Liver Cancer Specific Targeting System Used For Nuclear-Targeted Drug Carrier Transport In Vivo

Nuclear-targeted drug delivery system can release the anticancer agents which induce apoptosis of tumor cells mostly by oxidative DNA damage in the nucleus,and should be a promising strategy for cancer therapy.However,it is difficult for the nuclear-targeted drug delivery nanoparticles to enter nucleus because of many biobarriers.Therefore,the development of cell-nuclear-targeted intravenous drug delivery system is of significant importance.A Liver Cancer Specific Targeting Vehicles TLS11a-LB(liver cancer aptamer,TLS11a;lipid bilayer,LB)which can transport the Nuclear-Targeted Drug Carrier DOX/TATp-MSN(transactivator of transcription,TATp;mesoporous silica particles,MSN;doxorubicin,DOX)from the bloodstream to the tumor cell is synthesized.The whole press of achieving nuclear targeting was mainly divided into two steps:the first step is that TLS11a directed blood-to-cytomembrane targeting;the second step is that TATp directed cytoplasm-to-nuclear targeting.We have successfully developed a DOX/TLS11a-LB@ TATp-MSN nuclear-targeted drug delivery system which has significant antitumor effect in vivo.This study provides a new strategy for the application of the nuclear-targeted drug delivery system in vivo.Background:To release the anticancer agents which induce apoptosis of tumor cells mostly by oxidative DNA damage in the nucleus with the nuclear-targeted drug delivery system and provide a promising strategy for cancer therapy.Objective:To develop a cell-nuclear-targeted intravenous drug delivery system with DNA toxicity.Methods:A Liver Cancer Specific Targeting Vehicles TLS11a-LB which can transport the Nuclear-Targeted Drug Carrier DOX/TATp-MSN from the bloodstream to the tumor cell is synthesized.Firstly,we develop a novel nuclear-targeted nanodrug delivery system based on TAT peptide-conjugated MSNs(TATp-MSNs)that makes nuclear internalization and the release of the encapsulated drugs within the nucleoplasm easier.Secondly,a controlled releasesystem composed of MSNs with TLS11a-LB was been successfully synthesized.Therefore,the DOX/TLS11a-LB@TATp-MSN nuclear-targeted drug delivery system are expected to target nuclei of cancer cells and then deliver/release drugs into nuclei after passing through the cell membrane by such a cell-nuclear-targeted mechanism.The material structure characteristics of DOX/TLS11a-LB@TATp-MSN were examined by dynamic light scattering instrument(DLS),the Barrett,Joyner,and Halenda(BJH)method,Fourier transform infrared spectroscopy(FTIR)as well as Transmission Electron Microscope(TEM).The physiological function of DOX/TLS11 a-LB@TATp-MSN was tested by fluorescence microscope,flow cytometry and CCK-8 method in vitro.The distribution and the metabolism of DOX/TLS11a-LB@TATp-MSN were determine by the optical in vivo imaging system.The volume of tumor and the survival time of mice were also ovserved.Result:TEM image shows TLS11a-LB@TATp-MSN nanomaterial have an average diameter of about 100 nm,can clearly show the surface of the phospholipid bilayer(TLS11a-LB).Phagocytosis experiments showed DOX/TLS11a-LB @ TATp-MSN nanomaterials can be efficiently targeted to the cell nucleus interior of H22 tumor.DOX/TLS11a-LB@TATp-MSN show a slow and sustained rather than burst release of DOX was observed at physiological pH 7.4,which is proposed for tumor targeted drug delivery,as during the blood circulation,the drug loss must be as less as possible to avoid its side effects.DOX can be encapsulated into the.TLS11a-LB@TATp-MSN nanomaterial with a encapsulation efficiency of 83.3%.Cellular uptake examined by fluorescent microscopy and flow cytometry show that DOX/TLS11a-LB@TATp-MSN can significantly improved cellular uptake efficiency.A real-time imaging technique that show that TLS11a-LB@TATp-MSN was feasible to achieve long-term in vivo retention and superior tumor targeting.Frozen sections of tumor tissue showed DOX/TLS11a-LB @ TATp-MSN can be more efficiently distributed to the tumor and can significantly increase DOX accumulation in tumor.The DOX/TLS11a-LB@ TATp-MSN cell-nuclear-targeted drug delivery system can release drugs into nuclei,significantly improve the antitumor effect,inhibit the cancer growth and prolong the life time of tumor-bearing mice.Conclusion:The DOX/TLS11a-LB@ TATp-MSN cell-nuclear-targeted drug delivery system overcome the defect of DOX/TATp-MSN and provide a promising strategy for cancer therapy.