A new silicon phthalocyanine dye induces pyroptosis in prostate cancer cells during photoimmunotherapy  

作　　者：Isis Wolf Jonas Storz Susanne Schultze-Seemann Philipp REsser Stefan FMartin Susan Lauw Peer Fischer Wolfgang Melchinger Robert Zeiser Oliver Gorka Olaf Groß Christian Gratzke Reinhard Brückner Philipp Wolf 

机构地区：[1]Department of Urology,Medical Center–University of Freiburg,79106,Freiburg,Germany [2]Faculty of Medicine,University of Freiburg,79106,Freiburg,Germany [3]Faculty of Biology,University of Freiburg,79104,Freiburg,Germany [4]Institute for Organic Chemistry,University of Freiburg,79104,Freiburg,Germany [5]Allergy Research Group,Department of Dermatology,Medical Center–University of Freiburg,79104,Freiburg,Germany [6]Core Facility Signalling Factory&Robotics,University of Freiburg,79104,Freiburg,Germany [7]BIOSS Centre for Biological Signalling Studies,University of Freiburg,79104,Freiburg,Germany [8]Max Planck Institute for Medical Research,69120,Heidelberg,Germany [9]Institute for Molecular Systems Engineering and Advanced Materials,Heidelberg University,69120,Heidelberg,Germany [10]Department of Internal Medicine I,Medical Center-University of Freiburg,79106,Freiburg,Germany k [11]Institute of Neuropathology,Medical Center-University of Freiburg,79106,Freiburg,Germany [12]CIBSS Centre for Integrative Biological Signalling Studies,University of Freiburg,79104,Freiburg,Germany Received 12 Septembe

出　　处：《Bioactive Materials》2024年第11期537-552,共16页生物活性材料（英文）

基　　金：German Research Foundation(DFG,grant no.WO 2178/3–1 to PW);Federal Ministry of Economic Affairs and Climate Action(BMWK,grant no.03THW15H04 to RB and PW);supported by the Open Access Publication Fund of the University of Freiburg.

摘　　要：Photoimmunotherapy(PIT)combines the specificity of antibodies with the cytotoxicity of light activatable photosensitizers(PS)and is a promising new cancer therapy.We designed and synthesized,in a highly convergent manner,the silicon phthalocyanine dye WB692-CB2,which is novel for being the first light-activatable PS that can be directly conjugated via a maleimide linker to cysteines.In the present study we conjugated WB692-CB2 to a humanized antibody with engineered cysteines in the heavy chains that specifically targets the prostate-specific membrane antigen(PSMA).The resulting antibody dye conjugate revealed high affinity and specificity towards PSMA-expressing prostate cancer cells and induced cell death after irradiation with red light.Treated cells exhibited morphological characteristics associated with pyroptosis.Mechanistic studies revealed the generation of reactive oxygen species,triggering a cascade of intracellular events involving lipid peroxidation,caspase-1 activation,gasdermin D cleavage and membrane rupture followed by release of pro-inflammatory cellular contents.In first in vivo experiments,PIT with our antibody dye conjugate led to a significant reduction of tumor growth and enhanced overall survival in mice bearing subcutaneous prostate tumor xenografts.Our study highlights the future potential of the new phthalocyanine dye WB692-CB2 as PS for the fluorescence-based detection and PIT of cancer,including local prostate tumor lesions,and systemic activation of anti-tumor immune responses by the induction of pyroptosis.

关 键 词：Silicon phthalocyanine Photoimmunotherapy CANCER PYROPTOSIS Immunogenic cell death 

分 类 号：R737.25[医药卫生—肿瘤]