Multifunctional Drug Systems For Tumor Therapy And Imaging

During the last decades,tumor is one of the most threatening diseases in the whole world.While many traditional antitumor drugs have several limitations,such as poor water solubility,systemic instability,risk of seriously side effects and lack of tumor selectivity,which hindered their further clinical application.To address these problems,scientists have proposed many drug delivery systems,they could realize tumor targeted therapy and sensitive to specific extracorporeal physical stimuli or endogenous stimuli taking advantage of microenvironmental changes in tumor.Due to the non-invasiveness,and good spatio-temporal selectivity of light,light triggered drug delivery systems have received much attention in the past decades.Compared to the ultraviolet light with limited tissue penetration depth,near-infra red light is a more promising choice for light stimulus in these systems.Besides,the development of theranostic drugs can help to real-time monitor drug delivery,and further understand drug action mechanisms.Photodynamic therapy(PDT)is a new therapeutic strategy for cancer treatment.PDT efficacy is highly depending on three factors:photosensitizer(PS),light and oxygen.However,tissue penetration depth of the excitation light used in PDT is very low due to the strongly absorption of photons by tissue.Moreover,the severe tumor hypoxia further limits PDT efficiency.Under the circumstances,developing subcellular organelles targeted PS delivery,or tumor oxygenation PDT strategies are of great significance for high efficient PDT.In light of these,the work in this thesis is mainly focused on the following issues:In chapter 1,the recent progresses of stimuli-responsive prodrug systems,tumor targeted and organelles targeted peptides were reviewed.Besides,current challeges in photodynamic therapy as well as their terms of settlements were reviewed.In chapter 2,a red light activatable prodrug(designated as TPP-L-GEM)was developed with in situ drug tracking capability for fluorescence imaging guided tumor PDT therapy and cascaded chemotherapy.The prodrug was composed of a fluorescent photosensitizer(meso-tetraphenylporphyrin,TPP),a reactive oxygen species(ROS)cleavable thioketal linker,and an antitumor drug gemcitabine(GEM).Upon red light irradiation,TPP could generate singlet oxygen(1O2),which would not only cause cell damage by photodynamic therapy(PDT),but also cleave the thioketal linkage in prodrug and induce a cascaded gemcitabine release,resulting in sustained cell damage by additional chemotherapy.Moreover,in addition to the light illuminated tumor cells,the un-illuminated adjacent tumor cells were also damaged by the prodrug by the efficient 1O2 mediated subsequent drug release.Besides,the fluorescence in TPP(Em = 650 nm)allowed noninvasive tracking of drug distribution in mice,which could help provide information of when and where to apply the light illumination.In chapter 3,a charge reversible self-delivery chimeric peptide(C16-K(PpIX)RRK(DMA)K(DMA)-PEG-COOH,designated as C16-PRP-DMA)was developed for enhanced tumor therapy based on cell membrane-targeting.C16-PRP-DMA was easily prepared with excellent PpIX loading capacity(25.1%).It could self-assemble into nanoparticle and show good ROS generation property.After undergoing charge reverse and micelle disintergration in acidic tumor microenvironment,C16-PRP-DMA could stay on cancer cell membrane in a long time(more than 14 h)due to synergetic effect of the exposed cell membrane attachable alkyl chain PA and positively charged RRKK.C16-PRP-DMA could exhibit good antitumor effect attributed to the ROS induced effective plasma membrane disruption demonstrated in in vitro experiments.In chapter 4,an O2 self-sufficient ingenious liposome nano-platform(LipoMB/CaO2)is fabricated for hypoxia tumor PDT under dual-stage light irradiation.In this O2-generating liposome,hydrophilic photosensitizer methylene blue(MB)and O2 supplier calcium peroxide(CaO2)nanoparticle are encapsulated into the aqueous cavity and hydrophobic layer of polyethylene glycol(PEG)shelled liposomes,respectively.In hypoxia tumor microenvironment,CaO2 wound react with the weak acid to release O2 that contributed to the formation of 1O2 under a short time 660 nm laser irradiation to MB.Moreover,the generated 1O2 could oxidize the phospholipid bilayers to break the liposome,enhancing the contact of CaO2 with H2O,resulting in the accelerated O2 releasing.The elevated O2 level would further improve the PDT effect through a long time light irradiation and modulate tumor microenvironment.In this chapter,the dual-light irradiation elevated O2 generation,the elevated oxygen level in hypoxia tumor cells,and the improved therapeutic efficacy of LipoMB/CaO2 against hypoxia tumor were investigated in detail.