Tumor Microenvironment Guiding Smart Responsive Drug Delivery Polypeptides And Novel Fluorescence Probe

Tumors diagnosis and therapy was one of the most important scientific research fields.Tumor microenvironment has been verified the significant impact on tumor growth and progression,as well as cumulative genemutations.Tumor microenvironment acted as the beacon of nanomedicine to distinguish tumor cell from normal cell,which guide the way to precise diagnosis and therapy.This thesis based on polypeptides as well as fluorescence imaging.The emphasis of this thesis are developing smart responsive drug delivery system and novel fluorescence probe which under the guidance of the tumor microenvironment for better tumors diagnosis and therapy.In the chapter two,a reduction-responsive nanogel containing disulfide bonds has been developed which can be degraded reductively since high intracellular glutathione(GSH)content in tumor cell.Bromine atom substituent was introduced to the NIR cyanine photosensitizer IR808 by the exploitation of the heavy-atom effect to improve the singlet-oxygen generation level.The photosensitizer was loaded on nanogel and could be released from nanogel by GSH reduction.The nanogel was applied to Photodynamic Therapy and cell imaging successfully.Based on above work,mildly acidic extracellular tumor microenvironment pHe responsive charge reversal was introuduced to the surface of nanogel.The shell was then modified by 2,3-dimethylmaleic anhydride(DMA),whose amide group could be rapidly cleaved in pHe environment,the charge of surface thus turn from negative to positive.The charge reversal facilitated the high selectivity to tumor cell and the DOX which carried by hydrophobic inner core were then released in tumor cell,lead a direct cytotoxicity.The cytotoxicity test verified the success.Cy5.5,a NIR cyanine fluorophore,was introuduced to the nanogel to gain the imaging ability,those make the nanogel a theranostics drug delivery system.Aggregation-caused quenching of fluorophore at high concentration or nanoparticles limited its application in nanogel.By reverse thinking,schiff base group was introduced to a NIR cyanine Cy7 scaffold.Schiff base substituent Cy7(Sbs-Cy7)favours to aggregate in pH7.4 PB buffer with fluorescence quenching.While in pH5.8 buffer,the Sbs-Cy7 was hydrolysis by acid catalyst,the aggregation state turns to monomer state,which are not quenching and induces a huge recovery of fluorescence,that makes the dye a new NIR fluorescence probe with an ultrahigh pH-sensitive.On the other hand,we tried to develop dyes which could emission inboth solution and solid state,dual-state emission(DSE).A Schiff base dye conjugated with both pyrene and Cy7 has been synthesized,which showed a novel"see-saw" fluorescent performance via the combination of aggregation-induced emission(AIE)and aggregation-caused quenching(ACQ).The dye endows nanogel with imaging property in all states.Furthermore,a pH-sensitive dual-state emission(DSE)dye which comprised of hemicyanine and tetraphenylethene(TPE)also prepared.