Experimental And Theoretical Study On Transdermal Treatment Of Melanoma With Drugs Mediated By Transdermal Peptide TD

Melanoma is a malignant tumor with poor prognosis,aggressive metastasis,high drug-resistance,high incidence,and high mortality;therefore,it is necessary to explore an effective and safe therapeutic method for the treatment of melanoma.Chemotherapy is a powerful tool for treating melanoma at present,but the therapy still has many problems.The chemotherapeutic drugs are delivered to the targeting area mainly orally or by injection and the routes of administration not only will cause side effects and damage to some organs,but also cannot achieve the efficient,accurate,and controllable delivery of the drugs.Transdermal delivery of chemotherapeutic drugs has broad application prospects in the treatment of subcutaneous melanoma,but still faces some challenges.For example,skin barrier blocks the efficient delivery of drugs,poor solubility of chemotherapeutic drugs causes low bioavailability,and it is difficult to predict the transdermal process.In this dissertation,therefore,nanoliposomes loaded with chemotherapeutic drugs were developed firstly and then delivered via the skin for the safe,effective,accurate,and controllable treatment of the subcutaneous melanoma,with the biologically inspired peptide TD enhancing the skin permeation.The main research topics are as follows:Firstly,a nanoliposome encapsulating the traditional chemotherapeutic drug dacarbazine(Dac-Lip)was developed,and the size distribution,loading efficiency,and drug release of Dac-Lip were studied.The combined effect of the peptide TD and the liposome deformability on the delivery of dacarbazine was investigated in vitro.The main results showed that both the liposome deformability and the peptide TD could enhance the transdermal delivery of dacarbazine,and that the combination could further improve the transdermal efficiency of dacarbazine.Secondly,a liposome encapsulating the new chemotherapeutic drug vemurafenib,modified with the peptide TD,was developed(Vem-TD-Lip).Firstly,the morphology and size of Vem-TD-Lip were characterized.Then,the stability,limited cytotoxicity,intercellular uptake,inhibition of cancer cells,and the ability to across the skin were confirmed in vitro.Finally,the safety and efficacy of Vem-TD-Lip were studied in vivo in the transdermal treatment of subcutaneous melanoma.The main results showed that the administration of Vem-TD-Lip via skin not only effectively inhibited the growth of subcutaneous melanoma,but also was safer than that through intravenous injection in terms of reducing damage to liver,kidney,and lung.Thirdly,a theoretical model for the transport of drugs delivered via the skin under the mediation of the peptide TD was developed.Based on in vitro drug transdermal experiments,the relationships between skin porosity,drug diffusivity,and TD adsorption capacity of skin were derived.The results showed that the interaction between TD and skin complied with Langmuir equation.The variation trends of both porosity and diffusivity were S-shaped with the increase in the adsorption quantity of TD.In the transdermal drug delivery system mediated by TD,the skin barrier was gradually opened as TD diffused deep into the skin,which not only enhanced the transport of drugs,but also promoted the transport of TD itself and then further opened the skin pathway.This work proposed a safer and more effective approach of administration for the treatment of subcutaneous melanoma as an alternative to the traditional approaches of administration,which not only reduced the toxicity of drugs,but also enhanced the availability of drugs and improved the therapeutic effect of drugs.Therefore,this work will be of great theoretical significance and practical value in developing new strategies for the treatment of melanoma,optimizing the therapeutic process of melanoma,and developing chemotherapeutic drugs for melanoma.