Photostable Cascade‐Activatable Peptide Self‐Assembly on a Cancer Cell Membrane for High‐Performance Identification of Human Bladder Cancer

Abstract

Missed or residual tumor burden results in high risk for bladder cancer relapse. However, existing fluorescent probes cannot meet the clinical needs because of inevitable photobleaching properties. Performance can be improved by maintaining intensive and sustained fluorescence signals via resistance to intraoperative saline flushing and intrinsic fluorescent decay, providing surgeons with sufficiently clear and high‐contrast surgical fields, avoiding residual tumors or missed diagnosis. This study designs and synthesizes a photostable cascade‐activatable peptide, a target reaction‐induced aggregation peptide (TRAP) system, which can construct polypeptide‐based nanofibers in situ on the cell membrane to achieve long‐term and stable imaging of bladder cancer. The probe has two parts: a target peptide (TP) targets CD44v6 to recognize bladder cancer cells, and a reaction‐induced aggregation peptide (RAP) is introduced, which effectively reacts with the TP via a click reaction to enhance the hydrophobicity of the whole molecule, assembling into nanofibers and further nanonetworks. Accordingly, probe retention on the cell membrane is prolonged, and photostability is significantly improved. Finally, the TRAP system is successfully employed in the high‐performance identification of human bladder cancer in ex vivo bladder tumor tissues. This cascade‐activatable peptide molecular probe based on the TRAP system enables efficient and stable imaging of bladder cancer.

Photofabrication of fluorescent nanospheres from de novo designed peptides, and their enzyme-responsive dissociation in living cells

“…Peptides have been extensively studied as building blocks due to their chemical versatility, strong biocompatibility, and predictable assembly behavior, 1,2 which could be encoded with designable sequences to fabricate biofunctional conformations directly from primary structures and allow various applications in imaging, 3–7 drug delivery 8–12 and tissue engineering. 13–16 Peptide assemblies are ordinarily governed by a combination of noncovalent and covalent interactions, encompassing hydrogen bonds, 17 π–π stacking, 18 hydrophobic interactions, 19,20 coulombic forces, 21,22 disulfide S–S bonds, 23,24 l -phenylalanine polymerization, dityrosine crosslinking, 25–27 and so on, which could drive peptide self-assembly processes, stabilize secondary or tertiary structures, and establish conjugation patterns even at the protein level.…”

Imaging and Downstaging Bladder Cancer with the 177Lu-Labeled Bioorthogonal Nanoprobe

“…With respect to targeted drug delivery, various strategies based on specific interactions between a given drug and the targeted cell have been developed. − However, insufficient expression of natural receptors on the cancer cell membrane largely limits the delivery efficacy. To address this challenge, the expression of an artificial receptor, azid, on the membrane of cancer cells has been developed through metabolic glycoengineering.…”

Assembly-Induced Membrane Selectivity of Artificial Model Peptides through Entropy–Enthalpy Competition

“…The activities of peptides involve intricate mechanisms, such as supramolecular assembly, which are also crucial for peptide engineering in the development of therapeutic agents and bioimaging probes with improved performance. − Sun et al discovered that self-assembling tripeptides (Phe–Phe–Tyr) effectively reverse drug resistance in melanoma by interfering with microtubules . Furthermore, the experiments demonstrated that peptide self-assembly into micelles followed by transformation into nanofibers can induce apoptosis in cancer cells by disrupting HER2 dimerization .…”