Application of Inorganic Metal Nanoparticles in Tumor Microenvironment

Author:Zhang Chao

Supervisor:hu yong


Degree Year:2019





With the advance of medical technologies,the five-year survival of tumor patients has been improved.However,the cure rate of most tumors,especially those in advanced stage,is far away from satisfied.Tumor is not only a macroscopical mass,but is a complex tissue involving extremely complex microenvironment components.Diverse factors contribute to the tumor microenvironment,including endothelial cells,pericytes,cancer-associated fibroblasts,inflammatory cells,soluble growth factors and their receptors,collagen,elastin,microfibrin,and proteoglycans.Vascular abnormalities,hypoxia,acidic pH,autophagy and metabolic changes exist in tumor microenvironment compared with normal tissues.Tumor treatment,recurrence,infiltration and metastasis all could be influenced by the tumor microenvionment.It reduces the therapeutic effect of tumor treatment through inhibiting the drug efficacy,limiting immune cell infiltration of tumors,and accelerating tumor recurrence and metastasis.In this paper,a series of multifunctional inorganic metal nanoparticles were designed for improving the tumor microenvironment and therapeutic efficacy.The purposes of this study were as follows:(1)Considering the low efficiency of photodynamic therapy for tumors under hypoxic microenvironment and tumor recurrence due to further consumption of oxygen during photodynamic process,we tailor-made multifunctional Bi2WO6 NPs.These Bi2WO6 NPs could effectively convert water to·OH in aqueous solution under laser irradiation without oxygen,thereby killing tumor cells and effectively destroying solid tumors.This therapeutic strategy provides a novel direction in non-oxygenated PDT.Bi2WO6 NPs contained high atomic number W(Z=74)and Bi(Z=83).Hence,they exerted excellent CT imaging capabilities with a guidance value in PDT.In addition,Bi2WO6 NPs could convert laser energy into heat due to their strong localized surface plasmon resonance,which is beneficial to eliminate tumors by photothermal therapy(PTT).To the best of our knowledge,this was the first attempt to develop multifunctional nanoparticles integrated capabilities of CT imaging,PTT and oxygen-free PDT.We believed that this novel system could overcome the problem of PDT-aggravated tumor hypoxia,showing a promising role in clinical application.(2)Excessive production of ROS is observed in tumor tissues relative to normal ones,and the degree of autophagy differs a lot as well.At the early stage of tumorigenesis,autophagy helps to eliminate mutant cells.With the process of tumor progression,autophagy gradually becomes the accomplice to further deteriorate tumor development and provides energy for tumor growth.Hence,autophagy exerts a decisive influence on therapeutic efficacy of tumors.It is of great significance to monitor autophagy during the tumor treatment.Currently,in vivo monitoring of autophagy is only performed in high-cost transgenic animal models.Here,we proposed an autophagy response magnetic resonance imaging based on free radical conjugated magnetic nanoparticles for monitoring the dynamic changes of autophagy in tumors in vivo.In the absence of autophagy,both NO free radicals and Fe3O4 NPs are stable and contribute to the observation of enhanced T1 and T2-weighted imaging.Accompanied by excessive production of ROS,autophagy quenches the T1 signal of NO·.On this basis,dynamic process of autophagy is monitored by the ratio of T1-signal intensity to that of T2-signal.It is found that magnetic hyperthermia of Fe3O4-NO·NPs induces autophagy,providing energies for tumor survival.Administration of autophagy inhibitor markedly influenced the therapeutic effect of magnetic hyperthermia on tumors.Our study provided a viable strategy for monitoring ROS-related autophagy in vivo,which elucidated the potential effect of autophagy on tumor treatment.(3)Currently,immunotherapy is one of the most effective and preferred methods for tumor treatment.It inhibits tumor recurrence,regeneration and metastasis by acting on immune cells in the microenvironment.Nevertheless,hypoxia in tumor microenvironment induces immunosuppression by inhibiting T cells translocating into tumors.Meanwhile,tumor hypoxia is proved to accelerate the accumulation of bone marrow-derived suppressor cells(MDSC)in the tumor microenvironment.Here,multifunctional PM-BiW NPs were designed to achieve the goals of active targeting,cascade release and cascade RT sensitization,exerting a particularly decisive role in the treatment of primary tumors.Notably,RT-induced tumor hypoxia was remarkably reversed by PTT/PDT treatment,which sufficiently downregulated ENTPD2-mediated MDSC and successfully recruit cytotoxic T lymphocytes to inhibit tumor recurrence and metastasis.Our research provides a great hope for improving current immunotherapy and improving the prognosis of patients with tumor metastasis.