Enzyme-Driven Membrane-Targeted Chimeric Peptide for Enhanced Tumor Photodynamic Immunotherapy

Abstract

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 damageassociated 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.

Supramolecular Immunotherapy of Cancer Based on the Self‐Assembling Peptide Design

“…Interestingly, Zhang et al designed an enzyme-driven chimeric peptide (PpIX-C 6 -PEG 8 -KKKKKKSKTKC-OMe (PCPK)) photodynamic immunotherapy that targeted and destroyed cell membranes to induce cell necrosis ( Figure 8C). [75] PCPK self-assembled into nanoparticles with enhanced permeability and retention effect can able to target cell membranes, enhance immune response by PDT-induced cell necrosis and PD-1 blockade immunotherapy, and show a strong metastatic tumor suppression effect. In addition, Yang et al used organic-inorganic nanocarriers to load chlorin e6, a honey bee venom melittin (MLT) peptide to form nanomaterials with a rod-like structure (Ce6/MLT@SAB), which significantly reduced the hemolysis of free MLT for PDT and immunotherapy.…”

Recent Progress on Activatable Nanomedicines for Immunometabolic Combinational Cancer Therapy

“…[ 17 ] Phototherapy is also reported to induce immunogenic cell death (ICD) and dendritic cell (DC) activation, leading to the initiation of antitumor immune response. [ 18 ] However, phototherapy solely cannot afford a durable and effective T‐cell immune response due to cancer immune evasion. Therefore, recent studies have focused on the combination of phototherapy with immunotherapy to enhance therapeutic effects.…”

“…Single‐stimulus (ROS, GSH, pH, or enzyme)‐activatable nanosystems have been reported to induce the specific activation of photosensitizers and immunometabolic agents for photo‐immunometabolic cancer therapy. To further improve their specificity and effectiveness, multiple‐stimuli‐activatable nanosystems have been gradually proposed and developed [18b,34,48] . Gao et al designed a matrix metalloproteinase‐2 (MMP‐2)/GSH‐activatable prodrug vesicle (EAPV) to deliver a PEGylated photosensitizer (PPa) and a reduction‐sensitive prodrug IDO‐1 inhibitor (NLG919) for photo‐immunometabolic cancer therapy ( Figure a).…”

A NIR-I light-responsive superoxide radical generator with cancer cell membrane targeting ability for enhanced imaging-guided photodynamic therapy

“…37,38 For the cellular uptake, the very rst step is always to interact with the plasma membrane, which is a lipid bilayer decorated with proteins and holds the integrity of cells. [39][40][41] Clearly, PSs with a suitable hydrophilicity-lipophilicity balance that can be retained on the surface of cancer cells would in situ generate ROS to oxidize cholesterol and other unsaturated phospholipids, [42][43][44][45] which results in the changes of membrane permeability and the losses of membrane uidity and integrity and nally induces cell death [46][47][48] (for instance, apoptosis and necrosis). Therefore, it's reasonable to envision that NIR-I lightresponsive uorescent PSs with cancer cell membrane targeting ability, which can undergo the type-I pathway, would provide more effective imaging-guided PDT.…”