Mitigating Cannabidiol's Non-Selective Cytotoxicity via Subcellular Organelle Targeting: Exploring Mitochondrial...

Area of Science:

• Pharmacology and Toxicology
• Neuroscience
• Biochemistry

Background:

• Cannabidiol (CBD), a nonpsychoactive phytocannabinoid, shows therapeutic promise but is limited by nonselective cytotoxicity.
• Off-target effects of CBD impact various cell types, including microglia and oligodendrocytes, hindering its clinical use.
• Developing strategies to enhance CBD's therapeutic index by minimizing cytotoxicity is crucial for its application.

Purpose of the Study:

• To explore subcellular organelle-targeting strategies for CBD to minimize off-target effects and enhance its therapeutic index.
• To synthesize and evaluate CBD conjugates targeting specific organelles like mitochondria, endoplasmic reticulum, and lysosomes.
• To identify an optimized CBD conjugate with improved safety and efficacy for therapeutic applications.

Main Methods:

• Synthesis of three organelle-specific CBD conjugates targeting mitochondria, endoplasmic reticulum, and lysosomes.
• Evaluation of cytotoxicity and anti-inflammatory activity of the synthesized CBD conjugates.
• Optimization of a mitochondria-targeting conjugate (CBD-TPP-C4) using a four-carbon ether chain linker.
• In vitro assessment of mitochondrial ATP levels and in vivo studies in *Caenorhabditis elegans* and mice.

Main Results:

• Mitochondria-targeting triphenylphosphonium (TPP)-modified CBD conjugates showed reduced cytotoxicity and enhanced anti-inflammatory activity.
• The optimized CBD-TPP-C4 conjugate exhibited a 3-fold increase in antineuroinflammatory activity and a 1.6-fold decrease in cytotoxicity compared to unmodified CBD.
• CBD-TPP-C4 elevated mitochondrial ATP levels, improved mitochondrial morphology and locomotor function in *C. elegans*, and potentiated morphine analgesia in mice.

Conclusions:

• Subcellular organelle targeting is a viable strategy to enhance the safety and efficacy of cannabidiol (CBD).
• The mitochondria-targeting conjugate CBD-TPP-C4 demonstrates significant improvements in antineuroinflammatory activity and reduced cytotoxicity.
• Optimized CBD conjugates hold promise for improved therapeutic applications with enhanced safety profiles.