Study Of Triptolide-loaded Liposome-PEG Based Transdermal Nano-delivery System On Skin Cancer And Its Mechanism

Objective:Skin cancer is one of the most common malignancies,in which the cutaneous squamous cell carcinoma(cSCC)and skin malignant melanoma(SMM)present the most severe,and lack of effective chemotherapy.Triptolide(TPL)as one of the most active components of tripterygium wilfordii Hook F,has many pharmacological effects.Its good anti-cancer activities for skin cancer have attracted many attention.However,the strong toxicity,poor water solubility and severe side effects restrict its further application.Moreover,there has not yet been seen any kinds of research reports about skin squamous cell carcinoma SCL-1 treated by TPL.In this study,a liposome-based nano drug delivery system(TPL-LPs)and and its PEG-based transdermal delivery system(TPL-LPs-PEG)were developed to improve the therapeutic profiles of TPL.Methods:The nano-particles of liposome loading TPL(TPL-LPs)were firstly synthesized by thin-film hydration and characterized by particle size,zeta potential,shape,encapsulation efficiency and in vitro drug release profile.We then investigated the anti-cancer/anti-metastatic effect of TPL/TPL-LPs on human cutaneous squamous cell carcinoma SCL-1 and mouse melanoma B16F10 in vitro by MTT,flow cytometry,matrix adhesion and scratching assay.Furthermore,we took the advantage of PEG400 to develop liposome loaded with TPL and PEG-based transdermal drug delivery system(TPL-LPs-PEG),and the in vivo study of TPL-LPs-PEG were also performed.Finally,we investigated the anti-tumor/anti-metastasis mechanism of TPL/TPL-LPs/TPL-LPs-PEG by Western Blotting and immunohistochemistry.Results:We found that TPL/TPL-LPs could inhibit the proliferation of various cancer cell lines in a time and dose-dependent manner,and showed better inhibitory effects on skin cancer cells SCL-1 and B16F10.In addition,TPL/TPL-LPs could affect the cycle distribution,induce apoptosis,inhibit matrix adhesion and reduce the migration ability of SCL-1 and B16F10.Furthermore,TPL-LPs-PEG inhibited the growth of SCL-1 and B16710 xenografts in a dose-dependent manner after transdermal administration.The dosage of 200 μg/kg had a significant effect on tumor growth in vivo.The Western Blotting showed that TPL/TPL-LPs could up/down-regulate the expression of apoptosis and metastasis-related proteins including EGFR,p-EGFR,COX-2,VEGFA,Bcl-2/Bax,P53,JAK2 and STAT3.Moreover,immunohistochemistry results demonstrated TPL-LPs-PEG could result in down-regulation of EGFR in vivo.Conclusions:We firstly investigated the therapeutic effect and mechanism of TPL/TPL-LPs/TPL-LPs-PEG on human skin squamous cell carcinoma SCL-1 and demonstrated that TPL/TPL-LPs/TPL-LPs-PEG has good anti-skin cancer effects both in vitro and in vivo.The results suggest that the novel dosage form may be a new candidate for the treatment of cSCC,and provide reference for clinical practice.