The Synthesis And Application Of PH-response Theranostic Probes

Cancer is a disease with high morbidity and mortality.It has biological characteristics such as abnormal cell differentiation and proliferation,uncontrolled growth,infiltration and metastasis.Selective drug delivery in solid tumors is one of the main approaches to achieve disease remission and treatment.Selectively increasing drug concentrations in tumor regions has been a major goal of drug delivery research,based on the hypothesis that the higher the drug concentration in tumor tissue,the better the treatment effect.During treatment,drugs need to be delivered in the tumor area in response to pH values to increase the drug concentration.Different organs,tissues and cell regions have different pH values,which makes pH suitable as a stimulus for controlled drug release.pH-responsive drug delivery systems have attracted increasing attention due to their ability to deliver drugs in a controlled manner at a specific time and location,overcoming the shortcomings of traditional pharmaceutical preparations.Based on this,theranostic probes with pH responsiveness was designed and synthesized in this work to achieve real-time monitoring while delivering drugs.The details are as follows:(1)pH-sensitive polyethylene glycol metal-phenolic network(PEG-MPN)capsules were prepared to deliver photosensitizers to cancer cells by encapsulating hematoporphyrin monomethyl ether(HMME).With the assistance of folic acid(FA),HMME-doped PEG-MPN capsules(MPN@HMMEs)accumulated in carcinoma cells selectively followed by releasing HMME in the lysosomes because of the acidic pH environment.From the fluorescent ratiomatric sensing and reactive oxygen species(ROS)regionality distribution of MPN@HMMEs,we demonstrated the encapsulated photosensitizers are diffused from lysosomes to cytoplasm.Under irradiation at 638nm laser,ROS generated from the photosensitizers induced cancer cells undergoing apoptosis while normal cells survive.Therefore,MPN@HMME could be applied as a new strategy for targeted PDT against cancer and PEG-MPN capsules were expected to be general carries for drug delivering.(2)A cell membrane coated porous coordination polymer nanoparticles(PCP NPs)were fabricated for drug delivery and theranostics.Doxorubicin(DOX)was loaded with the capacity of 32.5?g mg~-11 and the fluorescence of DOX was quenched by PCPs in physiological environment.The cell membrane assisted recognizing cancer cells by homologous targeting.After uptake by targeted cancer cells,the acidic environment in endosomes/lysosomes facilitated the degradation of PCP NPs,leading the controlled release and the fluorescence recovery of DOX.(3)A theranostic nanoprobe was fabricated with the function of simultaneous detection and inhibition of P-gp to diagnose and combat multidrug-resistant cancer in vitro and in vivo.For constructing nanoprobe,elacridar modified quantum dots(QDs-Ela),acting as gatekeeper,were grafted onto the DOX loaded,folic acid(FA)decorated mesoporous silica nanoparticles(MSNs).Upon targeted uptake by multidrug-resistant cancer cells,adriamycin-resistant human hepatoma cells Bel-7402/ADR were used as a model,the acidic environment resulted in QDs-Ela removing from nanoprobe and subsequent DOX releasing.The removed QDs-Ela could specifically combine with P-gp on the cancer cell membrane and inhibit their active sites,which prevented the efflux of intracellular DOX and increases the retention of DOX.Another way,the fluorescence intensity of the binding QDs-Ela quantified the P-gp expression level.Subsequently,in vitro and in vivo experiments both demonstrated the enhanced multidrug-resistant cancer therapy efficacy,i.e.nanoprobe had 10 times better curative effect than free DOX.In addition,due to the conjugation of FA,the nanoprobe exhibited selective cell targeting ability to Bel-7402/ADR cells compared to human normal hepatic cells L-O2.This nanoplatform paved a new avenue for the accurate treatment of multidrug-resistant cancers.