Photodynamic therapy(PDT)has emerged as an efficient cancer treatment method with minimal invasiveness.However,the majority of current photosensitizers(PSs)display severe dark toxicity and low tumor specificity due to...Photodynamic therapy(PDT)has emerged as an efficient cancer treatment method with minimal invasiveness.However,the majority of current photosensitizers(PSs)display severe dark toxicity and low tumor specificity due to their"always-on"photoactivity in blood circulation.To address this concern,we herein report a series of acid-activatable PSs for ultrasensitive PDT of triple-negative breast tumors.These set of novel PSs are synthesized by covalently modifying tetrakis(4-carboxyphenyl)porphyrin(TCPP)with a variety of tertiary amines for acidity-activatable fluorescence imaging and reactive oxygen species(RoS)generation.The resultant TCPP derivatives are grafted with a poly(ethylene glycol)(PEG)chain via a matrix metalloproteinase-2(MMP-2)-liable peptide spacer and chelated with Mn^(2+)for magnetic resonance imaging(MRI)capability.The PEGylated TCPP derivatives are amphiphilic and self-assemble into micellar nanoparticles to elongate blood circulation and for tumor-specific PDT.We further demonstrate that the PEGylated TCPP nanoparticles could serve as a nanoplatform to deliver the anticancer drug doxorubicin(DOX)and perform fluorescence image-guided combinatorial PDT and chemotherapy,which efficiently suppress the growth of 4T1 breast tumors and lung metastases in a mouse model.These acid-activatable PS-incorporated nanoparticles might provide a versatile platform for precise PDT and combinatorial breast cancer therapy.展开更多
Glioblastoma(GBM) therapy is severely impaired by the blood-brain barrier(BBB) and invasive tumor growth in the central nervous system.To improve GBM therapy,we herein presented a dual-targeting nanotheranostic for se...Glioblastoma(GBM) therapy is severely impaired by the blood-brain barrier(BBB) and invasive tumor growth in the central nervous system.To improve GBM therapy,we herein presented a dual-targeting nanotheranostic for second near-infrared(NIR-Ⅱ) fluorescence imaging-guided photoimmunotherapy.Firstly,a NIR-Ⅱ fluorophore MRP bearing donor-acceptor-donor(D-A-D) backbone was synthesized.Then,the prodrug nanotheranostics were prepared by self-assembling MRP with a prodrug of JQ1(JPC) and T7 ligand-modified PEG5k-DSPE.T7 can cross the BBB for tumor-targeted delivery of JPC and MRP.JQ1 could be restored from JPC at the tumor site for suppressing interferon gamma-inducible programmed death ligand 1 expression in the tumor cells.MRP could generate NIR-Ⅱ fluorescence to navigate 808 nm laser,induce a photothermal effect to trigger in-situ antigen release at the tumor site,and ultimately elicit antitumor immunogenicity.Photo-immunotherapy with JPC and MRP dual-loaded nanoparticles remarkably inhibited GBM tumor growth in vivo.The dual-targeting nanotheranostic might represent a novel nanoplatform for precise photo-immunotherapy of GBM.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82102915,22074043 and U22A20328)Lingang Laboratory(No.LG-QS-202206-04)+1 种基金China Postdoctoral Science Foundation(No.2021M700157)Shanghai Post-Doctoral Excellence Program(No.2021424).
文摘Photodynamic therapy(PDT)has emerged as an efficient cancer treatment method with minimal invasiveness.However,the majority of current photosensitizers(PSs)display severe dark toxicity and low tumor specificity due to their"always-on"photoactivity in blood circulation.To address this concern,we herein report a series of acid-activatable PSs for ultrasensitive PDT of triple-negative breast tumors.These set of novel PSs are synthesized by covalently modifying tetrakis(4-carboxyphenyl)porphyrin(TCPP)with a variety of tertiary amines for acidity-activatable fluorescence imaging and reactive oxygen species(RoS)generation.The resultant TCPP derivatives are grafted with a poly(ethylene glycol)(PEG)chain via a matrix metalloproteinase-2(MMP-2)-liable peptide spacer and chelated with Mn^(2+)for magnetic resonance imaging(MRI)capability.The PEGylated TCPP derivatives are amphiphilic and self-assemble into micellar nanoparticles to elongate blood circulation and for tumor-specific PDT.We further demonstrate that the PEGylated TCPP nanoparticles could serve as a nanoplatform to deliver the anticancer drug doxorubicin(DOX)and perform fluorescence image-guided combinatorial PDT and chemotherapy,which efficiently suppress the growth of 4T1 breast tumors and lung metastases in a mouse model.These acid-activatable PS-incorporated nanoparticles might provide a versatile platform for precise PDT and combinatorial breast cancer therapy.
基金Financial supports from the National Natural Science Foundation of China (22074043, 22174047, 32050410287)Science and Technology Commission of Shanghai Municipality (20142202800, China)+1 种基金China Postdoctoral Science Foundation (2021M700157)Shanghai Post-Doctoral Excellence Program (2021424, China)
文摘Glioblastoma(GBM) therapy is severely impaired by the blood-brain barrier(BBB) and invasive tumor growth in the central nervous system.To improve GBM therapy,we herein presented a dual-targeting nanotheranostic for second near-infrared(NIR-Ⅱ) fluorescence imaging-guided photoimmunotherapy.Firstly,a NIR-Ⅱ fluorophore MRP bearing donor-acceptor-donor(D-A-D) backbone was synthesized.Then,the prodrug nanotheranostics were prepared by self-assembling MRP with a prodrug of JQ1(JPC) and T7 ligand-modified PEG5k-DSPE.T7 can cross the BBB for tumor-targeted delivery of JPC and MRP.JQ1 could be restored from JPC at the tumor site for suppressing interferon gamma-inducible programmed death ligand 1 expression in the tumor cells.MRP could generate NIR-Ⅱ fluorescence to navigate 808 nm laser,induce a photothermal effect to trigger in-situ antigen release at the tumor site,and ultimately elicit antitumor immunogenicity.Photo-immunotherapy with JPC and MRP dual-loaded nanoparticles remarkably inhibited GBM tumor growth in vivo.The dual-targeting nanotheranostic might represent a novel nanoplatform for precise photo-immunotherapy of GBM.