Enzyme-Driven Membrane-Targeted Chimeric Peptide for Enhanced Tumor Photodynamic Immunotherapy
journal contributionposted on 02.10.2019, 15:04 by Chi Zhang, Fan Gao, Wei Wu, Wen-Xiu Qiu, Lu Zhang, Runqing Li, Ze-Nan Zhuang, Wuyang Yu, Han Cheng, Xian-Zheng Zhang
Here, a protein farnesyltransferase (PFTase)-driven plasma membrane (PM)-targeted chimeric peptide, PpIX-C6-PEG8-KKKKKKSKTKC-OMe (PCPK), was designed for PM-targeted photodynamic therapy (PM-PDT) and enhanced immunotherapy via tumor cell PM damage and fast release of damage-associated molecular patterns (DAMPs). The PM targeting ability of PCPK originates from the cellular K-Ras signaling, which occurs exclusively to drive the corresponding proteins to PM by PFTase. With the conjugation of the photosensitizer protoporphyrin IX (PpIX), PCPK could generate cytotoxic reactive oxygen species to deactivate membrane-associated proteins, initiate lipid peroxidation, and destroy PM with an extremely low concentration (1 μM) under light irradiation. The specific PM damage further induced the fast release of DAMPs (high-mobility group box 1 and ATP), resulting in antitumor immune responses stronger than those of conventional cytoplasm-localized PDT. This immune-stimulating PM-PDT strategy also exhibited the inhibition effect for distant metastatic tumors when combined with programmed cell death receptor 1 blockade therapy.
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PEG 8inhibition effectcytoplasm-localized PDTEnhanced Tumor Photodynamic Immunotherapydeactivate membrane-associated proteinslipid peroxidationPM damagehigh-mobility group box 1PM-targeted photodynamic therapycell death receptor 1 blockade therapyimmune-stimulating PM-PDT strategyphotosensitizer protoporphyrinATPDAMPlight irradiationprotein farnesyltransferaseEnzyme-Driven Membrane-Targeted Chimeric Peptidecytotoxic reactive oxygen speciesPCPKmetastatic tumorsPpIX-C 6tumor cell PM damage