Research On Combined Chemotherapy Based On Cell Cycle Regulation And Photothermal Therap

Chemotherapy is one of the common methods for the treatment of malignant tumors,but there are still some problems such as side effects and poor efficacy.Combination chemotherapy is widely used to overcome multi-drug resistance(MDR)and enhance the therapeutic effect of anti-tumor drugs.However,due to different physical and chemical properties,the pharmacokinetic properties of different drugs in vivo are different,which makes it difficult to achieve the optimal therapeutic dose of drugs in tumor tissue.The application of nanotechnology and the development of combined drug delivery systems can help to solve the above problems.Co-delivery nanocarriers can improve the solubility,stability and targeting of drugs,and combine the advantages of nanocarriers to better exert the synergistic effect of drugs,thereby reducing side effects.The occurrence,development and metastasis of tumors are closely related to the cell cycle.The combination of cell cycle regulators and chemotherapeutic drugs can amplify the DNA damage caused by chemotherapeutic drugs,thereby achieving chemosensitization and reducing the drug resistance of tumor cells.10-Hydroxycamptothecin(HCPT)is a commonly used chemotherapeutic agent in various tumor models.HCPT was constructed as a polymeric prodrug(keto-)p HCPT using thioketal bonds cleaved in response to reactive oxygen species(ROS).Hydrophilic polyethylene glycol(PEG)was grafted at both ends to construct(keto-)p HCPT-PEG.This polymer prodrug can self-assemble into micelles in water,and its hydrophobic cavity can be loaded with hydrophobic drugs.Demethylcantharidin(DMC)is a cell cycle regulating drug that can increase the sensitivity of tumor cells to HCPT by inhibiting the synthesis of protein phosphatase 2A(PP2A).In this thesis,a multi-drug co-delivery carrier was constructed using polymer prodrug-loaded micelles(keto-)Micelle loaded with DMC for tumor therapy.Studies have shown that the particle size of(keto-)Micelle@DMC is about 110 nm,the drug loading of HCPT is47.8%,and the drug loading of DMC is 4.3%,and it has a good ROS-responsive release rate.In vitro experiments confirmed that(keto-)Micelle@DMC could be effectively taken up by tumor cells.In in vivo antitumor experiments,(keto-)Micelle@DMC exhibited low toxicity and synergistic antitumor effects.Photothermal therapy combined with chemotherapy is a novel tumor treatment option.Photothermal therapy not only has the advantages of short treatment period and less toxic and side effects,but also can reduce the pain experienced by patients.Prussian blue(PB)is a photothermal conversion agent with easy synthesis,low biotoxicity,controllable structure and high photothermal conversion efficiency.In this paper,PB nanoparticles were etched into hollow mesoporous structure hollow prussian blue(HMPB)nanoparticles in acidic environment as photothermal conversion agent and drug carrier.The free radical drug 2,2-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride(AIBI)was encapsulated in HMPB through the phase-change material1-pentadecanol(Pent)to construct a drug-loading system HMPB@Pent/AIBI.When the temperature of the drug-loading system rose to 41 °C under laser irradiation,Pent(with a melting point at 41 °C)was heated and melted,and AIBI was controllably released into tumor cells.Elevated temperature can accelerate the cleavage of AIBI azo bonds to release free radicals,thereby inducing lipid peroxidation,protein denaturation,and DNA fragmentation in cells,achieving the combined anticancer effect of chemotherapy and photothermal therapy.The prepared HMPB@Pent/AIBI has good photothermal effect and photothermal stability.It has been confirmed by in vitro experiments that it has good biocompatibility and anti-tumor effect,and it is expected to achieve good results in in vivo anti-tumor research.In conclusion,effective drug loading and controlled release targeting complex tumor microenvironment are the research directions of co-delivery systems.Using nanotechnology to achieve precise and efficient combination chemotherapy is of great significance for the design of drug delivery and tumor treatment strategies.In summary,in order to solve the problems of toxic side effects,poor efficacy and multidrug resistance in cancer treatment,this paper adopts the regimen of cell cycle regulation combined with chemotherapy and photothermal therapy combined with chemotherapy.We prepared(keto-)p HCPT-PEG polymer prodrug carrier and HMPB multidrug delivery carrier.These two carriers have high drug loading rate and can achieve effective accumulation in tumor sites through long circulation in vivo and then controlled release in tumor cells to achieve precise and efficient combined chemotherapy.