Study Of Breast Cancer Theranostics Based On Macrophage Repolarization And Modular Assembled Of Drug-SPIONs

Tumor-associated macrophages（TAMs）play a key role in the development,progression and metastasis of tumor.Activating macrophage-mediated antitumor effects through TAMs repolarization into M1 type has become a popular strategy in the field of cancer therapy.However,excessive M1 polarization of macrophages can cause systemic inflammation and promote tumour metastasis.On the other hand,based on the magnetic responsiveness and T₂ enhancement properties of superparamagnetic iron oxide nanoparticles（SPIONs）,the development of“theranostic agents”with both MRI imaging and drug delivery functions on the basis of SPIONs have become another research hotspot in the field of oncology.However,because the requirements of magnetic and contrast properties are not compatible with the dispersibility of the carrier,it has become a bottleneck in the development of integrated diagnostic and therapeutic agents.In this paper,TAMs were used as targets to screen and identify the effect of salinomycin（SAL）on macrophage polarization.Then,based on SAL,a set of drug-SPIONs-based magnetic theranostic system was constructed through modular assembly design,which solved the problem of incompatibility between drug delivery effect and MRI imaging performance.The specific content is as follows:Firstly,the activity of anticancer drugs such as paclitaxel,doxorubicin,sorafenib and SAL on macrophages was investigated through in vitro experiments.It was found for the first time that SAL can effectively promote the polarization of macrophages RAW264.7 to the M1-type.At the same time,the polarization of SAL on macrophages is time-dependent and dose-dependent,while other drugs did not show the same trend.Secondly,the effect and potential mechanism of intratumoral injection of SAL in the treatment of breast cancer 4T1 were investigated.The results showed that SAL exert an anti-tumor effect by inducing the differentiation of M1 macrophages.Meanwhile,the repolarization of SAL on TAMs did not induce systemic inflammation and reduced the lung metastasis caused by inflammation.On this basis,a magnetic targeting nanocarrier composed ofβ-cyclodextrin-modified SPIONs was designed and synthesized for SAL.Using the EPR effect of nanocarrier,intravenous SPIONs can deliver SAL to the tumor site,which produces better tumor therapeutic effect than free SAL.Finally,aiming at the inconsistent demands of theranostic agents in terms of water dispersion and drug loading,we used curcumin as a cross-linking agent to obtain SPIONs clusters（Cur/ALN-β-CD-SPIONs）by modular assembly of drugs and monodisperse SPIONs.Compared with monodisperse SPIONs,modular assembled products not only have significantly enhanced magnetic properties,but their T₂-imaging performance has also been significantly improved.Both in vivo and in vitro experiments showed good imaging performance and tumor suppression effect.Further,we investigated the targeting and tumor treatment effects of saln in the modularly assembled drug delivery system for 4T1 xenograft tumor.The results showed that the targeted vector could effectively deliver the TAMs activator to the tumor site,which leads to a better tumor treatment effect than free drugs.