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

Abstract

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 in vivo. Here, we report a smart sizetransformable 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 in vivo. More excitingly, the Mn 2+ -chelating probe (Ce6-Leu@Mn 2+ ) was demonstrated to have the capability to catalyze endogenous H 2 O 2 to persistently release O 2 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.

CBT‐Cys click reaction for optical bioimaging in vivo

“…[81][82][83] Considering that CBT-Cys click reaction enables enhanced accumulation and retention of theranostic agents in tumors, Wang et al for the first time designed a CBT-Cys probe Citraconic-Cys(StBu)-Lys(Cy7)-CBT (Cy-1) for FLI/PAI dual-modal imaging of tumors. 46 This probe was specifically activated by characteristic acidic pH and reductive GSH of tumor microenvironment, 48 underwent the CBT-Cys click reaction, then formed nanoparticles in tumors, exhibiting a significantly enhanced sensitivity of NIR FLI/PAI of tumors in living mice. More recently, Fu et al proposed a caspase-3-activable CBT-Cys NIR-II FLI/PAI bimodal nanoprobe IR1048-Asp-Glu-Val-Asp-Cys(StBu)-(AuNNP)-CBT (7) for early evaluation of radiotherapy (RT) effect (Figure 2H).…”

Development of nanotechnology-mediated precision radiotherapy for anti-metastasis and radioprotection

“…In addition to single endogenous stimulus-responsive radiosensitization, radiosensitizers that can respond to two endogenous stimuli, such as pH/GSH, 103 GSH/hypoxia, 256 pH/enzyme, 257,258 pH/hypoxia, 259 GSH/ROS, 60,260 etc. , are also trending.…”

“…3.1.6 Dual endogenous stimuli responsiveness. In addition to single endogenous stimulus-responsive radiosensitization, radiosensitizers that can respond to two endogenous stimuli, such as pH/GSH, 103 GSH/hypoxia, 256 pH/enzyme, 257,258 pH/ hypoxia, 259 GSH/ROS, 60,260 etc., are also trending. These dual endogenous stimuli-responsive radiosensitizers can yield a better radiosensitizing effect and improve the accuracy of radiosensitizer delivery for more precise cancer RT.…”

A tumor-targetable NIR probe with photoaffinity crosslinking characteristics for enhanced imaging-guided cancer phototherapy

“…Over the past few decades, in an attempt to improve cancer diagnostic and therapeutic outcomes, tremendous efforts have been devoted to promoting the enrichment of theranostic agents within tumors through passive targeting based on the EPR effect, [19][20][21][22] long-term blood circulation, 23 and active targeting using specic ligands (e.g. antibodies, peptides, and folic acid [24][25][26] ) that can signicantly improve the ligand-receptor binding affinity. Recently, a stimulus-responsive strategy has aroused increasing interest for locally inducing self-assembly of small molecules to form nanostructures at tumorous sites under specic physiological or pathological environments.…”