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

Cannabidiol (CBD), a phytocannabinoid from Cannabis sativa, is renowned for its nonpsychoactive properties and therapeutic potential. However, its clinical application is limited by nonselective cytotoxicity, affecting microglia, oligodendrocytes, and other cells. To address this, subcellular organelle-targeting strategies were explored to minimize off-target effects and enhance CBD's therapeutic index. Three organelle-specific conjugates targeting mitochondria, endoplasmic reticulum, and lysosomes were synthesized. Among these, the mitochondria-targeting triphenylphosphonium (TPP)-modified CBD conjugates demonstrated reduced cytotoxicity and enhanced anti-inflammatory activity. Further optimization identified a four-carbon ether chain linker (CBD-TPP-C4) that increased antineuroinflammatory activity by 3-fold and reduced cytotoxicity by 1.6-fold, compared to unmodified CBD. CBD-TPP-C4 also elevated mitochondrial ATP levels in vitro, improved mitochondrial morphology and locomotor function in Caenorhabditis elegans, and potentiated morphine analgesia in mice. These findings highlight subcellular targeting as a promising strategy to enhance CBD's safety and efficacy, paving the way for improved therapeutic applications.