Wolf Isis, Storz Jonas, Schultze-Seemann Susanne, Esser Philipp R, Martin Stefan F, Lauw Susan, Fischer Peer, Peschers Marie, Melchinger Wolfgang, Zeiser Robert, Gorka Oliver, Groß Olaf, Gratzke Christian, Brückner Reinhard, Wolf Philipp
Department of Urology, Medical Center - University of Freiburg, 79106, Freiburg, Germany.
Faculty of Medicine, University of Freiburg, 79106, Freiburg, Germany.
Bioact Mater. 2024 Aug 16;41:537-552. doi: 10.1016/j.bioactmat.2024.07.025. eCollection 2024 Nov.
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 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.
光免疫疗法(PIT)将抗体的特异性与光激活光敏剂(PS)的细胞毒性相结合,是一种很有前景的新型癌症治疗方法。我们以高度汇聚的方式设计并合成了硅酞菁染料WB692-CB2,它是一种新型的光激活PS,首次能够通过马来酰亚胺接头直接与半胱氨酸偶联。在本研究中,我们将WB692-CB2与一种人源化抗体偶联,该抗体在重链中经过工程改造含有半胱氨酸,可特异性靶向前列腺特异性膜抗原(PSMA)。所得的抗体-染料偶联物对表达PSMA的前列腺癌细胞显示出高亲和力和特异性,并在红光照射后诱导细胞死亡。处理后的细胞呈现出与细胞焦亡相关的形态学特征。机制研究表明,活性氧的产生引发了一系列细胞内事件,包括脂质过氧化、半胱天冬酶-1激活、gasdermin D裂解和膜破裂,随后释放促炎细胞内容物。在初步实验中,用我们的抗体-染料偶联物进行PIT可显著降低携带皮下前列腺肿瘤异种移植物的小鼠的肿瘤生长,并提高总体生存率。我们的研究突出了新型酞菁染料WB692-CB2作为PS在基于荧光的癌症检测和PIT中的未来潜力,包括局部前列腺肿瘤病变,以及通过诱导细胞焦亡实现抗肿瘤免疫反应的全身激活。
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