System for the targeted delivery of endocannabinoid drugs

System for the targeted delivery of endocannabinoid drugs

Nanosystems with different compositions and biological properties have been extensively studied for drug and gene delivery applications. Nanoparticles have tremendous potential as effective drug delivery systems as they release their cargo and release their structural components.

Study: Design and function of targeted endocannabinoid nanoparticles. Credit: WuttikitStudio/Shutterstock.com

Due to the endocannabinoid-like activity of N-acylethanolamines (NAEs), oleoylethanolamide (OEA), and linoleoylethanolamide (LEA), a paper published in Scientific Reports presented OEA-LEA-derived target-specific endocannabinoid nanoparticles by conjugation with tissue-specific molecules capable of are able to reduce inflammation by localizing to a specific target site.

The present work offers a novel drug delivery system that utilizes the target-specific pharmacological effects of endocannabinoids to treat conditions such as cancer, epilepsy and arthritis and improve quality of life and patient management.

Endogenous cannabinoids

NAEs are body lipids that occur naturally, are involved in various physiological and metabolic activities, and include endocannabinoids as one of the component groups. Anandamide, a key biochemical lipid molecule, is a widely studied NAE.

Although the anti-inflammatory benefits of anandamide are well known, its function and effectiveness live are restricted by fatty acid amide hydrolase (FAAH). Due to their anti-inflammatory and analgesic properties, several lesser-known NAEs such as OEA, LEA, palmitoylethanolamide (PEA), and stearoylethanolamide (SEA) have been thoroughly studied for their potential as therapeutic substitutes for anandamide.

LEA’s ability to inhibit FAAH has been shown to prolong anandamide’s half-life and enhance its therapeutic efficacy in inflammatory diseases. Similarly, OEA exerts significant anti-inflammatory effects by increasing peroxisome proliferator-activating receptor (PPARα) expression and limiting the production of pro-inflammatory cytokines.

The glutamate signaling pathway mediates the decreased nociceptive effects of OEA. In general, the endocannabinoid system is beneficial in regulating immune cell motility, nociceptive transmission, and cytokine production.

Nanomedicine and nanodelivery systems are a relatively new but rapidly evolving science that utilizes nanoscale materials to serve as diagnostic tools or to deliver therapeutic agents to specific target sites in a controlled manner. Nanotechnology offers numerous advantages in treating human diseases through the site-specific and targeted delivery of precise drugs.

Nanoparticles used as drug delivery vehicles are generally smaller than 100 nanometers in size and are composed of various biodegradable materials such as natural or synthetic polymers, lipids or metals. Nanoparticles are taken up by cells more efficiently than larger micromolecules and can be used as effective transport and delivery systems.

Drugs can be integrated into the matrix of nanoparticles or bound to the surface of nanoparticles for therapeutic applications. A drug targeting system should be able to control the fate of a drug entering the biological environment.

Targeted endocannabinoid nanoparticles

Previous studies have demonstrated the self-assembly behavior of the NAE-lipid mixed lyotropic mesophase, indicating the ability of LEA and OEA mixtures to form different types of nanoparticles. Thus, the present study demonstrated the optimal ratio of LEA to OEA required to develop stable crystalline liquid mesophases and nanoparticles at physiological temperatures and in aqueous solutions.

Synovium targeting peptide (HAP-1) conjugated polyethylene glycol (PEG)-oleoyl was integrated into the membrane of nanoparticles and administered to an adjuvant-induced mouse model to study the localization and therapeutic efficacy of nanoparticles.

Testing of the prepared nanoparticles in vitro and live showed that conjugation of HAP-1 to the surface of nanoparticles was possible and resulted in specific binding with greater uptake of nanoparticles to fibroblast-like synoviocytes (FLS).

Target sites had greater release of membrane components of nanoparticles according to biodistribution studies of targeted and non-targeted nanoparticles, which regulated endocannabinoid levels and cytokine generation and reduced inflammation.

RNA sequencing revealed the anti-inflammatory effects mediated by inhibition of cytokine pathways, Toll-like receptors (TLR), Janus kinase signaling transducers and transcription activators (JAK-STAT), and peroxisome proliferator-activated receptors (PPAR) be mediated, as well as the regulation of transcription factors at sites of inflammation. These results were consistent with previous reports showing that OEA and LEA have inherent anti-inflammatory and analgesic properties.

The possibility of using the endocannabinoid nanoparticles as therapeutics for hepatic fibrosis, interstitial lung disease, scleroderma and other fibrosing diseases has been indicated by controlling the canonical pathway of hepatic fibrosis.

By preventing hepatic stellate cell activation live, administration of OEA suppressed the progression of liver fibrosis. In addition, endocannabinoid nanoparticles may have therapeutic utility in allergic inflammation by controlling pro-inflammatory mediators such as vasoactive amines, cysteinyl leukotrienes, and cytokines.

Conclusion

In summary, the present study presents tailored nanoparticles with built-in endocannabinoid activity in the target region, which has been employed as a drug delivery system. This research showed several benefits and potential treatment in the management of fibrosis, chronic pain and neurological disorders such as Alzheimer’s disease.

Relation

Barri, N et al. (2022). Design and function of targeted endocannabinoid nanoparticles. Scientific Reports. https://www.nature.com/articles/s41598-022-21715-1

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