The Application Of A Novel Anti-tumor Nano Drug-loading System In The Treatment Of Lung Cancer

Background:Lung cancer is the most common cancer worldwide and accounts for the most cancer caused death among all of the cancers.So far,operation is the most effective way to cure cancer.However,most patients are diagnosed in advanced stage and have no chance for operation.In this case,chemotherapy is the only way for treatment.It is demonstrated that chemotherapy is effective to lengthen the survival.Paclitaxel,one of the most important drug in the history of chemotherapy,has been included as the components of first-line therapy regimen in the treatment of Non Small Cell Lung Cancer.Nevertheless,the responsive rate of Ptx alone or in combination is less than 50%in clinic.In addition,Tetrandrine,a small molecule of Tranditional Chinese Medicine,has been proved in our previous study of its potential antitumor effect.Therefore,the problems that need to be solved in urgent are how to increase the effect of chemotherapeutics and lower the toxicity of cytotoxic drugs.Moreover,novel agents that possess potential antitumor effect are also warranted.Nano-drug delivery systems seem to be a feasible way to solve the problems with many advantages.For instance,drug loaded nanoparticles could increase the solubility of lipophilic drugs and lead to a sustained release,thereby strengthening the anticancer effect.Objectives:Two kinds of nano-drug delivery systems were prepared.First,we prepared Tetrandrine loaded nanoparticles with PVP-PCL by a nano-precipitation method.Second,we synthesized Ptx-SA based on the concept of Carrier free and prepared Ptx-loaded nanofibers with Ptx-SA as carriers.Then the physical characteristics of the two kinds of nano-drug delivery systems were evaluated such as median size,zeta potential,and in vitro release curve.In vitro and in vivo anti cancer effects were also studied to show the advantage of the two kinds of nano-drug delivery systems and lay a strong foundation for the future development of novel nano-drug loading system.Methods:Poly(N-vinylpyrrolidone)-block-poly(ε-caprolactone)(PVP-PCL)and Ptx-SA were synthesized by chemical methods.Then Tetrandrine loaded PVP-PCL nanoparticles and Ptx-SA nanofibers were prepared.The microscopic morphology of the two kinds of nano-drug delivery systems were studied by Transmission Electron Microscopy(TEM)and Scanning Electron Microscopy(SEM).The size and zeta potential were measured by Dynamic Laser scattering.The loading efficiency of the drug loaded nano-systems were examined by HPLC.In vitro cytotoxicity and in vivo antitumor efficacy were studied in lung cancer cells and xenograft models.Results:First,SEM and TEM images indicate that Tetrandrine loaded nanoparticles are spherical shape with smooth surface.The size of Tet-NPs is about 120 nm with the drug loading content being 18.2%.In vitro release study demonstrates the sustained release pattern and satisfied stability.In vitro uptake study shows that Tet-NPs are effective in entering the cells within the short period of incubation time.In vitro apoptosis test indicates that Tet-NPs are more effective in inducing the apoptosis than the equivalent dose of free Tet through stronger regulation of apoptosis related proteins.Moreover,the anti-metastasis effect of Tet-NPs are much more effective than the equivalent dose of free Tet by regulating MMP proteins.Second,SEM and TEM images indicate that the diameter of Ptx-SA nanofibers is about 30-40 nm with the length being 1-3 micrometer.In vitro release study demonstrates the effective controlled release pattern of Ptx-SA.In addition,uptake study shows that Ptx-SA nanofibers are effective in penetrating the cell membrane.In the part of in vitro cytotoxicity test,Ptx-SA is much more effective than the equivalent dose of free Ptx through regulating the expression of Akt pathway and apoptotic proteins.In vivo study demonstrates that Ptx-SA is much more effective in inhibiting the growth of tumor than the equivalent dose of free Ptx.Conclusion:The two kinds of nano-drug delivery systems reported in the current study show enhanced therapeutic effect in treating lung cancer when compared with free drugs.Therefore,the development of novel nano-drug delivery systems emerges as a novel field in designing new anticancer drugs,which merits intensive research with potential application.