Prodrugs for Skin Delivery of Menahydroquinone-4, an Active Form of Vitamin K2(20), Could Overcome the Photoinstability and Phototoxicity of Vitamin K2(20)

Abstract

The effective delivery of menahydroquinone-4 (MKH), an active form of menaquinone-4 (MK-4, vitamin K2(20)), to the skin is beneficial in the treatment of various skin pathologies. However, its delivery through the application of MK-4 to the skin is hampered due to the photoinstability and phototoxicity of MK-4. This study aimed to evaluate the potential of ester prodrugs of MKH for its delivery into the skin to avoid the abovementioned issues. The ester prodrugs, MKH 1,4-bis-N,N-dimethylglycinate hydrochloride (MKH-DMG) and MKH 1,4-bis-hemisuccinate (MKH-SUC), were prepared using our previously reported methods. Photostability was determined under artificial sunlight and multi-wavelength light irradiation, phototoxicity was determined by intracellular ROS formation and cell viability of UVA-irradiated human epidermal keratinocyte cells (HaCaT), and delivery of MKH into HaCaT cells was assessed by measuring menaquinone-4 epoxide (MKO) levels. MKH prodrugs showed higher photostability than MK-4. Although MK-4 induced cellular ROS and reduced cell viability after UVA irradiation, MKH prodrugs did not affect either ROS generation or cell viability. MKH prodrugs enhanced intracellular MKO, indicating effective delivery of MKH and subsequent carboxylation activity. In conclusion, these MKH prodrugs show potential for the delivery of MKH into the skin without photoinstability and phototoxicity.

Overcoming the Photochemical Problem of Vitamin K in Topical Application

“…Analysis of the PK photolysis reaction by Hangarter et al showed that charge transfer from the β,γ-double bond of the isoprenyl side chain to the quinone moiety Overcoming the Photochemical Problem of Vitamin K in Topical Application DOI: http://dx.doi.org/10.5772/intechopen.99310 initiates intramolecular proton transfer from the side chain and yields a 1,3-quinone methide (meta-quinone methide) as a mixture of singlet and triplet species diradical in polar solvents, subsequently forming 1,2-quinone methide (ortho-quinone methide), which can be used to generate PK chromenol [9]. Chromenol levels tend to increase with irradiation time, and this compound is expected to be the final product of photodegradation of vitamin K [9,12,13].…”

“…We have previously confirmed that irradiation of PK and MK-4 with UVA increases singlet oxygen generation, intracellular reactive oxygen species (ROS) generation, and cytotoxicity in HaCaT human keratinocytes. Thus, vitamin K has phototoxic properties [12,13]. Moreover, 1,3-quinone methide diradical and 1,2-quinone methide, which are produced during the photodegradation of vitamin K, are highly reactive and show phototoxicity via type I reactions.…”

“…The ethanol solutions of PK, MK-4, phyllohydroquinone derivatives (PKH-DMG and PKH-SUC), and menahydroquinone-4 derivatives (MKH-DMG and MKH-SUC) in quartz cells were exposed to artificial sunlight (12000 lx) from the vertical direction at 25°C with and without shading. The residual concentrations were determined by liquid chromatography tandem mass spectrometry [12,13].…”

“…To confirm whether the VKH derivatives had phototoxic properties, singlet oxygen generation, intracellular ROS generation, and cytotoxicity after irradiation with UVA were evaluated in HaCaT cells [12,13].…”

“…To confirm whether VKH derivatives function as VKH prodrugs in skinderived cells, the delivery properties of VKH to HaCaT cells were evaluated [12,13]. Table 4 shows the area under the curve (AUC) of intracellular VKO up to 72 h after the administration of MK-4 and VKH derivatives to HaCaT cells.…”