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-10172951-B2
Publication Date
2019-01-08
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 nanodevices comprising therapeutically active agents conjugated to dendrimers or multiarm polyethylene glycol (PEG) polymers via linker molecules forming disulfide bridges. These nanodevices enable rapid and site-specific intracellular release of the attached agents under the reducing conditions in vivo, primarily facilitated by glutathione exchange reactions. Preferably, poly(amidoamine) (PAMAM) dendrimers up to generation 10 or multiarm PEG polymers of molecular weights between 10 kDa and 80 kDa are employed. The disulfide bond linkage offers a rapid release advantage over amide or ester bonds, resulting in enhanced efficacy and reduced side effects due to lowered doses of the therapeutic agents.
The invention addresses the problem of poor bioavailability and ineffective delivery of bioactive agents such as N-acetyl cysteine (NAC) in clinical treatments, particularly in neuroinflammation and maternal-fetal medicine. Existing delivery systems face challenges including low intracellular delivery efficiency, degradation, rapid elimination, and toxicity associated with other vectors such as viral or cationic polymers. This nanodevice design overcomes these by enabling targeted, controlled, and rapid intracellular release of agents specifically at the site in need of treatment, while limiting exposure to non-target tissues such as the fetus in pregnant women.
The nanodevices are capable of selectively crossing the blood-brain barrier under diseased conditions and preferentially localizing within activated microglial cells and astrocytes that contribute to neuroinflammatory disease processes such as cerebral palsy. The compositions can be administered through various routes including intravenous, subdural, intra-amniotic, topical, or oral, and formulated in hydrogels, suspensions, gels, powders, tablets, capsules, or patches. The dendrimer-drug conjugates demonstrate significantly increased efficacy, with 10- to 100-fold dose reductions compared to free drug forms, by enhanced intracellular delivery and inhibition of plasma protein binding.
Claims Coverage
The patent includes one independent claim that addresses a method for differential delivery of bioactive compounds to mother and fetus using dendrimers.
Differential administration of PAMAM dendrimer-linked bioactive compounds for mother and fetus
This method involves administering a PAMAM dendrimer linked to a first bioactive compound outside the placental and amniotic sac barrier to treat the mother, and administering a PAMAM dendrimer linked to a second bioactive compound inside the placental and amniotic sac barrier to treat the fetus.
The claims focus on the method of using PAMAM dendrimer-linked bioactive compounds for targeted treatment of the mother and fetus by exploiting the placental and amniotic sac barrier, enabling selective delivery and therapeutic targeting.
Stated Advantages
Enhances bioavailability of therapeutic agents by overcoming plasma protein binding and increasing intracellular delivery efficiency.
Allows for significant dose reduction, leading to fewer side effects while maintaining or improving efficacy.
Enables rapid and site-specific intracellular release of drugs via disulfide bond cleavage under reducing conditions.
Selective targeting and uptake by activated microglia and astrocytes, particularly in neuroinflammatory diseases.
Does not cross placental and amniotic membranes significantly, enabling selective treatment of mother or fetus with minimal off-target exposure.
Can be administered via multiple routes and formulated in diverse dosage forms suitable for specific therapeutic needs.
Documented Applications
Treatment of neuroinflammation associated with maternal-fetal infections, specifically targeting cerebral palsy and other CNS diseases.
Topical antimicrobial treatment for intrauterine infections such as chorioamnionitis, bacterial vaginosis, urinary tract infections, HIV/AIDS, herpes, Group B streptococcus, and listeriosis in pregnant women.
Targeted delivery of anti-inflammatory and antioxidant agents, in particular N-acetyl cysteine, to activated microglial cells and astrocytes in the fetal brain.
Use as antibacterial and antimicrobial agents for treating infections in maternal-fetal settings without fetal exposure.
Use in imaging and diagnostics by linking imaging agents to dendrimers for targeted delivery and localization.
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