Cathepsin B Responsive Peptide-Purpurin Conjugates For Highly Efficient PA Imaging-guided Cancer Sonotheranostic Therapy

Representative ultrasound(US)triggered sonodynamic therapy(SDT)is now emerging as a highly promising strategy for cancer therapy.It depends on the activation of sonosensitizer by low-frequency US to generate toxic reactive oxygen species(ROS).Notwithstanding the significant progress of SDT themselves,developing multifunctional sonosensitizer with bioavailability,tumor accumulation and visualization remains challenging to ultimately enable their clinical translation.To address these issues,a new supramolecular strategy is developed by utilizing rationally designed enzyme responsive peptides(AAGFLGRRRRRRRR)to conjugate a novel porphyrin-based sonosensitizer purpurin 18 as small molecule precursors(P18AAGFLGRRRRRRRR,P18-P).This amphiphile P18-P peptide was composed of P18 as the functional molecule,Gly-Phe-Leu-Gly(GFLG)as the cathepsin B enzyme responsive peptide linker,and eight arginines(RRRRRRRR,R8)as the cell-penetrating ligand,Ala-Ala as structural ligand.Initially,P18-P in physiological environment readily diffused,extravasated,and penetrated cancer cell membranes.Then,cathepsin B,which was overexpressed in the tumoral microenvironment,selectively cut the GFLG linker of P18-P.This enhanced the hydrophobicity of the P18 molecules and reduced their steric hindrance,resulting in simultaneous self-assembly of the building blocks in tumor cells.Finally,the self-assembled fibrous nanostructures exhibited prolonged retention time in tumor cells,directly resulting in enzyme responsive PA signal,ROS generation,and sonodynamic effect.In conclusion,these peptideporphyrin conjugates may serve as a promising sonotheranostic platform.