Targeted Combined Therapy Of Breast Cancer Achieved By Polyethyleneimne-grafted Oxidized Mesoporous Carbon Nanospheres

Part 1 TKD peptide as a ligand targeting drug delivery systems to memHsp70-positive breast cancerBreast cancer has been considered as a serious threat to females’ life.Active targeting drug delivery is a potential strategy in cancer therapy,which however is hindered by the targeting efficiency.Herein,a 14-mer peptide(TKD)derived from the oligomerization domain of membrane heat-shock protein 70(memHsp70),for the first time,was exploited as a tumor-targeting ligand to modify polymeric micelles.NMR results demonstrated the successful synthesis of TKD-PEG-PLGA polymer.No difference was observed in the drug release between TKD-modified doxorubicin(DOX)-loaded micelles(TKD-D-M)and unmodified counterparts.The modification of TKD mediated apparently higher cellular uptake within memHsp70-positive MCF-7 cells,compared to normal MCF-10A cells.Excessive TKD pretreatment significantly inhibited the cellular uptake of TKD-D-M,indicating the receptor-mediated mechanism.Enhanced accumulation of TKD-D-M within the tumor of MCF-7 bearing mice further demonstrated the targeting ability of TKD in vivo.CCK-8 assay showed that the modification of TKD significantly increase the anti-proliferation effect against MCF-7 cells.The findings demonstrated that TKD peptide is a potential ligand which can target drug delivery systems to memHsp70-positive breast cancer.Part 2 Photothermal combined gene therapy achieved by polyethyleneimine-grafted oxidized mesoporous carbon nanospheresCombining controllable photothermal therapy and efficacious gene therapy in a single platform holds great promise in cancer therapy due to the enhanced combined therapeutic effects.Herein,polyethyleneimine-grafted oxidized mesoporous carbon nanospheres(OP)were developed for combined photothermal combined gene therapy in vitro and in vivo.The synthesized OP was characterized to have three dimensional spherical structure with uniformed diameter,ordered mesopores with graphitic domains,high water dispersion with zeta potential of+22 mV,and good biocompatibility.Consequently,OP was exploited as the photothermal convertor with strong NIR adsorption and the gene vector via electrostatic interaction,which therefore cannot only deliver the therapeutic gene(pING4)to tumors for gene therapy,but also can eliminate the tumors by photothermal ablation.Moreover,the improved gene therapy accompanied by the NIR photothermally enhanced gene release was also well achieved based on OP.The excellent combined therapeutic effects demonstrated in vitro and in vivo suggested the OP’s potential for cancer therapy.Part 3 Multifunctional polymer coated on odered mesoporous carbon nanospheres for targeted trimodel therapyIn the second part,the combined effect of gene therapy and PTT has been demonstrated to be of great significance in cancer therapy.Then doxorubicin(DOX)was loaded into the mesopores based on the well-developed surface chemistry of OMCN,such as abundant pores on the surface,tunable pore sizes and large surface area and pore volume.The negatively charged DOX@OMCN could electrostatically interact with positively charged PEI-PEG-TKD(PPT),which is a synthesized co-polymer by covalent bonding of PEI,PEG and TKD.The obtained DOX@OMCN/PPT(DOPPT)could pack therapeutic gene pING4 via electrostatic interaction for effective transcription and expression in MCF-7 breast cancer cells.Henceforth,in this work,OPPT not only served as a photothermal convertor and a gene carrier,but also a transporter of chemotherapeutics.This drug delivery system integrated triple treatments pathway of PTT,gene therapy,and chemotherapy in one platform for targeting cancer cells.Moreover,DOX release from OPPT indicated pH and NIR sensitive behavior,which is of great significance in controllable release triggered by microenvironment in tumor cells and external equipments.In vitro study verified the combination of the triple treatments exhibited more potent than any combination of two treatments.Therefore,the active target nanoplatform has superior potential in the development of cancer treatment.