Assembly Transformation Jointly Driven by the LAP Enzyme and GSH Boosting Theranostic Capability for Effective Tumor Therapy

• Published in: ACS applied materials & interfaces Vol. 13; no. 50; pp. 59787 - 59802
• Main Authors: Wang, Anna, Fang, Jing, Ye, Shuyue, Mao, Qiulian, Zhao, Yan, Cui, Chaoxiang, Zhang, Yuqi, Feng, Yali, Li, Jiachen, He, Lei, Qiu, Ling, Shi, Haibin
• Format: Journal Article
• Language: English
• Published: United States 22.12.2021
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; aqueous solutions; Biocompatible Materials - chemical synthesis; Biocompatible Materials - chemistry; Biocompatible Materials - pharmacology; Cell Proliferation - drug effects; Cell Survival - drug effects; Chlorophyllides - chemistry; Chlorophyllides - pharmacology; condensation reactions; Drug Screening Assays, Antitumor; enzymes; fluorescence; glutathione; Glutathione - metabolism; Hep G2 Cells; Humans; leucine; Leucyl Aminopeptidase - metabolism; liver; Liver Neoplasms, Experimental - drug therapy; Liver Neoplasms, Experimental - metabolism; Liver Neoplasms, Experimental - pathology; magnetism; Materials Testing; moieties; Molecular Structure; neoplasms; Optical Imaging; oxygen; Particle Size; Photochemotherapy; photosensitizing agents; Photosensitizing Agents - chemistry; Photosensitizing Agents - pharmacology; radiotherapy; shrinkage; Theranostic Nanomedicine; radiotherapy; smart probe; assembly transformation; stimulus-responsive; photodynamic therapy; bioimaging
• DOI: 10.1021/acsami.1c21062
• ISSN: 1944-8244; 1944-8252

Developing intelligent and morphology-transformable nanomaterials that can spatiotemporally undergo stimulus-responsive size transformation holds great promise for improving the tumor delivery efficiency of drugs . Here, we report a smart size-transformable theranostic probe Ce6-Leu consisting of a leucine amino peptidase (LAP) and glutathione (GSH) dual-responsive moiety, an 1,2-aminothiol group, and a clinically used photosensitizer Ce6. This probe tends to self-assemble into uniform nanoparticles with an initial size of ∼80 nm in aqueous solution owing to the amphiphilic feature. Surprisingly, taking advantage of the biocompatible CBT-Cys condensation reaction, the large nanoprobes can be transformed into tiny nanoparticles (∼23 nm) under the joint action of LAP and GSH in a tumor microenvironment, endowing them with great tumor accumulation and deep tissue penetration. Concomitantly, this LAP/GSH-driven disassembly and size shrinkage of Ce6-Leu can also activate the fluorescence/magnetic resonance signals and the photodynamic effect for enhanced multimodal imaging-guided photodynamic therapy of human liver HepG2 tumors . More excitingly, the Mn -chelating probe (Ce6-Leu@Mn ) was demonstrated to have the capability to catalyze endogenous H O to persistently release O at the hypoxic tumor site, as a consequence improving the oxygen supply to boost the radiotherapy effect. We thus believe that this LAP/GSH-driven size-transformable nanosystem would offer a novel advanced technology to improve the drug delivery efficiency for achieving precise tumor diagnosis and treatment.