Anthracyclines rank among the most efficacious anticancer medications. However, their clinical utility and oncologic efficacy are severely compromised by the cardiotoxicity risk facing the early-diagnosis difficulty and their unclear molecular mechanism. Herein, a two-photon-excitable and near-infrared-emissive fluorescent probe, TPNIR-FP, was fabricated and endowed with extraordinary specificity and sensitivity and a rapid response toward peroxynitrite (ONOO), as well as mitochondria-targeting ability. With the aid of TPNIR-FP, we demonstrate that mitochondrial ONOO is upregulated in the early stage and contributes to the onset and progression of anthracycline cardiotoxicity in cardiomyocyte and mouse models; therefore, it represents an early biomarker to predict subclinical cardiotoxicity induced by drug challenge. Furthermore, TPNIR-FP is proved to be a robust imaging tool to provide critical insights into drug-induced cardiotoxicity and other ONOO-related pathophysiological processes.

Alzheimer's disease (AD) involves multiple pathological factors that mutually cooperate and closely contact to form interaction networks for jointly promoting the AD progression. Therefore, the comonitoring of different factors is particularly valuable for elucidating their level dynamics and complex interactions. However, such significant investigations remain a major challenge due to the lack of unimolecular fluorescent probes capable of simultaneous and discriminative visualization of multiple targets. To address this concern, as proof of principle, we rationally designed a unimolecular fluorescent probe to discriminate and simultaneously profile amyloid-β (Aβ) plaques and peroxynitrite (ONOO − ), which are both the pronounced AD pathological factors. Herein, a novel ONOO − reaction trigger was installed onto an Aβ plaque binding fluorophore to generate a dual functional fluorescent probe, displaying completely separate spectral responses to Aβ plaques and ONOO − with high selectivity and sensitivity. With this probe, for the first time, we comonitored the distribution and variation of Aβ plaques and ONOO − through two independent fluorescence channels, demonstrating their close apposition and tight correlation during AD course in live cell and mouse models through two-photon imaging mode. Notably, Aβ aggregates induce the neuronal ONOO − generation, which conversely facilitates Aβ aggregation. The two critical events, ONOO − stress and Aβ aggregation, mutually amplify each other through positive feedback mechanisms and jointly promote the AD onset and progression. Furthermore, by coimaging of the level dynamics of Aβ plaques and ONOO − , we found that the cerebral ONOO − is a potential biomarker, which emerges earlier than Aβ plaques in transgenic mouse models. Overall, the dual-channel responsive performance renders this probe as a powerful imaging tool to decipher Aβ plaque− ONOO − interactions, which will facilitate AD-associated molecular pathogenesis elucidation and multitarget drug discovery.

Peroxynitrite (ONOO − ) is attracting increasing attention due to its involvement in multiple facets of pathophysiological processes. However, ONOO − bioimaging is still challenging due to (1) the lack of highly specific reaction triggers, (2) the tedious and low-yielding synthesis of current sophisticated probes, and (3) the lack of availability of a versatile chemical strategy. To address these challenges, on the basis of amine formylation/deformylation chemistry, we have developed a novel strategy for ONOO − bioimaging. As proof of principle, we designed, synthesized, and evaluated four novel fluorescent probes equipped with the formamide functionality. Although they feature distinctly different fluorophore classes, all probes can be synthesized in one step in high yields and exhibit particularly specific, highly sensitive, and rapid responses to ONOO − . The bioimaging capability is well demonstrated by successfully visualizing ONOO − fluctuation in live cells and major organs of mice suffering from paraquat poisoning. The proposed strategy has proved to be a facile, versatile, and highly efficient methodology for ONOO − visualization, which will greatly facilitate ONOO − biochemistry and pathophysiology.

No abstract

Maspin, a non-inhibitory member of serine protease family, acts as an effective tumor suppressor by inhibiting cell inhesion and mobility. We found that exogenous wild-type rMaspin had a low effect on tumor growth in vivo. However, when the peptide Arg-Gly-Asp-hexahistidine (RGD-6His) was introduced into rMaspin, the modified rMaspin showed significant inhibitory activity in angiogenic assays and tumor-bearing animal models. Overall, our data suggested that both the RGD and hexahistidine fragments contributed to improve the fusion protein activity and polyhistidine peptide could be considered as flexible linker to separate RGD and Maspin moieties to avoid function interference. Besides, it is an efficient tag to achieve purified recombinant proteins. Furthermore, rMaspin fusing with RGD and hexahistidine could be a viable anticancer candidate.