| Cancer,also known as cancer,second only to cardiovascular disease has risen to the second largest human "killer." Chemotherapy refers to the application of anti-cancer drugs to kill cancer cells in vivo,so as to achieve the purpose of treatment of cancer.The first class of drugs in human history has a sense of chemotherapy-mechlorethamine(nitrogen mustard)was born in 1942,for the treatment of lymphoma.Since then,a variety of different types of cancer drugs have been found to be in clinical research and,at the same time,research and development of chemotherapeutic agents also entered a stage of industrialization.Although chemotherapy on primary tumors,metastases and subclinical metastases have a therapeutic effect,but chemotherapy drugs in killing tumor cells,but also the normal cells and immunity(resistance)to kill cells together,so in a way that chemotherapy is a "crash and burn" method of treatment.Even in today's era of highly developed medical standards,chemotherapy still can not cure cancer,particularly in patients with advanced.So look for tumor-targeted chemotherapeutic drugs have become an efficient goal.Ideal macromolecular prodrug wherein: when drug entities does not reach the lesion site in an inactive form,and when the drug reaches the lesion sites entities release the active drug efficacy play,so not only improve the selectivity of the drug in the lesion site collection,reducing the drugs on normal tissues and organs of the toxic side effects,and can make the actual dose of the drug dose level close to the theoretical needs.In recent years,drug-loaded liposome system is considered one of the most promising targeting drug carrier,which has been widely studied and applied.The coated using linear PEG changing the charge and surface hydrophilicity of liposomes in the liposome surface so as to change liposome binding to plasma proteins,increasing the stability and circulation time of liposomes in vivo.To make PEG can be inserted into the liposome membrane,it needs to end with a hydrophobic group distearoyl phosphatidyl ethanolamine(DSPE)connection to prepare the amphiphilic molecules.Connected product DSPE-PEG.Vitamin E polyethylene glycol 2000 succinate(TPGS)is a water-soluble derivative of vitamin E by vitamin E succinate(VES)and the carboxyl group of polyethylene glycol(PEG)2000esterifying,TPGS for P glycoprotein inhibition,based on this,we use the DSPE-PEG2000/TPGS1000 polymer end load doxorubicin(DOX),DOX drug molecules will be wrapped into the micelle core to prepare a controlled molecular weight,particle size small,slow release,biocompatibility,proliferation of lung cancer cells have a strong inhibitory effect and endocytosis,in the blood circulation is effectively protected,micelles group longer than small molecule blood group cycle time,and exhibits good antitumor effect.In short,this simple prescriptions contained in the DOX DSPE-PEG2000/TPGS1000 end polymer micelle is an effective treatment for lung cancer,to a certain extent,to avoid rapid clearance of the drug in the blood,thereby increasing the efficacy of anti-cancer ideal drug delivery systems.Cancer metastasis and resistance to chemotherapy is a major obstacle to the treatment of cancer and lead to more than 90% of metastatic cancer treatment failure.DOX treatment can often prolong patient survival time,however,the cancer may eventually appear multidrug resistance in a considerable number of patients,lead to cancer recurrence,metastasis or death.Single administration is impossible successful treatment of cancer.Therefore,the combination of a variety of non-cross-tolerance anti-cancer drugs that are widely used clinically.Applications with a variety of drugs across different molecular targeted cancer gene barrier and delay the process of adaptation.Multiple drug targeting cellular pathways may be the same synergies,results in a higher therapeutic effect and the targeting selective.In short,to develop a combination of methods may enhance the anticancer effect of chemotherapy and overcoming intolerance is very critical.Curcumin(curcumin,CUR)is the main active ingredient of turmeric ginger plants,in addition to anti-cancer effects,but also resistance to DOX normal tissue toxicity and no significant long-term toxicity.Height of the development of nanotechnology in the field of new anti-cancer drug combination has opened up unprecedented opportunities.In our previous work,compared to small molecule drugs,the use of in vitro and in vivo tests DSPE-PEG2000/TPGS1000 polymeric micelles transmission anticancer drug DOX hasshown less toxicity and greater anticancer effect.And some studies have proved that the same nanoparticles load two kinds of anti-cancer drugs can enhance the anti-tumor and anti-metastatic efficiency.In fact,since the nanoparticles can guarantee the transmission of two or more therapeutic agents to a single cell,they can be well suited for the reversal of