Construct A Composite Carrier System With Efficient And Synergistic Effects Of Thermochemotherapy

Although chemotherapy has become the standard therapy for cancer treatment,the disadvantages of overly toxic side effects and inadequate targeting of chemotherapy are also important factors for long-term clinical application of tumor chemotherapy.At present,some basic studies have found that hyperthermia as an adjuvant therapy can significantly enhance the cytotoxicity of chemotherapeutic agents when used in combination with chemotherapy.Therefore,the combination of hyperthermia and chemotherapy is an effective method to improve the efficacy of cancer treatment,reduce the concentration of chemotherapy drugs,and reduce the side effects of chemotherapy.However,how to organically combine hyperthermia and chemotherapy so that they can efficiently target the tumor site is a key issue in determining the efficacy of thermochemotherapy.In order to solve the above problems,this paper proposes to combine the pH-responsive macromolecular prodrugs and superparamagnetic nanoparticles through self-assembly,so as to obtain magnetic composite prodrug micelles that can be combined with hyperthermia and chemotherapy.Among them,the pH-responsive macromolecular prodrug is an amphiphilic polymer obtained by coupling a cisplatin prodrug to a macromolecule via an ester bond.The pH-responsive macromolecular prodrug can encapsulate hydrophobic superparamagnetic nanoparticles in an aqueous phase by self-assembly to form magnetic complex prodrug micelles.When the magnetic composite prodrug micelles enter the blood circulation and reach the tumor tissue,the local acidic environment of the tumor tissue can lead to the cleavage of the ester bond,resulting in the cisplatin prodrug detachment from the macromolecule.Immediately afterwards in the tumor cells,the cisplatin prodrug was reduced to cisplatin acting on the tumor cells.At the same time,superparamagnetic nanoparticles can produce heat locally in the tumor under the action of an alternating magnetic field,thereby improving the cytotoxicity of cisplatin,and finally achieving the high-efficiency synergy between hyperthermia and chemotherapy in the tumor tissue.The specific research content is as follows:In the second chapter,polymer prodrug micelles were prepared and their physicochemical properties were characterized.In this chapter,we first prepared the two-block hydrophilic polymer mPEG-b-pHEMA through macromolecular RAFT reagent mPEG-DDAT to regulate the polymerization of monomer HEMA.In order to make the small molecule cisplatin contain groups that can be reacted,in this chapter,cisplatin was modified in two steps,first oxidized and then acidified to obtain a carboxyl group-containing Pt?IV?.on the basis of,Pt?IV?was coupled via an ester bond to the two-block hydrophilic polymer mPEG-b-pHEMA to give an amphiphilic macromolecularprodrugmPEG-b-p[HEMA-Pt?IV?].Theamphiphilic macromolecular prodrug mPEG-b-p[HEMA-Pt?IV?]can self-assemble in the aqueous phase to form a micellar structure with PEG as a hydrophilic shell,p[HEMA-Pt?IV?]is a hydrophobic core.Next we performed a series of characterizations of polymer prodrug micelles.We determined the cisplatin drug content in polymer prodrug micelles was 13.27?g/ml and the drug loading was 16.59%by Inductively coupled plasma mass spectrometry?ICP-MS?,demonstrating that the amphiphilic polymer mPEG-b-pHEMA has higher drug loading capacity.Through drug release studies,we have demonstrated that this polymer prodrug micelles can trigger rapid drug release through the hydrolysis of ester bonds under acidic conditions.The cisplatin macromolecule prodrug was successfully prepared in this chapter,and the controlled release of the drug was achieved,which laid a good foundation for the subsequent preparation of magneto-thermochemotherapy carriers.In the third chapter,magnetic composite prodrug micelles were prepared and their physicochemical properties were characterized.In this chapter,we prepared magnetic nanoparticles Mn_0.6Zn_0.4Fe₂O₄ with a diameter of about 8 nm.Characterized by transmission electron microscopy?TEM?,the particle size distribution of the superparamagnetic nanoparticles Mn_0.6Zn_0.4Fe₂O₄ was uniform and monodisperse in non-polar solvents.Through the vibration sample magnetometer?VSM?characterization,we can see that the hysteresis curve of Mn_0.6Zn_0.4Fe₂O₄ passed the origin,no remanence,superparamagnetism,and saturation magnetization is relatively high,reaching 74.6 emu/g.Then we will pack the superparamagnetic nanoparticles into the polymer prodrug micelles through self-assembly to obtain magnetic composite prodrug micelles.The content of superparamagnetic nanoparticles Mn_0.6Zn_0.4Fe₂O₄ in the magnetic composite prodrug micelles was 30.34%by means of thermal gravimetric analyzer?TGA?,and it was confirmed by drug release experiments that the coated magnetic nanoparticles had no effect on the release of the drug.In the fourth chapter,the synergy of thermochemotherapy of magnetic compound prodrug micelles was studied.Material cytotoxicity studies confirmed the mPEG-b-pHEMA,which constitutes a macromolecular prodrug,has good biocompatibility.The phagocytosis experiments confirmed that the cells were able to efficiently phagocytize the magnetic complex prodrug micelles and obtain cisplatin from them.The related curative effect study found that the magnetic compound prodrug micelles are mediated by hyperthermal chemotherapy can effectively inhibit the proliferation of tumor cells derived from three different tissues of MCF-7,A549and SKOV-3,and their therapeutic effects are significantly higher than those of hyperthermia and chemotherapy alone.In summary,the preparation of magnetic composite prodrug micelles can organically combine hyperthermia with chemotherapy,effectively inhibit the proliferation of multiple tumor cells,and achieve efficient collaboration between magnetic hyperthermia and chemotherapy.Since the magnetic composite prodrug micelles have improved drug solubility,good biocompatibility,no leakage of the drug during the transport process,and can achieve conditional release of the drug,this study provides a new research idea for the coordinated treatment of multiple tumor therapies.