A smart Neuron-Targeted Drug Delivery Platform for the treatment of brain diseases

Unmet Need: Treating brain disorders has long been hindered by the impermeability of the blood-brain barrier (BBB). Even if the drugs or nanoparticles cross the impaired BBB following brain injury or neuroinflammation, their uptake in the key cells involved in the brain diseases, especially neurons, specifically at the site of brain injury, remain the most significant challenge. This is due to their lower abundance, reduced phagocytic activity, and the diversity of neuron types, each with distinct functions. Addressing these hurdles is critical for advancing treatments for traumatic brain injury (TBI) and other neurological disorders.

Technology: We have developed a novel mixed layered 2-deoxy-D-glucose (2DG) based glycodendrimer nanoplatform (2DG-D) that addresses these challenges by selectively targeting and delivering drugs to neurons at the site of brain injury from systemic administration. The 2DG-D is an innovative, water-soluble mixed-layer glycodendrimer designed for targeted drug delivery to neurons specifically at brain injury sites. It integrates 2- deoxy glucose (2DG) on its surface to exploit GLUT transporters for neuron-specific targeting. This dendrimer is synthesized using a streamlined approach with biocompatible materials, ensuring ease of production and scalability. It features a neutral surface charge, high water solubility, and nanoscale size, allowing it to extravasate through impaired vasculature and target neurons at the site of brain injury. The dendrimer is designed for renal clearance, reducing unwanted accumulation in major organs and minimizing systemic toxicity.

In preclinical studies, the 2DG-D demonstrated efficient localization in disease associated neurons and enhanced delivery of neuroprotective agents like pioglitazone to neurons in a pediatric mouse model of traumatic brain injury (TBI). This targeted delivery demonstrated efficacy delivering pioglitazone to injured neurons, reducing neuroinflammation, and improving behavioral outcomes in TBI mice. Its neuron-targeted delivery mechanism, ease of production, and therapeutic versatility position it as a potential platform for addressing critical unmet needs in brain health.

Applications:

Targeted Treatment for Traumatic Brain Injury
Diverse platform for targeted delivery which can deliver a range of therapeutic molecules to neurons in multiple neurodegenerative diseases
Water soluble nanocarrier for delivering hydrophobic drugs to brain
2DG-D based novel theranostics for neurological diseases

Advantages: Enhanced BBB Penetration, Neuron-Specific Targeting, Water Soluble Nanocarrier, Versatile Drug Delivery Platform, Improved Drug Efficacy and Safety, Rapid Clearance and Biocompatibility, Facile and Scalable Synthesis

Technology Readiness Level: The Technology Readiness Level (TRL) of the 2DG-D platform appears to be at TRL 4-5.

Synthesized and characterized in a reproducible way at lab scale in multiple batches, and validated in vitro, and in vivo studies demonstrating safety, efficacy, and efficient delivery of hydrophobic drugs like pioglitazone, rosiglitazone. Successfully tested preclinically in a pediatric TBI mouse model, demonstrating targeted neuronal delivery, enhanced drug efficacy, and improved behavioral and neuroinflammatory outcomes.

Patent & Manuscript Information:

Provisional patent application has been filed. Non-provisional filing is in process. Link for published papers; https://pmc.ncbi.nlm.nih.gov/articles/PMC11155412/