Journal
ACS NANO
Volume 13, Issue 10, Pages 11249-11262Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.9b04315
Keywords
tumor; cell membrane; peptide; photodynamic therapy; immunotherapy
Categories
Funding
- National Natural Science Foundation of China [51833007, 51573142, 51690152]
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Here, a protein farnesyltransferase (PFTase)-driven plasma membrane (PM)-targeted chimeric peptide, PpIX-C-6-PEG(8)-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 mu M) 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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