Alzheimer’s disease (AD) is the most common cause of dementia affecting ∼ 5.8 million Americans and 40-50 million people worldwide. Despite the burden of this disease, there is no cure for Alzheimer’s with standard-of-care treatments only able to manage symptoms. Furthermore, clinical diagnosis is imprecise and only suitable for later stages of the disease as it relies on detecting impaired memory and cognitive function, which consequently also results in late intervention. However, changes in neurological biomarkers precede cognitive decline by 15 – 20 years and can thus act as indicators of Alzheimer’s disease enabling early diagnosis and clinical intervention. Though several techniques such as cerebrospinal fluid sampling and various medical imaging methods have demonstrated promise in this regard, none of these have progressed to routine use.
Inventors at the University of Toronto have developed a multi-functional theranostic nanoconstruct for the early detection and treatment of Alzheimer’s disease. Synthesis is easily achieved using a “one-pot” method. The main components of the nanoconstruct include MnO2 nanoparticles for MRI imaging, a polymer/lipid structural core, and an exterior surface containing antibodies to selectively target the causative components of Alzheimer’s disease, i.e. soluble amyloid-β (Aβ) and Aβ-plaque. Further, recruitment of apolipoprotein from the plasma by the nanoparticles facilitates BBB-crossing, where the nanoconstruct can then exert its function as a diagnostic and therapeutic.
Figure 1. Nanoconstruct for diagnosis and therapy of Alzheimer’s disease. Key motifs include a brain-targeting (BT) polymer, manganese oxide nanoparticles (MnO2) for diagnosis, and anti-Aβ (aAβ) antibodies for localization and therapy.
The theranostic proposed has the following advantages for detection and treatment of Alzheimer’s disease:
- Easy “one-pot” synthesis method
- Effectively crosses blood brain barrier
- Accumulates in damaged brain tissue
- Diagnostic potential high
- High detection sensitivity (89%) and specificity (100%) even at early-stage Alzheimer’s disease (AD)
- Therapeutic potential
- Protected primary cortical neural cells from oxidative stress (~30% increase in survival of cortical neurons)
- Decreased ROS (~25% reduction in AD mice)
- Reduction in proinflammatory cytokines (~70% reduction in IL-1b)
- Early detection and treatment of neurodegenerative diseases (e.g. Alzheimer’s disease)
INTELLECTUAL PROPERTY STATUS
- Provisional patent filing (Title: Blood-brain barrier penetrating nanotheranostics for acute and chronic neurodegenerative diseases and the like; US 63/085,729)
Proof-of-concept studies have been conducted up to the small animal level. Nanoconstructs have been synthesized and thoroughly characterized in vitro. In vivo studies conducted on mice demonstrated the ability to detect Alzheimer’s disease from three areas of the brain (i.e. cerebrospinal fluid, cortex and hippocampus) with high sensitivity and specificity. Therapeutic potential was demonstrated in vitro where the viability of neurons exposed to oxidative stress increased by 20% – 30%.