration of the nanodevice
Nanodevice compositions can be administered by parenteral, oral, or topical delivery systems.
Nanodevice capability to target and rapidly release therapeutics at absorption or action site
The nanodevice enables targeting and rapid release or delivery of therapeutics intracellularly or in interstitial spaces.
Nanodevice for targeting microglia and astrocytes
The nanodevice contains therapeutically active agents that localize and target activated microglial cells and astrocytes.
Nanodevice delivery of drugs crossing blood-brain barrier for cerebral palsy treatment
The nanodevice delivers drugs crossing the blood-brain barrier for treatment of cerebral palsy.
Nanodevice delivery of drugs crossing blood-brain barrier for neuroinflammation treatment
The nanodevice delivers drugs crossing the blood-brain barrier for treatment of neuroinflammation.
The claims cover nanodevice compositions comprising N-acetyl cysteine linked to PAMAM dendrimers via disulfide bonds, employing specific spacer molecules, enabling targeted delivery and rapid intracellular release of therapeutics. The nanodevices preferentially target activated microglia and astrocytes, cross the blood-brain barrier selectively under diseased states, and address treatments including cerebral palsy and neuroinflammation. Multiple modes of administration and dendrimer variants are included.
Stated Advantages
The nanodevices provide rapid intracellular drug release under reducing conditions for enhanced therapeutic efficacy.
They enable site-specific delivery of therapeutics to targeted cells such as activated microglia and astrocytes, improving the treatment of neuroinflammation and cerebral palsy.
Conjugation of therapeutics to dendrimers prevents plasma protein binding and enhances bioavailability, reducing required dose and associated side effects.
The nanodevices selectively cross the blood-brain barrier only under diseased conditions, minimizing exposure to healthy tissue.
Nanodevices exhibit selective permeability at the maternal-fetal interface, allowing treatment of mother without fetal exposure, or vice versa.
Dendrimer-based nanodevices are significantly more efficacious—10 to 100 times—than free drugs in in vivo models.
The nanodevices allow formulation into diverse dosage forms including injections, gels, tablets, and topical patches.
Documented Applications
Treatment of neuroinflammation and cerebral palsy through targeted delivery of N-acetyl cysteine.
Treatment of maternal-fetal infections such as chorioamnionitis, bacterial vaginosis, urinary tract infections, HIV/AIDS, herpes, Group B streptococcus, and listeriosis.
Selective topical treatment of pregnant women without fetal exposure via nanodevices that do not appreciably cross fetal membranes.
Targeted drug delivery across the blood-brain barrier in neurodegenerative and neuroinflammatory CNS diseases including cerebral palsy, Alzheimer's disease, multiple sclerosis, and Parkinson's disease.
Antimicrobial applications such as antibacterial activity against E. coli in vivo and in vitro.
Use as imaging agents to selectively localize to activated neuroinflammatory cells using PET and fluorescence imaging techniques.
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