Application Of Multiple Responsive Hydrogels In Combined Tumor Therapy Of Mild Photothermal And Chemotherapy

In recent years,photothermal therapy has attracted extensive attention due to its advantages of controllable space-time selectivity,minimally invasive treatment and high killing efficiency.However,due to the irregular shape and heterogenous characteristics of tumor and the limitation of light penetration depth,it is difficult to completely cure tumor with single photothermal therapy.In addition,the high temperature in photothermal therapy can also cause tissue damage and inflammatory reaction,which restricts the development of photothermal therapy.In this work,a series of nanohydrogels and hydrogels with various stimulus responsive properties were developed for drug delivery and cancer therapy.The hydrogel with p H,hypoxia,temperature and GSH stimuli-responisve properties was constructed as a multistage drug delivery system for mild-temperature photothermal and chemotherapy.First,the antivascular drug Combretastatin A4Phosphate(CA4P)was released to weaken the tumor cells.Then,the photothermal agents was released from the hydorgel and distributed uniformly in the lesions due to the low p H and hypoxia in the tumor area.Afterwards,the anticancer drug-loaded nanohydrogels were released because of the mild-temperature therapy for long-term chemotherapy.The specific content includes the following three parts:(1)Development and application of dual stimuli-responsive polyethylene glycol nanohydrogels.The direct preparation and multi-step preparation of polyethylene glycol nanohydrogels by different reflux precipitation polymerization methods were studied.The effects of different total amount of monomer and the presence of oxygen on reflux precipitation polymerization were studied.The effects of different content of reactants,initiator type and reaction time on click chemical reaction were explored.The results showed that the polyglycol m PEG-NG nanohydrogel prepared by multiple steps had good morphology and particle size of about 350 nm.The surface of m PEG-NG is electronegative,and it can adsorb THZ through electrostatic interaction,and has p H/GSH double stimulus response characteristics.Cell experiments showed that m PEG-NG were easy to be absorbed by cells,with good biocompatibility,low cytotoxicity and therapeutic effect on tumor cells after drug loading.(2)Preparation and application of europium fluorescence nanohydrogels with dual stimulation.Fluorescence nanohydrogels containing Eu(Ⅲ)were prepared by traditional reflux precipitation polymerization method.The particle size was about 500 nm.Under 405 nm laser irradiation,fluorescence imaging of Eu-NG could be observed.The surface of Eu-NG was electronegative.DOX,a positive anticancer drug drug,could be loaded by electrostatic interaction.Eu-NG had good biocompatibility and showed obvious killing effect on tumor cells after loading DOX.This study expands the application of reflux precipitation polymerization in the development of fluorescent nanomaterials.(3)Development of multiple response hydrogel drug delivery system and its application in mild-temperature and chemotherapy.The hydrogel was successfully prepared by the schiff base reaction between the amino group in four-arm polyethylene glycol-amine and the aldehyde group in four-arm polyethylene glycol-aldehyde.The hydrogel could be degraded in low p H environment.The hydorgel was successfully prepared by the host-guest interaction between PEG chain polymer and α-cyclodextrin or polyethylene glycol nanohydrogels and α-cyclodextrin.The hydrogel formed by host-guest interaction underwent gel-solution phase transition at higher temperature.Based on the research of single stimuli-response hydrogel,multiple stimulus-response hydrogel(NMHG)was constructed for mild photothermal and chemotherapy to achieve good tumor inhibition effect.The NMHG hydrogel exhibited multiple stimulus response behaviors such as temperature,p H and hypoxia stimuli,also showed good biocompatibility and low cytotoxicity to cells.Moreover,the NMHG hydrogel loaded with CA4 P exhibited a significant inhibitory effect on the growth of tumor vessels.The suppression time of tumor treatment by starvation therapy alone was limited.The combination therapy of NMHG loaded with anticancer drug THZ under NIR showed better inhibition of tumor cell activity.