| The chemotherapy of cancer is one of the most effective methods used in the clinical treatment of cancer currently.However,the traditional chemotherapy method is a kind of systemic treatments with poor specificity,which will produces serious toxicity and side effects.With the development of nanotechnology,people find that nanoparticles can be used for drug delivery to protect the drug activity and improve the efficacy of drug.Meanwhile,people also realize that it is difficult to achieve desired effect of cancer treatment only rely on the passive targeting of nanoparticles.The undecorated nanoparticles can increase the drug concentration in cancer cells partly,however,on the one hand,there is still a large number of drug can not be uptaken by cancer cells,on the other hand,it is hard to deliver drug to the acting site after endocytosis of cells,both of which tend to reduce the effect of treatment.In order to increase the drug concentration of anti-cancer drug in the tumor cells and improve the anti-cancer efficiency,a series of active targeting nanoparticles for drug delivery have been exploited.Along with the development of nanotechnology of targeting nanoparticles and the in-depth study of drug acting sites,the precision of drug delivery has been gotten more and more attention,while many suborgan-targeted nanoparticles have been synthesized for the treatment of cancer.In this paper,sevel kinds of mitochondrial targeting nanoparticles were designed and synthesized,which can be used to deliver drug that can induce cells apoptosis through the damage of mitochondria in cancer cells.The main research includes:Chapter 1 mainly introduces the current situation of cancer treatment,and the research progress of targeting nanoparticles acting on different targets.This chapter also focuses on the application and disadvantages of new suborgan targeting nanoparticles in cancer treatment.In chapter 2,we prepare a kind of mesoporous iron-oxide nanorods(MNRs),while mitochondrial targeting polymer TPP-PEG-NH2 is synthesised and decorated on to the surface of MNRs to form TPP-PEG-MNRs.ATO is loaded into the mitochondrial targeting TPP-PEG-MNRs.The appearance and morphology of nanoparticles are characterized by infrared,transmission electron microscopy,dynamic light scattering and so on.The toxicity of ATO-MNRs to human breast cancer MCF-7 is evaluated by MTT and flow cytometry.In addition,CLSM is used for observing the localization of nanoparticles in the cancer cells and confirming the enhancement of mitochondrial targeting of nanoparticles.The release of cytochrome c,caspase-3 and caspase-9 in the cancer cells are also measured,and all results show that ATO@TPP-PEG-MNRs increase the cells apoptosis by enhancing the mitochondrial damage.In the chapter 2,we can find that the toxicity of ATO to cancer cells can be significantly enhanced when ATO is deliverd into the mitochondria in vitro.However,once mitochondrial targeting nanoparticles entrance into the body,the highly positive surface charge of TPP-containing nanocarriers lead to rapid clearance in blood and decrease accumulation in tumor tissue after i.v.injection,which limite the application in vivo.In order to eliminate the negative effects of TPP groups,in the third chapter,we have successfully developed a strategy for improving the anticancer efficacy of paclitaxel via redox-triggered intracellular activation of mitochondria-targeting in vivo.The positive charges of TPP in PLGA/CPT/DSSP are shielded by the longer PEG4000 chains coated on the surfaces of LPNPs outside the cancer cells.The loss of highly positive charge in PLGA/CPT/DSSP is advantageous to prevent the nanocarriers from the rapid clearance from the bloodstream after injection,which ensures the high accumulation of PTX-loaded LPNPs in tumor tissue.After entrance into cancer cells,the mitochondria-targeting of PTX-PLGA/CPT/DSSP is activated by detachment of DSSP under intracellular reduction conditions to enhance mitochondria-targeting,mitochondria dysfunctions and anticancer effect.This kind of activatable mitochondria-targeting nanoplatform,combining the advantages of the EPR effect and mitochondria-targeting of nanocarriers in drug delivery,has showed great potential in the delivery of PTX for cancer treatment with high efficacy.The nanoparticle size,surface charge and other properties of the nanoparticles are characterized by a series of characterization methods.The change of surface charge of nanoparticles under the condition of high concentration of GSH is also observed.The anticancer results of PTX-loaded nanoparticles in vivo show that the activated mitochondria-targeting nanoparticles can effectively solve the adverse effects of the high positive charge of the traditional mitochondrial targeting nanoparticles in systemic circulation,and can significantly improve the anti-cancer efficiency of the anticancer drugs in vivo.In the third chapter,the synthesis of activable mitochondrial targeting nanoparticle can increase the concentration of drugs in the mitochondria of cancer cells.However,in the blood circulation,it is finitely that nanoparticle accumulate in tumor sites only through EPR effect.It can be deduced that majority of drug can not entrance into the cancer cells,which led to serious side-effects.To improve the efficacy of anti-cancer drugs,we designe and synthesize a novel dual-targeting nanocarrier by introducing targeting group of cancer cells on the surface of activable mitochondrial targeting nanoparticle.Different from the traditional dual-targeting nanoparticles,the targeting of this new carrier is defined as programmed targeting.There is no interference between cellular and subcellular targeting,cell-targeted polymer DSPB not only introduce cancer targeting,but also effectively solve the problem of the highly positive charge caused by mitochondrial targeting group TPP.Through the results of in vitro and in vivo anticancer experiments,we find that this programmed dual-targeting nanoparticles exhibit good effect of anti-cancer.We think this programmed dual-targeting nanoparticle is a potential drug delivery system of the clinical anti-tumor treatment in the future. |
PDF Full Text Request