Synthesis Of Oxygen-generating Nanomaterials And Its Application In Cancer Diagnosis And Treatment

Cancer threatens public health severely.Although cancer treatments used in clinic including surgical resection,radiotherapy and chemotherapy can postpone the progression of cancer to a certain extent,there are also many defects,such as unclean surgical resection,severe side effects caused by chemotherapy and radiotherapy,recurrence after surgery etc.Photodynamic therapy（PDT）,as an emerging effective treatment for cancer,has attracted extensive attention of researchers in recent years,which utilizes photosensitizers to generate singlet oxygen under photoactivation to kill cancer cells.Compared with traditional tumor treatments,PDT with minimally invasive,low toxicity,and superior selectivity has good application prospects for tumor treatment.However,hypoxia,as an intrinsic feature of solid tumors,greatly restrains the efficacy of photodynamic therapy.To address the above problem,we have prepared a DOX/Ce6-loaded dual-layer inorganic nanoparticles（H-PDA@Mn O₂@RGD-Ce6/DOX）.This delivery system utilizes hollow polydopamine（H-PDA）to act as inner shell,and then is sequentially coated with manganese dioxide（Mn O₂）and modified with targeted cyclic peptides（RGD）followed by loading Ce6 and DOX simultaneously.The prepared nanoparticles can realize the accumulation in tumor tissues via the active targeting effect of RGD.Once under lower p H and peroxides of the tumor microenvironment,Mn O₂ degrades to generate O₂ and Mn²⁺accompanied with releasing the encapsulated DOX and Ce6.The released O₂ is converted by Ce6 to produce singlet oxygen under the near-infrared laser irradiation（660 nm）.Taken together,the singlet oxygen and the released DOX kill cancer cells significantly,achieving the highly-efficient cancer therapy.In addition,Mn²⁺generated from Mn O₂can also be directly used for T1 real-time magnetic resonance imaging（T1-MRI）.The nano-system that integrates PDT,traditional chemotherapy and T1-MRI real-time imaging as a theranostic agent for tumor treatment has promising potential in future clinical applications.The research content of this paper is mainly divided into the following two parts.1.Synthesis of Oxygen-generating Nano-system H-PDA@Mn O₂@RGD-Ce6/DOX and In Vitro Study of Combination TherapyIn this chapter,we use the stober method to synthesize Si O₂ nanoparticles.Dopamine is oxidized and polymerized on its surface to form polydopamine（PDA）nanospheres with shell-core structure.The Si O₂ is etched and removed with hydrofluoric acid to form a PDA hollow shell followed by coating Mn O₂on its surface reduced by potassium permanganate under ultrasound to form H-PDA@Mn O₂nanoparticles.H-PDA@Mn O₂@RGD is prepared by mixing SH-PEG-RGD with H-PDA@Mn O₂,and then H-PDA@Mn O₂@RGD-Ce6/DOX is obtained by mixing the material with DOX and Ce6.The morphology of the prepared nanoparticles were characterized by transmission electron microscopy（TEM）,ultraviolet spectrophotometer（UV-Vis）,and Fourier infrared spectrometer（FT-IR）,and the tumor microenvironment was simulated to evaluate its degradation behavior and the subsequent generation of O₂ during the degradation process.The results show that the nanosystem can degrade stimulated by the tumor microenvironment,whereas keep stable in normal tissues.And the generation of a large amount of O₂ during the degradation process at the tumor site can significantly solve the problem of tumor hypoxia.Furthermore,the near infrared light（NIR）-triggered production of singlet oxygen from the prepared nano-delivery system was monitored by a singlet oxygen probe（SOSG）,the results of which suggest that the photosensitizer Ce6 can convert the O₂into cytotoxic singlet oxygen.The in vitro cell assays further reveal that the nanosystem exhibits subtle dark toxicity and achieves the augment of PDT and synergistic effect when combined PDT and chemotherapy.2.The in Vivo Integrated Diagnosis and Treatment Study of Oxygen-Generating Nanosystem H-PDA@Mn O₂@RGD-Ce6/DOXOn the basis of the enhancement of PDT effect and the cooperative treatment of PDT and chemotherapy,this chapter preliminary explores the research of nano-delivery system for tumor diagnosis and treatment integration through animal experiments.The prepared H-PDA@Mn O₂@RGD-Ce6/DOX is tracked after intravenous injection using small animal living fluorescence imager.The results show that nanoparticles can actively target tumor sites due to the targeting capacity of RGD.Since the nanoparticles will produce paramagnetic Mn²⁺after degradation in the tumor site,nuclear magnetic resonance（MRI）imaging can be achieved to trace the tumor region.Through MRI imaging,the brightness of the tumor site of mice changes significantly after the nanoparticles are injected intravenously,indicating the enrichment and degradation of the prepared nanoparticles at the specific site and confirming the MRI imaging property of the prepare nano-delivery system.Anti-tumor experiments confirmed that the nano-delivery system can effectively inhibit B16 F10 tumor growth and has good biological safety.