Novel Mesoporous Platinum Based Dual-modal Imaging Guided Enhanced Breast Cancer Photodynamic Synergy Therapy

Hypoxia is an important characteristic of the microenvironment of tumors,which can easily lead to a series of adverse consequences such as drug resistance,invasion,and metastasis of tumor.Photodynamic therapy(PDT)is an effective and noninvasive treatment for tumor,which has fewer side effects than the traditional methods such as surgery,radiotherapy and chemotherapy.As photosensitizers need oxygen to exert cytotoxicity,so solving the problem of hypoxia is the key to enhance the efficacy of PDT and reduce the adverse consequences of drug resistance and metastasis.Nanomaterials have high permeability and retention effect,which can prolong the blood circulation time,more effectively spread and retain to tumor tissues,thus attracting more and more attention in the study of tumor treatment.There are three types of nanomaterials to improve tumor hypoxia,including oxygen-carrying nanocarriers,natural/artificial oxygen nanocarriers,and in-situ oxygen-producing nanomaterials.Based on their catalase like activity,in situ oxygen-producing nanomaterials can catalyze the production of oxygen by high concentration hydrogen peroxide(H2O2)in tumor cells,thus relieving the hypoxic microenvironment.It overcomes the defects of the other two nanomaterials that need additional carriers to deliver catalytic enzymes and have complex design,and is expected to be the most promising method to enhance the efficacy of PDT.In this study,focusing on the scientific issues of tumor hypoxia microenvironment that affect PDT efficacy and tumor prognosis,we designed a novel mesoporous platinum(mPt)nanoplatform on the premise of high concentration of H2O2 in tumor cells to catalyze H2O2 in situ without an extra enzyme.Focusing on the nanoplatform of theranostics and its application in cancer,systematic research is carried out,mainly including the following aspects.1.Construction of Pt@PEG-Ce6 and its application in computed tomography(CT)/photoacoustic dual-mode imaging of breast cancer.Firstly,the noble metal mPt nanomaterials with good near infrared absorbance were prepared with chloroplatinic acid as the precursor.And then the Pt@PEG-Ce6 nanoplatform with computed tomography(CT)/photoacoustic dual-mode imaging function was constructed via connecting the polyethylene glycol-modified photosensitizer chlorin e6(Ce6)onto the mPt nanoparticles.The composite were characterized by transmission electron microscopy,dynamic light scattering,and ultraviolet visible spectrometer,and then the CT and photoacoustic imaging ability of the composite in vitro and in vivo were studied.The results confirmed that Pt@PEG-Ce6 nanoplatform has excellent capability of CT,photoacoustic microscopy,and photoacoustic tomography imaging,which provide an important tool for monitoring tumor hypoxia microenvironment.2.Pt@PEG-Ce6 nanoprobe is used to PDT for breast cancer and its mechanism.mPt nanomaterials have the function of in-situ catalysis,and Ce6,as a photosensitive molecule,has the capacity of producing reactive oxygen species(ROS)in the presence of laser and oxygen(O2).Therefore,we further discussed the potential application of the Pt@PEG-Ce6 nanoprobe in the treatment of breast cancer.We studied the ability of the nanoprobe to catalyze H2O2 to produce O2 in solution and the ability to generate ROS under laser irradiation.The results showed that Pt@PEG-Ce6 has good catalytic and photodynamic abilities.The cell and animal experiments showed that the Pt@PEG-Ce6 nanometer platform could catalyze the generation of O2 by H2O2 in tumor cells.Under laser irradiation,Ce6 can transform O2 to generate ROS,which significantly enhances the therapeutic effect of PDT.Its good biocompatibility and high efficiency of tumor aggregation lay a good foundation for other biological applications to solve hypoxia.The experiment preliminarily discussed the effect of Pt@PEG-Ce6 nanoprobe on the expression of hypoxia-inducible factor-1α(HIF-1α)and programmed death-1(PD-1)in tumors,laying an experimental foundation for further exploration of the immune regulation mechanism of this nanoplatform to hypoxia.