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.

Keywords: allosteric modulation; biased signaling; endocannabinoid system; endocannabinoid tone; g-protein coupled receptors; receptor-mediated drug delivery; surface-modified nanoparticles.

Figure 5

The signal transduction pathways associated with the G_(i) signaling complex. The G_(i) protein comprises three components, namely alpha, beta and gamma subunits. Therefore, they are called the G_i protein heterotrimer. G_iα inhibits the production of Camp G_iβγ activates K+ channels and inhibits the opening of Ca2+ channels. The downstream effects involve the Mitogen-activated protein kinases pathways; ERK, p38 and JNK. β-arrestin attachment to the G_(i) complex initiates receptor desensitization and internalization. Adapted with text and annotation from reference [134] licensed under a Creative Commons Attribution 4.0 (CC BY) license.

Figure 1

(A) Helical structure of CB1-R [85]. (B) Helical structure of the G(i)-signaling complex made up of the CB1-R and the G(i) subunit alpha-1, subunit beta-1, and subunit gamma-2 heterotrimeric proteins [26]. Seven hydrophobic transmembrane segments are connected by loops that extend into the extracellular and intracellular domains alternatively [26]. Modified using Schrödinger Release Software 2021-4: Maestro, Schrödinger, LLC, New York, NY, 2021.

Figure 2

Helical representation of the CB1 receptor. The seven-transmembrane receptor is embedded into the cell membrane, having extracellular helices extending into the extracellular environment and the intracellular helices protruding into the intracellular environment where it interacts with the Guanine nucleotide-binding protein G(i) subunit alpha-1. The extracellular domain has an N-terminal that possesses glycosylation sites, while the intracellular domain has a C-terminal coupled to a G-protein complex. Adapted from reference [26]. Modified using Schrödinger Release Software 2021-4: Maestro, Schrödinger, LLC, New York, NY, 2021.

Figure 3

Comparison of the binding pocket of CB1-R and CB2-R. Modified using Schrödinger Release software 2021-4: Maestro, Schrödinger, LLC, New York, NY, 2021.

Figure 4

Superposition of AM6538@CB1-R (5TGZ from PDB) (pink) and AM10257@CB2-R (5ZTY from PDB) (purple). The crystal structure of human CB2-R in complex with antagonist AM10257 and crystal structure of human CB1-R in complex with AM6538 shows the conformational lock holding the binding site in the ligand-binding conformation [32,85]. Modified using Schrödinger Release software 2021-4: Maestro, Schrödinger, LLC, New York, NY, 2021 [32,85].

Figure 6

The functions and pharmacotherapy targets of the endocannabinoid system [150]. Figure modified with text, and annotation after adaptation of “Nervous System” from Servier Medical Art by Servier, licensed under a Creative Commons Attribution 3.0 Unported License [180] and reference [181] with permission.

Figure 7

The four families of G-proteins interact differently with effector proteins to initiate signaling [233].

Figure 8

Graphical representation shows a comparison of nanocarrier shape and ligand-binding capability. (A) Represents a spherical shape nanocarrier. (B) Represents rod-shaped nanocarrier. The differently shaped nanoparticles have different active fractional area which presents variability in binding avidity [291].

Figure 9

(A) A spherical-shaped nanoparticle with a low-density ligand pattern most likely to encounter clathrin pit for endocytosis. The clathrin-coated pit is deeply invaginated and pinched off from the plasma membrane to form a clathrin-coated vesicle following endocytosis. (B) A spherical-shaped nanoparticle with a high-density ligand pattern most likely enters the cell through caveolae-mediated endocytosis. The caveolae, a flask-shaped vesicle at the plasma membrane, is internalized and fused to form caveosomes. Adapted with permission from reference [326].