Preparation And Evaluation In Vitro Of Three Kind Of Hrbird Nanoparticles Against Drug Resistant Tumor Cell MCF-7/ADR

Tumor multi-drug resistance?MDR?is a common phenomenon where cancer cells become resistant to the cytotoxic effects of various structurally and mechanistically unrelated chemotherapeutic agents.Once the MDR occurred,the tumor cells c an remove drugs from the interior of the cell to reduce drug accumulation and the sensitivity of tumor cells to drugs was significantly decreased.Therefore,development of MDR is a major obstacle to the success of cancer chemotherapy.An attempt to overcome MDR in cancer chemotherapy is to co-administered a specific anti-MDR agent along with the anticancer drug to increase the drug accumulation and improve treatment efficacy.Curcumin has selective toxicity on many cancer cells with extensive antitumor effects and tumor multidrug resistance reversal superiority,it can acts as a mediator of chemoresistance by sensitizing cancer cells to conventional chemotherapeutic agents.Here,we directly incorporated curcumin into a disulfide-linked hydrophobic backbone of PEGylated amphiphilic diblock copolymer.Moreover,we introduced biotin into this copolymer as an active targeting ligand to the over-expressed biotin receptor widely found on cancer cell surface.This amphiphilic material defined as Biotin-PEG-PCDA can assemble into stable core-shell nanoparticle?NP?,which could be used as nanocarrier to load anticancer drug paclitaxel,then the chemotherapeutic agent and chemosensitizer can be delivered into the same cell at the same time.The hydrophobic core being made up of PCDA can be readily degraded at intracellular GSH-rich reduction environment,thus,co-releasing its active pharmaceutical ingredient?curcumin?and load ed drugs?PTX?into cell.Curcumin could downregulate the expression of P-gp,which can increase PTX accumulation within the cells,thus,may amplifying PTX induced cytotoxicity of drug-resistant MCF-7/ADR cells.Therefore,we expect such kind of drug combination would beneficial to combat cancer MDR.While,drug itself is demanded to act on cancer cells effectively,how it can reach targeted tissue is also need to be discussed.Delivering drugs to the tumor specifically is more selective than traditional systemic treatment.The high drug concentration around tumor cells with the result of reducing harmful effects on healthy cells is the key point for successful anti-tumor therapy.In order to achieve such requirement,besides the targeting biotin,we loaded magnetic Fe₃O₄ particles into the hydrophobic cavity of Biotin-PEG-PCDA nanoparticles.The guiding effect of magnetic particles enhanced the tumor-targeting efficiency of the multifunctional systems by driving them to concentrate on the tumor site with a external magnetic field.Next,in order to prove that particles had entered tumor cells under the guiding effect,we choose Quantum dots CuInS₂/ZnS as an imaging probe to be incorporated into hybrid particle simultaneously,to track the location of this medicine system.In this paper,an biotin modified and intracellularly degradable amphiphilic block copolycurcumin?Biotin-PEG-PCDA?,which could assemble into stable core-shell nanoparticle,was used as efficient carrier for hydrophobic PTX,MNPs and QDs delivery.These hybird nanoparticles,PTX/MNPs@Biotin-PEG-PCDA?PTX/QDs@Biotin-PEG-PCDA and PTX/MNPs/QDs@Biotin-PEG-PCDA could keep their structural integrity at physiological condition.PTX/MNPs@Biotin-PEG-PCDA and PTX/MNPs/QDs@Biotin-PEG-PCDA can be efficiently uptaken by the tumor cells due to the combined effect of magnet field guided nanoparticle concentration and biotin receptor-mediated internalization,which further lead to the cleavage of disulfide bonds of PCDA at intracellular GSH-rich reduction environment,thus releasing curcumin and PTX payloads.The curcumin,a P-gp inhibitor,could increase PTX accumulation within the cells,thus improving the therapeutic efficacy of nanoparticle comparing with free drug for treatment of drug-resistant MCF-7/ADR cells.Meanwhile,PTX/QDs@Biotin-PEG-PCDA and PTX/MNPs/QDs@Biotin-PEG-PCDA can be detected by equipment to track the route of drugs.Therefore,combination of MNP/biotin-mediated targeting and curcumin-mediated overcoming MDR efforts,these nanoparticles are expected to provide a promising approach to combat tumor drug resistance...