Calcium Phosphate Based Cancer Nanotheranostics For Enhanced Photo/chemodynamic Therapy By Depleting Tumor Associated Macrophages

At present,tumor is still an important killer of people’s health and life because of its high incidence,high lethality and high economic loss.Combination therapy that uses more than one type therapeutic modalities plays an important role in tumor treatment.Chemodynamic therapy（CDT）emerges as a new treatment modality that convert hydrogen peroxide into the hydroxyl radical with transition metal ions(e.g.,Fe²⁺,Cu⁺,and Mn²⁺)by the Fenton/Fenton-like reactions to induce tumor cell apoptosis and necrosis.At the same time,some transition metal ions(eg.Mn²⁺)can be utilized as magnetic resonance imaging（MRI）contrast agents for tumor imaging.Phototherapy could not only directly kill tumor cells by the photothermal effect or ROS upon irradiation of photosensitizers,but also can improve the effect of other therapies such as CDT.However,the complex microenvironment within tumor greatly limits the efficacy of tumor therapy.Tumor-associated macrophages（TAM）,an important member of tumor microenvironment,play a vital role in the maintenance of tumor microenvironment,and they endow the tumor cells with resistance to photo/chemodynamic therapy,so the treatment efficiency of simple combination therapy still be limited.Therefore,designing a multifunctional theranostics which can inhibit TAM to reshape the tumor microenvironment and thus enhance the therapeutic efficiency is a powerful way to cure tumor.In view of the above background,this thesis aimed to construct a multifunctional calcium phosphate based nanotheranostics for the synergistic antitumor effect of depleting TAM and the photo/chemodynamic therapy under the guidance of MRI/fluorescence imaging.The PEG stabilized calcium phosphate nanotheranostics ICG/ZOL@MnCaP（abbreviated as IZ@MnCaP）was synthesized by one-step to encapsulate the TAM inhibitory drug zoledronic acid（ZOL）,photosensitizer indocyanine green（ICG）and CDT reagent Mn²⁺into the calcium phosphate matrix.The characterization results of transmission electron microscope（TEM）,scanning electron microscope（SEM）and dynamic light scattering（DLS）.showed that IZ@MnCaP was spherical in shape with the size of c.a.50 nm.IZ@MnCaP was stable with good dispersity in aqueous solution and had the ability to quickly respond to acidity.IZ@MnCaP had no obvious toxicity to normal cells and tumor cells in dark.Under near infrared laser irradiation,it could increase the local temperature and promote the ROS production of CDT,thus effectively induced the tumor cell apoptosis and necrosis through lysosome pathway.The in vivo study showed that IZ@MnCaP specifically released MRI contrast agent Mn²⁺at the tumor site in responsive to tumor acid microenvironment and remained in the body for a longer time than free small molecular drugs or photosensitizers.Furthermore,the changes of tumor mass and volume and the related pathological examination confirmed that IZ@MnCaP exhibited a significant anti-tumor effect against the 4T1 mammary carcinoma model by effectively depleting TAM,reprograming the tumor microenvironment and enhanced photo/chemodynamic therapy simultaneously.In conclusion,this thesis shows that the multi-functional calcium phosphate-based nanosystem IZ@MnCaP is a simple but a highly efficient theranostic agent that has an important application prospect in the imaging guided combination treatment of tumors.