The design of an intelligent nanoprobe capable of intracellular controlled release of apoptosis inducers and subsequent high-fidelity imaging of the drug-induced apoptosis is highly desirable for precise cancer treatment. Herein, we report an intelligent nanoprobe that combined therapeutic and imaging functions in one agent. Briefly, a gold nanoparticle is designed to be conjugated with acid-responsive DNA duplexes (Dox intercalates in this region) and caspase-3-specific cleavable peptides (labeled with fluorophore). We demonstrated that the nanoprobe could efficiently deliver an anticancer drug (Dox) into cancer cells and achieve acid-responsive drug release. Furthermore, the apoptotic process was in situ-monitored by detection of fluorescence through the cleavage of the peptide linker by caspase-3, which is one of the executioner caspases involved in apoptosis. This newly developed nanoprobe could serve as a theranostic agent for targeted responsive chemotherapy and also provide feedback apoptosis imaging of the self-therapeutic effect.
Kai Han,Wei-Yun Zhang,Zhao-Yu Ma,Shi-Bo Wang,Lu-Ming Xu,Jia Liu,Xian-Zheng Zhang,He-You Han
Photodynamic therapy (PDT) holds great promise in tumor treatment. Nevertheless, it remains highly desirable to develop easy-to-fabricated PDT systems with improved tumor accumulation/internalization and timely therapeutic feedback. Here, we report a tumor-acidity-responsive chimeric peptide for enhanced PDT and noninvasive real-time apoptosis imaging. Both in vitro and in vivo studies revealed that a tumor mildly acidic microenvironment could trigger rapid protonation of carboxylate anions in chimeric peptide, which led to increased ζ potential, improved hydrophobicity, controlled size enlargement, and precise morphology switching from sphere to spherocylinder shape of the chimeric peptide. All of these factors realized superfast accumulation and prolonged retention in the tumor region, selective cellular internalization, and enhanced PDT against the tumor. Meanwhile, this chimeric peptide could further generate reactive oxygen species and initiate cell apoptosis during PDT. The subsequent formation of caspase-3 enzyme hydrolyzed the chimeric peptide, achieving a high signal/noise ratio and timely fluorescence feedback. Importantly, direct utilization of the acidity responsiveness of a biofunctional Asp–Glu–Val–Asp–Gly (DEVDG, caspase-3 enzyme substrate) peptide sequence dramatically simplified the preparation and increased the performance of the chimeric peptide furthest.
We demonstrated a novel nanocomposite based on fluorescent turn-on gold nanostars for simultaneous tumor targeting photothermal therapy (PTT) and feedback apoptosis imaging of the self-therapeutic effect. In this theranostic agent ( [email protected] ), gold nanostars (AuNSs) and fluorescent dye Atto 655, as a fluorophore/quencher pair, were conjugated to form intermolecular fluorescence quenching in virtue of the linkage of a caspase-3 responsive peptide. Folic acid targeting moiety facilitated the selective accumulation in cancer cells via receptor-mediated endocytosis. Upon photo irradiation, [email protected] demonstrated excellent photothermal effect and induced cell death with apoptosis related mechanism. The typical apoptosis-effector proteases, caspase-3, was subsequently activated and terminated intramolecular fluorescent quenching process. Obvious fluorescence recovery could be applied to precisely assess the activated caspase-3 expression and the real time therapeutic efficacy. This novel versatile nanocomposite could serve as a theranostic agent for tumor targeting PTT and also provide self-therapeutic monitoring for precise cancer therapeutic applications.
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