Camptothecin Loaded Positive Phase Thermosensitive Micelles For Combined Photothermal-Chemotherapy Of Cancer

Micelles are a kind of nano-carrier composed of hydrophobic core and hydrophilic shell which have good thermodynamic stability and can be used as a carrier system for many hydrophobic anticancer drugs.The positive phase thermosensitive micelles are micelles with upper critical solution temperature?UCST?.When the temperature rises to the critical temperature,the thermosensitive micelles can be disassembled to release drug quickly.Photothermal therapy?PTT?is a minimally invasive tumor technology developed in recent years that can achieve fixed-point killing and greatly reduce systemic toxicity.Fe₃O₄ nanoparticle is a photosensitizer with low toxicity,high photothermal conversion efficiency and good photothermal stability in PTT.A single treatment method fails to achieve the desired anti-tumor effect.The combination of two treatment methods can improve the therapeutic effect,so as to achieve the maximum effect of cancer treatment.In this study,a UCST-type thermosensitive compound micelle Fe₃O₄@PAAP based on Fe₃O₄ nanoparticles and the amphiphilic polymer poly?AAm-co-AN?-g-PEG?PAAP?was prepared.CPT-Fe₃O₄@PAAP was loaded with CPT by dialysis method.Fe₃O₄ nanoparticles could generate heat under irradiation of near-infrared light?NIR?and thermosensitive micelles could be disassembled when the phase transition temperature was reached to promote the rapid release of CPT,so that the combined photothermal-chemotherapy could be realized and the toxic side effects during drug delivery could be avoided.Concrete study content as follows:In the second chapter,the oil-soluble Fe₃O₄ nanoparticles and amphiphilic polymer PAAP were prepared by high temperature thermal decomposition and reversible addition-fragmentation transfer?RAFT?method,respectively.The Fe₃O₄@PAAP thermosensitive micelles were formed by ultrasonic self-assembly method,then related characterizations were conducted.The results showed that the prepared Fe₃O₄@PAAP micelles with a sphere-like shape,a particle size of about 150nm was thermosensitive.UCST was about 43°C and it had a superparamagnetic property which was used for magnetic targeting and magnetic resonance imaging at a later stage.The whole blood of healthy ICR mice were taken to examine the hemolysis of Fe₃O₄@PAAP which showed that the blank carrier had good biocompatibility.MCF-7 cells were selected as a model to investigate the cytotoxicity of Fe₃O₄@PAAP and the results showed that the blank carrier had no significant toxicity.In the third chapter,the hydrophobic drug CPT was loaded on Fe₃O₄@PAAP by dialysis method.The photothermal properties of Fe₃O₄@PAAP were investigated in vitro which had a good photothermal effect and the photothermal properties was stable.By comparing the results of drug release triggered by NIR at different pH values,it could be seen that Fe₃O₄@PAAP had a NIR response release function which can achieve rapid drug release.Cellular experiments showed that CPT-Fe₃O₄@PAAP could be uptaken by cells through the lysosomal pathway and CPT was released into the nucleus triggered by NIR.For the study of cytotoxicity of CPT-Fe₃O₄@PAAP in vitro,it was found that the hyperthermia and chemotherapy alone had no significant effect on cell killing but the combination of photothermal-chemotherapy could significantly improve the therapeutic effect.In the fourth chapter,S180 tumor-bearing mice were used as a model to study the effect of CPT-Fe₃O₄@PAAP combined therapy in vivo.Fe₃O₄@PAAP micelles were marked with ICG to investigate the distribution and the photothermal effect was observed under NIR irradiation in vivo.The results showed that the carrier can accumulate at the tumor site and maintain a long time,at the same time,it had good photothermal effect in vivo.The antitumor effect in vivo showed that the combination of photothermal-chemotherapy with CPT-Fe₃O₄@PAAP was significantly superior to the effects of simple hyperthermia and chemotherapy.After 2 weeks of treatment,the tumor almost disappeared.Histopathological analysis showed no influence on normal tissues during the treatment.