GSH/HAase/pH Triple-responsive Nanotheranostic Agent for Synergistic Therapy Guided by Tumor-targeting Fluorescence/Photoacoustic Dual-mode Imaging
In this work,a multifunctional nanotheranostic agent FePDA/DOX@HA-CYS-TTDPP was constructed for pho-to/chemodynamic/chemo synergistic therapy guided by tumor-targeting fluorescence/photoacoustic dual-mode imaging.The diketopyrrolopyrrole(DPP)derivative(TTDPP)with near-infrared(NIR)absorption was coupled with tumor-targeting bio-molecule hyaluronic acid(HA)via cystamine(CYS)to obtain the amphiphilic polymer HA-CYS-TTDPP.It was then self-assembled with Fe3+-coordinated polydopamine nanoparticles(FePDA)and anti-tumor drug doxorubicin(DOX)to form this nanomaterial.Its photothermal conversion efficiency reached 65.6％and it showed good photoacoustic performance,which can be attributed to the excellent photothermal conversion performance of TTDPP and PDA.TTDPP was a D-π-A-π-D type DPP derivative formed by the electron acceptor(A)DPP,the electron donor(D)triphenylamine,and the conjugated bridge thiophene,which exhibited excellent photothermal and photoacoustic performance,and a certain degree of photody-namic effect.PDA was formed by dopamine oxidation self-polymerization,which showed the advantages of good biocom-patibility,high photothermal conversion efficiency,and easy functionalization;moreover,due to the d-d transition of exoge-nous Fe3+in FePDA,the photothermal effect of PDA can be further enhanced.Furthermore,the weak acidity of tumor mi-croenvironment(TME)facilitated the dissolution and release of DOX,and the overexpressed hyaluronidase(HAase)and glutathione(GSH)in tumor cells can also trigger the degradation of HA and the cleavage of disulfide bonds in CYS,respec-tively,leading to the release of DOX.Thus,the distance between DOX and PDA and TTDPP was increased,and the fluores-cence of DOX was recovered,thereby achieving TME-responsive fluorescence activation and controlled drug release,and the tumor-targeting effect was further enhanced.Therefore,this nanotheranostic agent can realize triple response to the weak acidity,overexpressed GSH and HAase of TME.On the other hand,Fe3+can react with GSH and H2O2 in tumor cells to induce Fenton reaction,generating cytotoxic·OH and resulting in chemodynamic therapeutic performance.Cell experiments confirmed that FePDA/DOX@HA-CYS-TTDPP can intelligently respond to TME and achieve targeted fluorescence imag-ing,and effectively inhibit the proliferation of HeLa tumor cells through photo/chemodynamic/chemo synergistic therapy.This system provides new ideas for achieving precise and efficient tumor theranostics.
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