Construction Of Self-Delivery Nanomedicine Based On Photosensitizer To Enhance Photodynamic Therapy

Cancer as an important public health problem worldwide poses a huge threat to human life and health.With the steadily deepened understanding of people to cancer,there are more and more means for cancer treatment,such as surgery,radiotherapy,chemotherapy,immunotherapy and the synergy of multiple therapies.In recent years,photodynamic therapy(PDT)has attracted increasing attention in cancer treatment due to its unique advantages of less side effect,noninvasiveness,and reproducibility.PDT utilizes photosensitizers(PSs)to convert oxygen into cytotoxic reactive oxygen species(ROS)to kill cancer cells in the presence of light.However,the characteristics of tumor microenvironment(TME),such as hypoxia and immunosuppression,greatly reduced the antitumor effect of PDT.In thesis paper,different self-delivery nanomedicines are constructed to enhance the PDT efficacy by regulating TME and combining with other antitumor mechanisms.Most photosensitizers generally have disadvantages such as lack of targeting and poor water solubility.Self-delivery nanomedicine can promote the drug accumulation in tumor tissue by enhanced penetration and retention(EPR)effect,leading to an improved drug delivery efficiency and antitumor effect.Thesis article is divided into three chapters:Chapter 1 summarizes the current treatment methods and research status of cancer.Moreover,we introduce the PDT,synergistic therapy,drug delivery system,tumor microenvironment,and related applications to seek breakthrough for improved tumor therapy.Finally,it is proposed to construct self-delivery nanomedicine for synergistic tumor therapy.Chapter 2 proposes a self-delivery nanomedicine(CeTam)based on photosensitizer chlorin e6(Ce6)and the mitochondrial electron transport chain(mETC)inhibitor Tamoxifen(Tam).CeTam is prepared by the self-assembly of Ce6 and Tam through the non-covalent interactions in the absence of additional carriers,which possesses high drug loading rate and has a favorable stability.CeTam can avoid the carrier-induced toxicity and immunogenicity.Compared with free drugs,CeTam shows better tumor accumulation and cellular uptake abilities after intravenous injection.In addition,CeTam can inhibit mETC to reduce oxygen consumption,thereby relieving tumor hypoxia and promoting ROS generation.Besides,CeTam can down-regulate the expression of anti-apoptotic protein Bcl-2 to reverse the anti-apoptotic pathway,contributing to the PDT effect on tumor inhibition.Chapter 3 constructs a ternary self-assembled nanodrug(CDZ)based on Ce6,STING agonist DMXAA and PI3K inhibitor ZSTK474.CDZ can damage cellular DNA by PDT of Ce6.The resulting cytoplasmic secretion of DNA and DMXAA will activate STING pathway to enhance the immune response of tumor cells.In addition,Ce6-mediated PDT can induce immunogenic cell death(ICD)and ZSTK474induced PI3K inhibition can improve the immunosuppressive microenvironment,leading to an improved immunotherapy.Ultimately,CDZ will achieve an efficient tumor inhibition by the synergistic effect of PDT and immunotherapy.