Recent Advances in Endocannabinoid System Targeting for Improved Specificity: Strategic Approaches to Targeted Drug Delivery

Abstract

Opportunities for developing innovative and intelligent drug delivery technologies by targeting the endocannabinoid system are becoming more apparent. This review provides an overview of strategies to develop targeted drug delivery using the endocannabinoid system (ECS). Recent advances in endocannabinoid system targeting showcase enhanced pharmaceutical therapy specificity while minimizing undesirable side effects and overcoming formulation challenges associated with cannabinoids. This review identifies advances in targeted drug delivery technologies that may permit access to the full pharmacotherapeutic potential of the ECS. The design of optimized nanocarriers that target specific tissues can be improved by understanding the nature of the signaling pathways, distribution in the mammalian body, receptor structure, and enzymatic degradation of the ECS. A closer look at ligand-receptor complexes, endocannabinoid tone, tissue distribution, and G-protein activity leads to a better understanding of the potential of the ECS toolkit for therapeutics. The signal transduction pathways examine the modulation of downstream effector proteins, desensitization, signaling cascades, and biased signaling. An in-depth and overall view of the targeted system is achieved through homology modeling where mutagenesis and ligand binding examine the binding site and allow sequence analysis and the formation of libraries for molecular docking and molecular dynamic simulations. Internalization routes exploring receptor-mediated endocytosis and lipid rafts are also considered for explicit signaling. Furthermore, the review highlights nanotechnology and surface modification aspects as a possible future approach for specific targeting.

Sleep, Glial Function, and the Endocannabinoid System: Implications for Neuroinflammation and Sleep Disorders

“…These endocannabinoids act as retrograde messengers, traveling backward across synapses to bind to cannabinoid receptors on presynaptic neurons. This retrograde signaling mechanism allows the ECS to regulate neurotransmitter release and synaptic plasticity [ 108 , 109 ].…”

“…CB1R modulates the release of specific neurotransmitters, safeguarding the CNS against excessive stimulation or inhibition induced by other neurotransmitters. Conversely, CB2R primarily assumes a peripheral role with immunomodulatory activities, chiefly regulating the release of cytokines [ 108 , 109 , 110 , 111 ]. Consequently, cannabinoids may influence neurodegenerative diseases through their neuro- and immunomodulatory effects [ 112 ].…”

Cannabinoid-Based Ocular Therapies and Formulations

“…As commented on in previous sections, these observations could be ultimately explained by the unfavorable physicochemical and biological properties of cannabinoids along with restrictive ocular barriers, where the use of nanocarriers could be a valuable approach. It is also worth mentioning that the interest in cannabinoid delivery is also increasing greatly for a wide range of other therapeutic applications [14] and hence, the knowledge generated on cannabinoid encapsulation is expected to be translated to several administration strategies. Potentially, those cannabinoid-based formulations not initially developed for ocular administration could be considered for this purpose, providing they are compatible with the requisites of ophthalmic administration.…”

“…The therapeutic potential of cannabinoids in ocular pathologies is mainly due to their role in the endocannabinoid system. This physiological system is constituted by several receptors, mainly cannabinoid receptors CB 1 and CB 2 (Figure 1), and their natural endogenous ligands, such as anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol (2-AG), which are synthesized on demand by different enzymatic pathways [14] (Figure 2). In addition, non-cannabinoid receptors such as transient receptor potential vanilloid 1 (TRPV1), G-protein-coupled receptor 18 (GPR18), GPR55, GPR119 and peroxisome proliferatoractivated receptors (PPARs), GABA receptors and ion channels are also activated by endocannabinoids (Figure 1) [15].…”

“…Thus, drug delivery tools are required to enable them to exert an adequate pharmacological effect. In this arena, nanotechnology-based approaches are gaining increasing relevance [14,19,20].…”