Morphological Transformation and In Situ Polymerization of Caspase‐3 Responsive Diacetylene‐Containing Lipidated Peptide Amphiphile for Self‐Amplified Cooperative Antitumor Therapy

Abstract

In order to artificially regulate cell behaviors, intracellular polymerization as an emerging chemical technique has attracted much attention. Yet, it is still a challenge to achieve effective intracellular polymerization to conquer tumors in the complex cellular environment. Herein, this work develops a tumor‐targeting and caspase‐3 responsive nanoparticle composed of a diacetylene‐containing lipidated peptide amphiphile and mitochondria‐targeting photosensitizer (C3), which undergoes nanoparticle‐to‐nanofiber transformation and efficient in situ polymerization triggered by photodynamic treatment and activation of caspase‐3. The locational nanofibers on the mitochondria membranes lead to mitochondrial reactive oxygen species (mtROS) burst and self‐amplified circulation, offering persistent high oxidative stress to induce cell apoptosis. This study provides a strategy for greatly enhanced antitumor therapeutic efficacy through mtROS burst and self‐amplified circulation induced by intracellular transformation and in situ polymerization.

Synthesizing biomaterials in living organisms

“…Diacetylene-containing peptide amphiphiles also have the potential of polymerization initiated by intracellular ROS. 165,166 Zhu et al designed two precursors, PA-OH and PA-NH 2 , with different charge properties (Fig. 31).…”

Elucidating the cell penetrating properties of self-assembling β-peptides

“…H3570) in phenol-free αMEM for 30 min. Cells were rinsed again with PBS before incubating with C14-tripeptide-670 or tripeptide-670 at 1 μg mL −1 (0.87 mM or 1.13 mM, respectively) for 1, 3,5,10,15,20,25,30,35,40,45,50,55, or 60 min in low light conditions. A concentration of 1 μg mL −1 was selected to provide appropriate fluorescence dynamic range across the imaging period whilst avoiding hydrogelation.…”

“…Lipidated peptides with cell penetrating properties can be applied to direct peptide drugs, or other cargo, to specific subcellular regions, such as the mitochondrial membrane 28 in targeted cancer treatments. [29][30][31][32] Our laboratory has developed self-assembling peptide hydrogels for a range of applications including 2D cell culture, 8,9,[33][34][35][36][37][38] cellular guidance 36 and drug delivery. 9 Fibres are generated from the hierarchical self-assembly of N-acetylated β 3 -peptides 39,40 and functionalisation with a lipid promotes hydrogelation.…”

“…Lipidated peptides with cell penetrating properties can be applied to direct peptide drugs, or other cargo, to specific subcellular regions, such as the mitochondrial membrane 28 in targeted cancer treatments. 29–32…”

Caspase-3-Responsive Fluorescent/Photoacoustic Imaging of Tumor Apoptosis

“…Therefore, we rationally developed a tumor-targeted FL/PA probe for Caspase-3-responsive imaging of tumor apoptosis. As shown in Figure , the tumor-targeted FL/PA probe ( Bio-DEVD-HCy) can be divided into three parts: (1) the biotin part for tumor targeting; , (2) the peptide part Asp-Glu-Val-Asp (DEVD) for specific Caspase-3 cleavage; , (3) the hemicyanine dye (HCy) part with outstanding near-infrared (NIR) optical property for responsive FL/PA imaging. − The FL/PA signal is “off” due to the caged amino group of HCy inhibiting intramolecular charge transfer (ICT) in Bio-DEVD-HCy . Once tumor cells are encountered, Bio-DEVD-HCy binds to the highly expressed biotin receptor on the surface and then enters and accumulates in tumor cells.…”