A Theoretical Study On Treatment Of Melanoma With Transdermal Sirna Mediated By Peptide

Melanoma is a malignant tumor that resides mainly in the skin.It is characterized by high mortality,wide incidence,fast transfer,and poor prognosis.In recent years,small interference ribonucleic acid(siRNA)emerges as a promising strategy to treat melanoma by inducing the apoptosis of melanoma cells.Currently,siRNA is delivered mainly through injection.The injection way cannot avoid the first pass effect of the liver and its controllability is relatively poor.Transdermal drug delivery is a novel way of administration that can overcome the shortcomings of traditional ways.However,the barrier of the skin,especially the stratum corneum,makes it difficult for macromolecular drugs to pass the skin.Transdermal proteins(peptides),such as TD,SPACE,and TAT,provide effective carriers for macromolecules across the skin.Lately,studies have confirmed that SPACE can mediate the transdermal delivery of siRNA in the treatment of melanoma,but the related theoretical model has not been reported.In this thesis,a mathematical model is developed to describe the process in which siRNA mediated by SPACE-EGF reaches melanoma through the skin,induces the apoptosis of melanoma cells,and inhibits the growth of melanoma.The main contents are as follows:(I)The transport model of siRNA under the effect of SPACE-EGF was established,coupling the macroscopic processes of the siRNA diffusion in skin and melanoma with the microscopic processes of the adsorption,internalization,and degradation of siRNA.(2)The growth model of melanoma under the inhibition of siRNA was developed.In the model,melanoma cells are regarded as incompressible fluid,Darcy's Law is adopted to simulate the tumor boundary,and the effect of tumor growth on the skin morphology is considered.(3)The reliability of the model was validated with the experimental data in the literature.The tumor growth curve was simulated with the fitted proliferation rate of melanoma cells and the fitted relationship between the apoptosis rate of melanoma cells and the drug concentration.The simulated tumor growth curve agrees well with the experimental results.The results are summarized as follows:(?)In the skin,the diffusion depth of siRNA increases with time and the concentration of siRNA decreases along the depth direction;in the melanoma,the concentrations of siRNA at all points always increase with time,but the increase rates are different,causing the uneven drug distribution.(?)The growth of melanoma is significantly inhibited by siRNA.Due to the uneven distribution of siRNA,the inhibition in melanoma is also uneven.(?)The increase in either dosage or frequency can slow down the growth of melanoma.When either dosage or frequency is high enough,the size of melanoma will decrease after some days.When the time of administration is delayed,the inhibitory effect of the drug on the tumor will also be delayed.(?)When the tumor grows for some time and then shrinks,the skin will uplift first and then gradually restores.The model presented here is a useful tool to understand the whole process of the SPACE-EGF-mediated delivery of the siRNA to melanoma through skin,to predict the therapeutic effect,and to optimize the therapeutic strategy,providing valuable references for the clinical treatment of melanoma.