Targeted nanoparticle for the treatment of traumatic brain injury and other CNS diseases
Inventors
Perumal, Venkatesan • Ravula, Arun Reddy • Chandra, Namas • RamaRao, Venkata Kakulavarapu • Kumar, Vivek • Siddiqui, Zain
Assignees
New Jersey Institute of Technology
Publication Number
US-12329765-B2
Publication Date
2025-06-17
Expiration Date
2042-04-27
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Abstract
A composition, and method for a targeted drug delivery is disclosed in treating central nervous system injury, including blast hearing loss, traumatic brain injury (TBI) and the like, by administering a subject with nanoparticle-based minocycline formulations. The formulation contains nanoparticles encapsulating minocycline for neuroprotective effect in TBI. Albumin nanoparticle-based minocycline formulations provide enhanced delivery to brain, and reduced toxicity at minimal dosage for treating a subject suffering from central nervous system injury including blast induced traumatic brain injury (bTBI). Nanoparticle administered at minimal dose in rat blast TBI model crossed blood-brain barrier (BBB) and enhanced therapeutic concentration compared to free minocycline. Provided is an effective and safe minocycline delivery in TBI with minimal or no toxicity for neuroprotective therapy. Studies indicate performance for behavioral (acute and chronic), pathological (chronic) and hearing loss mitigation using the disclosed drug and nanoparticles in rat moderate bTBI model.
Core Innovation
The disclosed invention provides a targeted drug delivery composition and method for treating central nervous system injuries, including traumatic brain injury (TBI) and blast-induced hearing loss, by administering nanoparticle-based minocycline formulations. The innovation involves encapsulating minocycline within albumin nanoparticles—optionally further conjugated with ligands such as transferrin—to enable efficient crossing of the blood-brain barrier (BBB) and targeted accumulation in the brain. This approach is specifically formulated to enhance therapeutic delivery while minimizing systemic toxicity.
Current therapeutic strategies for blast and trauma-induced central nervous system injuries face significant limitations, including inadequate bioavailability, lack of targeted delivery to relevant regions, and toxicity arising from high systemic doses of minocycline. The blood-brain barrier and poor distribution of drugs to the brain have hindered effective neuroprotective therapies for CNS injuries, with previous delivery methods failing to consistently reach therapeutic concentrations in affected brain regions without adverse side effects.
The described nanoparticle system is designed to address these challenges. The formulation uses a modified desolvation method to encapsulate minocycline in bovine serum albumin, crosslinked for stability, and functionally modified with ligands like transferrin for BBB targeting. Evidence from rat models of blast TBI demonstrates that minimal doses of these nanoparticles achieve higher therapeutic concentrations in brain tissue with reduced toxicity, enhanced behavioral and pathological recovery, and mitigation of hearing loss. The approach is also applicable to other neurological conditions where targeted brain delivery of therapeutics is required.
Claims Coverage
The patent includes three main independent inventive features as claimed, covering the targeted nanoparticle composition, its method of formulation, and its method of therapeutic delivery.
Targeted nanoparticle composition encapsulating minocycline
A nanoparticle composition comprising minocycline encapsulated within an albumin nanoparticle, wherein the nanoparticle may be further conjugated with targeting ligands such as transferrin and/or a CD11b antibody. The composition is specifically formulated to possess an anionic surface charge (−3.14 mV) and a defined polydispersity index (0.275±0.01), optimizing it for brain delivery.
Method of formulating minocycline loaded albumin nanoparticle (tfMANP)
A process including: 1. Preparing an unmodified minocycline loaded albumin nanoparticle (MANP) by dissolving bovine serum albumin in sodium chloride, incubating with minocycline, and adjusting pH for nanoparticle formation, followed by desolvation with ethanol, crosslinking with glutaraldehyde, centrifugation, and ultrasonication. 2. Introducing a sulfhydryl group to transferrin via reaction with 2-iminothiolane. 3. Activating the nanoparticles using NHS-PEG-MAL-5000 crosslinker (10-fold molar excess), covalently coupling sulfhydryl-reactive transferrin to MANP to obtain a targeted MANP (tfMANP).
Method of delivering the therapeutic composition for CNS treatment
A method involving: - Providing the targeted minocycline-loaded nanoparticle composition as defined above. - Delivering the composition to the inner ear of a patient, with specific mention of intravenous injection of PEGylated non-targeted minocycline nanoparticles, or delivery to the brain for treatment of traumatic brain injury, blast hearing loss, or CNS diseases, including mitigation of blast/noise-induced hearing loss via a central auditory system mediated mechanism.
The claims cover a targeted nanoparticle composition with specific physicochemical properties, a detailed formulation method yielding brain-targeting minocycline nanoparticles, and therapeutic delivery methods for treating traumatic brain injury, blast hearing loss, and other central nervous system diseases.
Stated Advantages
Enhanced delivery of minocycline to the brain, achieving higher therapeutic concentrations than free minocycline while minimizing systemic toxicity at reduced dosage.
Efficient crossing of the blood-brain barrier and targeting of injured brain regions, improving neuroprotective effects in central nervous system injuries.
Reduced accumulation of drug in non-target organs such as liver, spleen, kidney, and heart, thereby lowering risk of adverse effects in these tissues.
Improved behavioral and pathological recovery as well as mitigation of hearing loss in animal models of blast-induced traumatic brain injury.
Demonstrated safety and minimal or no observable toxicity in treated animal models, even with repeated administration.
Documented Applications
Treatment of traumatic brain injury (TBI) using targeted minocycline-loaded nanoparticles for neuroprotective effect.
Treatment of blast-induced hearing loss, including mitigation of acute and chronic hearing loss in animal models.
Therapeutic application for other diseases affecting the brain, including Parkinson's disease, Alzheimer's disease, brain HIV, and cancer.
Reduction of neuroinflammation and recovery of behavioral and cognitive function following central nervous system injury.
Improvement in delivery and sustained release of minocycline for various inner ear disorders.
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