drug resistance.Therefore,in this study,by DSPE-PEG2000/TPGS1000 vector that is loaded with a load and has CUR+DOX polymer micelles.The effects of these two drugs with respect to drug use as the polymer alone or in combination with small molecule drugs,anti-tumor effect of their human lung cancer cell A549 and resistance to DOX-resistant A549(A549/ADR)two cell lines.This study provides a strategy of joint use of a polymeric carrier to achieve the combination therapy and chemotherapy medicine CUR of DOX.Determining the presence prove synergistic effect on A549 cells and MTT evaluate A549/ADR cells by two types of cells in vitro,which has also been supported from confocal microscopy to cells within the micelles swallow behavior.And polymer micelles common load CUR and DOX not only retard blood clearance rate,but also synergistic inhibition of cancer cell growth and proliferation,but also help alleviate the resistance.Therefore,this strategy is expected to be used in clinical treatment of cancer in the future,especially in patients resistant.In recent years,research and treatment of anti-tumor gradually become hot,especially in terms of screening anticancer drugs induce apoptosis has become a new direction,looking at the key targets of apoptosis,which is of great significance for cancer treatment.Pathogenesis of lung cancer cell proliferation and decreased apoptosis strong imbalance leads to proliferation and apoptosis is closely related to tumor growth is the result of the strong role of cell cycle factors,which is selectively expressed in the G2 phase of the cell cycle,and ultimately positioned on the mitotic spindle microtubules,so that by mitogenic achieve resistance to apoptosis.Apoptosis is through the terminal effector protease activated caspase-3 and caspase-7,the effect on DNA and cleavage,blocking cell mitosis proceeds,inhibits tumor growth.Many molecules mutate adjustment signal balance between life and death in precancerous cells,which is the key to the development of lung cancer.In lung cancer cells proapoptotic molecules physiological inactivation or downregulation,or excessive activation of anti-apoptotic signal,which is the cause of loss of normal cellproliferation and death balance.Therefore,selective inhibition of lung cancer cells in anti-apoptotic signaling pathway and new strategies to promote the expression of apoptotic signaling proteins in cancer therapy,for the treatment of lung cancer provides a viable and effective tool.According to the role of apoptosis Bcl gene family is divided into two,inhibit apoptosis and promote cell apoptosis.Bcl-2 anti-apoptotic mechanism is not fully understood,studies show possible causes are:(1)Bcl-2 gene prevents p53-induced apoptosis.Bcl-2 is apoptosis suppressor gene,p53 gene is the induction of apoptosis,overexpression of Bcl-2 can inhibit the p53-induced cell apoptosis,p53 can activate the expression of Bax transcription through direct and indirect suppression of Bcl-2.(2)affect cell membrane transport,changing the calcium ion distribution,cut regulate calcium activated enzymes and glutamyl transferase enzymes.(3)direct antioxidant effects,reactive oxygen species can damage DNA,protein damage,lipid oxidation.Bcl-2 antioxidant,inhibits apoptosis.(4)inhibition of pro-apoptotic protein Bax of cytotoxicity,Bcl-2 levels higher than the level of Bax,Bcl-2 and Bax heterodimer,inhibition of apoptosis.Conversely,when Bax was higher than the level of Bcl-2,is formed homodimer,induction of apoptosis.(5)prevented apoptotic protein caspase family of activation and inhibition of mitochondrial release of pro-apoptotic proteins,including cytochrome C,inhibition of mitochondrial release of pro-withered death protein,mitochondrial apoptosis and caspase family is the central link.Based on this,the third part of this experiment is contained CUR and DOX micelles for use in human lung cancer A549 cells,using protein blotting and immunohistochemistry assay for the protein Bcl-2,Bax expression to explore the nano carrier CUR and DOX Are micelle anti-tumor effects by influencing the expression of Bcl-2 family of proteins and thus the regulation of tumor cell apoptosis.It was found that contained CUR and DOX micelles inhibited the expression of A549 cells,Bcl-2 protein expression increased Bax protein.The possible reason for this is contained CUR and DOX micelles prevents apoptotic protein caspase family of activation,inhibition of cytotoxic pro-apoptotic protein Bax when Bax was higher than the level of Bcl-2,the formation of a homodimer induce apoptosis,and thus play an anti-tumor effect.But it is by affecting the expression or cytoplasmic Bax mitochondrial membrane,or byother means to play a role in the mechanism needs further study.Therefore,the load CUR and DOX micelles on A549 cell proliferation may Bcl-2,Bax protein expression and regulation related. |
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