Iron Oxide Self-Assembled Nanocomposites For Application In The Brain Glioma Theranostics

Magnetic hyperthermia therapy(MHT)is tumor treatment in which magnetic materials are used in high frequency alternating magnetic fields(AMF)to convert magnetic energy into heat energy via Néel-Brown relaxation,thus increasing focal site temperature to induced cell death.Due to the excellent tissue penetration,non-invasiveness,injury-free,and availability of remote control,it is a promising clinical treatment for deep tumors.Superparamagnetic iron oxide nanoparticles(SPIONs),the magnetic materials that are the most widely studied magnetocaloric reagents,have the characteristics of adjustable size and shape,simple synthesis,high specific surface area,easy modification and low toxicity.However,the application of MHT for SPIONs is restricted to some extent due to the poor magnetothermal effect of single disperse particles and the limited efficacy of single MHT.Therefore,the physical and chemical properties of prepared SPIONs still need to be further optimized.In view of this,SPION composite material are constructed by means of self-assembly,which overcome the disadvantages of existing SPIONs as magnetocaloric reagents,and can be used to enhance the effect of tumor MHT.By using the construction strategy of self-assembly enhanced magnetothermal properties,SPIONs coated with chemotherapeutic drugs,photoacoustic molecules and surface modified with temperature-sensitive agents were transformed into SPION composite material,which could be used as an integrated magnetocaloric reagents in the theranostics of glioma.The main research contents and results are summarized as follows:(1)In order to solve the problem of poor magnetothermal effect of monodisperse SPIONs and to prevent excessive magnetothermal effect,a SPION composite material sensitive to temperature was constructed by O/W emulsion self-assembly method to improve the magnetothermal effect.By characterizing the physical and chemical properties of SPIONs with different sizes prepared by high temperature thermal decomposition and self-assembled SPION composite material with different sizes,SPION composite material was designed with more suitable size,excellent magnetic thermal heating effect,and at a certain temperature(43 ~oC),which can be dissociated and prevent excessive magnetic heat.The magnetothermal heating efficiency reaches 5.7 times that of the monodisperse SPIONs,which proves that the SPION composite material that has been developed can be used as a magnetocaloric reagents for MHT.(2)In order to investigate the long-term safety of SPIONs in vivo,the subcellular distribution and metabolism of SPIONs modified with different functional molecules were explored.By qualitative and quantitative comparison of subcellular structure distribution,blood circulation and removal of SPIONs in major organs(heart,liver,spleen,lung,kidney)and brain regions(temporal lobe,cerebral cortex,thalamus,brainstem,substantia nigra)of rats under different administration modes and different modifications,it was verified that SPIONs modified by bovine serum albumin(BSA)have better biocompatibility than those modified by polyethylene glycol(PEG).Especially when used in the brain,SPIONs modified by bovine serum albumin(BSA)can better enter cells and interact with organelles,and BSA promotes SPIONs proliferation and metabolism.This work lays a foundation for further research on SPION composite material and its clinical application.(3)In view of the poor effect of single-use MHT tumors,the developed SPION composite material with efficient drug loading function was used for drug delivery combined with MHT to improve its role in tumor theranostics.The prepared SPION composite material could track the accumulation and drug release of SPION composite material in tumor under the guidance of Near-Infrared II Window(NIR-II)Photoacoustic(PA)imaging,and precisely guide tumor chemotherapy-MHT,reducing side effects on healthy tissue.The composite material can efficiently carry the chemotherapy drug Doxorubicin(DOX).The distribution of the composite material in the tumor was monitored by NIR-II PA imaging.When the concentration difference of SPION composite material between the tumor area and normal tissue reached the maximum,MHT was activated,then,the local temperature increase at the focal site triggered the rapid dissociation of the thermosensitive agent and released DOX,which led to the combination of chemotherapy and MHT,thus achieving precise treatment and improving the efficacy.Compared with monodisperse SPIONs,the composite material has a shorter magnetothermal treatment time,and when combined with chemotherapy,the rate of tumor inhibition can reach as high as 90%.This indicates that SPION composite material can be used as an integrated magnetocaloric reagents for tumor theranostics.(4)Convection-enhanced delivery(CED)can effectively overcome the problem of the effective delivery of drugs inhibited by the blood-brain barrier(BBB)in brain glioma,but the diffusion of the drugs and the real-time monitoring of the therapeutic efficacy of local-delivered drugs still need to be solved.The SPION composite material was delivered into the brain of mice with in situ glioma by CED drug delivery method,and the spread of the drug in the brain and the therapeutic effect of in situ glioma were monitored by NIR-II PA imaging.Under the guidance of NIR-II PA imaging,the tumor inhibition rate of glioma combined with MHT and chemotherapy reached over 90%,and the survival time of mice was more than doubled.This proves that SPION composite material has a good application prospect in the theranostics of in situ glioma.