Reduction of focal sweating by lipid nanoparticle-delivered myricetin

Abstract

Myricetin-a flavonoid capable of inhibiting the SNARE complex formation in neurons-reduces focal sweating after skin-application when delivers as encapsulated in lipid nanoparticles (M-LNPs). The stability of M-LNP enables efficient delivery of myricetin to sudomotor nerves located underneath sweat glands through transappendageal pathways while free myricetin just remained on the skin. Furthermore, release of myricetin from M-LNP is accelerated through lipase-/esterase-induced lipolysis in the skin-appendages, enabling uptake of myricetin by the surrounding cells. The amount of sweat is reduced by 55% after application of M-LNP (0.8 mg kg −1) on the mouse footpad. This is comparable to that of subcutaneously injected anticholinergic agents [0.25 mg kg −1 glycopyrrolate; 0.8 U kg −1 botulinum neurotoxin-A-type (BoNT/A)]. M-LNP neither shows a distal effect after skinapplication nor induced cellular/ocular toxicity. In conclusion, M-LNP is an efficient skin-applicable antiperspirant. SNARE-inhibitory small molecules with suitable delivery systems have the potential to replace many BoNT/A interventions for which self-applications are preferred. Focal hyperhidrosis is an idiopathic abnormality characterized by excessive sweating concentrated in certain regions of the body, such as palms, soles, face, and armpits 1. Nearly 3% of the general population-most people aged 25-64 years-experiences hyperhidrosis. Due to its interference with daily activities, this condition carries a substantial emotional, psychological, social, and professional burden 2 , even resulting in social anxiety disorders 3. Various treatments for blocking the sweating-mechanisms have been employed to treat this abnormality. Systemic agonists, antiperspirants, iontophoresis, local excision, and botulinum neurotoxins type A (BoNT/A) have been approved by the US Food and Drug Administration 4. Systemic agonists are usually used to treat generalized hyperhidrosis. Glycopyrrolate, phentolamine, clonidine, propranolol, and diltiazem lessen the symptoms as they act as anticholinergic 5 , α-adrenergic 6 , α2-adrenergic 7 , β-blocker 1 , and calcium channel blockers 8 , respectively. These agents show various side effects such as daytime sedation, dry mouth, constipation, blurred vision, urinary retention, and tachycardia 1. Aluminum chloride solutions mechanically obstruct sweat gland ducts, which in turn leads to atrophy of the eccrine acini 9. Limitations of aluminum chloride include skin irritation, burning, stabbing dysesthesias, temporary relief, and cumbersome application 4. Iontophoresis with tap water or glycopyrrolate solution also has drawbacks, such as erythema, local burning pain, and blistering 10. The adverse effects of surgical treatments include scars, paresthesia, pigmentation, partial alopecia, compensatory hyperhidrosis, Horner's syndrome, hemothorax, and pneumothorax despite improvement in the symptoms 1. BoNT/A, produced by an anaerobic bacterium Clostridium botulinum, is a safe and effective method for treating focal hyperhidrosis, p...

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