State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Sciences, School of Chemical Engineering, Dalian University of Technology, Dalian, Liaoning 116024, China.
Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning 116023, China.
J Pharm Sci. 2021 May;110(5):2167-2176. doi: 10.1016/j.xphs.2020.12.024. Epub 2020 Dec 26.
Cutaneous melanoma is the deadliest form of skin cancer, and gambogic acid (GA) exhibits potent anti-melanoma activity. However, clinical application of GA via intravenous injection and oral administration is limited by systemic toxicity and rapid metabolism in the blood. Here, we developed a new, topical route of GA delivery for anti-melanoma activity and reduction of systemic toxicity. The results indicated that the barrier of the stratum corneum (SC) and low diffusion of GA in the hydrophilic viable skin (epidermis and dermis) limited the GA penetration through intact skin. The combination of azone (AZ) and propylene glycol (PG) showed obvious synergistic effects on skin penetration by GA via improving the permeability of the SC and greatly increasing the skin accumulation of GA, thereby forming a high drug concentration in the skin and achieving a topical targeted treatment of melanoma. In addition, GA (AZ-PG) achieved the same anti-melanoma effect via topical delivery as via intravenous injection. Intravenous injection and oral administration of GA induced remarkable pathological changes in various organs in mice, whereas GA was not toxic to various organs or to the skin via topical delivery. These findings indicated that topical administration of GA is an alternative route for melanoma treatment.
皮肤黑色素瘤是最致命的皮肤癌，藤黄酸（GA）表现出很强的抗黑色素瘤活性。然而，GA 通过静脉注射和口服途径的临床应用受到全身毒性和血液中快速代谢的限制。在这里，我们开发了一种新的 GA 经皮给药途径，用于抗黑色素瘤活性和降低全身毒性。结果表明，角质层（SC）的屏障和 GA 在亲水性活皮（表皮和真皮）中的低扩散性限制了 GA 通过完整皮肤的渗透。氮酮（AZ）和丙二醇（PG）的组合通过改善 SC 的渗透性并大大增加 GA 在皮肤中的蓄积，对 GA 的皮肤渗透表现出明显的协同作用，从而在皮肤中形成高药物浓度，实现对黑色素瘤的局部靶向治疗。此外，GA（AZ-PG）通过经皮给药达到与静脉注射相同的抗黑色素瘤效果。GA 通过静脉注射和口服给药在小鼠的各种器官中引起明显的病理变化，而 GA 经皮给药对各种器官或皮肤没有毒性。这些发现表明，GA 的局部给药是治疗黑色素瘤的一种替代途径。
