| Cancer is one of the most malignant diseases in the world.Its complicated pathogenesis has brought great difficulties for treatment.Nanocarrieris regarded as one of the most promising delivery methods of chemotherapeutic drugs in the field of tumor therapy.The ideal nanocarrier should not only effectively promote the delivery of drugs in blood and accumulation in tumor tissue,but also make an appropriate response to the tumor microenvironment and external stimulation,so as to realize the controllable release of drugs.According to environmental factors,stimuli can be divided into endogenous stimuli and exogenous stimuli.Endogenous stimulation mainly comes from the physiological characteristics with obvious differences between tumor tissue and normal tissue,including p H,enzymes,reactive oxygen species,and so on.Exogenous stimulation comes from controllable external factors,including temperature,light,sound,magnetism,and so on.Based on this,secretory phospholipase A2(s PLA2),tumor acidic microenvironment,and near-infrared(NIR)light were selected as stimulation sources to prepare a series of stimuli-responsive nanomedicines.Secondly,erlotinib,as a common and widely used chemotherapeutic drug in clinics,can play a synergistic effect with various chemotherapeutic drugs.Therefore,this study established the combination system of erlotinib and nanomedicine,analyzed the inhibitory effects of different administration methods on the tumor,and discussed its application potential as a combined therapeutic drug in anti-tumor therapy.The specific research contents are summarized as follows:1.Hydrogenated phosphotidylcholine(HSPC)was selected as the s PLA2 response substrate to prepare doxorubicin(DOX)-loaded s PLA2-responsive liposomes and nanomicelles,and the optimal reaction temperature,time,and raw material composition were discussed.The results showed that the content of HSPC and the concentration of s PLA2 would affect the drug release rate.DOX could be effectively released from the carrier under the hydrolysis catalysis of s PLA2 and showed antitumor activity.The combined effect of erlotinib and DOX is affected by the sequential administration.Adding erlotinib at least 4 hours before DOX can significantly improve the cytotoxicity of DOX,so that the chemotherapeutic drugs can show a good antitumor effect at lower concentration.2.Polymer-DOX conjugated drugs were synthesized by using acid-sensitive hydrazone bond as a p H-responsive group.Due to the amphiphilic nature of polymer adriamycin,it can self assemble to form nano micelles,and encapsulte the hydrophobic drug erlotinib in the hydrophobic core of the micelles.In the acidic tumor microenvironment,the hydrolysis of hydrazone bond leads to the destruction of the micelle structure,and the release rate of erlotinib is faster than that of DOX from the polymer.Comparing the antitumor effects of conjugated drug micelles at different p H,it was found that the results showed p H and concentration dependence.Sequential administration significantly improved the antitumor activity of the drug.3.Indocyanine green(ICG),a NIR fluorescent reagent approved for clinical use,and erlotinib are selected to assemble together.Based on the amphiphilic characteristics of ICG structure,it can be used to encapsulte erlotinib and form nanoparticles without polymer carrier.By comparing the cell survival rate and live/dead staining results,it was found that the nanoparticles could not only exert the photothermal effect under NIR light irradiation but also significantly improve the antitumor effect.Therefore,a series of stimuli-responsive nanocarriers were prepared in this study,which can respond to s PLA2 overexpressed in the tumor microenvironment,acidic p H,and external NIR light,thus release the loaded drugs and exert the anti-tumor effect.Exploring the drug combination effect and sequential administration effect of erlotinib,it is expected to further improve the antitumor effect of nano drugs in the mode of administration. |
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