Deep Tissue Penetration Of Thermo-Responsive Peptide-Polymer And In Vivo Self-Assembly

Nanomaterials are widely used in cancer therapy due to their unique properties.For instance,nanomaterials can effectively enrich at tumor sites and enter cells.However,the specific physiological structure of tumor tissue can only allow small-sized nanomaterials penetrate deeper.Targeted peptide-polymer and functional molecules with specific functions modified on response polymers can realize a variety of assembly behaviors,and effectively improve the deep penetration and anti-cancer ability of nanomaterials through precise particle size changes.In this paper,firstly we synthesized a temperature-responsive polymer with poly(ethylene glycol)diacrylate(PEGDA)and dithiothreitol(DTT),then modified the bioactive peptides.The structure of the peptide-polymer were studied by 1H NMR.The particle size and thermo-sensitive properties were investigated by dynamic light scattering(DLS),the fluorescence intensity changes of nonpolar fluorescent probes,and transmission electron microscope(TEM)morphology changes.Secondly,the ability of the peptide-polymers to accumulate at tumor sites at elevated temperatures was characterized by photothermal imaging in vivo,the fluorescence imaging in vivo system,and material distribution of mouse ex vivo tissues.At the cellular level,lysosome co-localization experiments were performed to characterize the peptide-polymers that enter cells via endocytosis and rapidly take up approximately 35 nm nanoparticles.At the cellular level,fluorescence intensity measurements and bio-electron microscopy experiments showed that the polymer was self-assembled into nanoparticles in a monolayer state when the temperature increased.It was characterized that polypeptide-polymer with monolayer state has deep tissue permeability through penetration experiments of peptide-polymer in multicellular spheroid(MCS),photoacoustic experiments at living level and cryosections experiments of tumor tissueFinally,pharmacodynamics evaluation of peptide-polymers was first performed at the cellular level to discover that the peptide-polymer ultimately induces apoptosis by disrupting mitochondria.Cytotoxicity experiments showed that temperature-responsive peptide-polymers affect the cells during self-assembly.Thereafter the experiment of MCS disaggregation showed that the temperature-responsive peptide-polymer was effective at the tissue level.At last,therapeutic experiments at the level of living organisms indicated that the temperature-responsive peptide-polymer under the irradiation of near-infrared light had a highly effective anti-cancer effect.In summary,a temperature-responsive peptide-polymer was synthesized in this paper.It penetrated deeply in the tumor tissue at 37 oC in random-coiled molecule state;when the temperature rose to 41 oC,in situ self-assembly increased in the tumor tissue.Enrichment effect and ability to enter the cell,thereby effectively improved the anti-cancer effect.