Activatable Mitochondria-Targeting Organoarsenic Prodrugs for Bioenergetic Cancer Therapy.

Despite widespread applications for cancer treatment, chemotherapy is restricted by several limitations, including low targeting specificity, acquired drug resistance, and concomitant adverse side effects. It remains challenging to overcome these drawbacks. Herein, we report a new bioenergetic approach for treating cancer efficiently. As a proof-of-concept, we construct activatable mitochondria-targeting organoarsenic prodrugs from organoarsenic compounds and traditional chemotherapeutics. These prodrugs could accomplish selective delivery and controlled release of both therapeutic agents to mitochondria, which synergistically promote mitochondrial ROS production and induce mitochondrial DNA damage, finally leading to mitochondria-mediated apoptosis of cancer cells. Our in vitro and in vivo experiments reveal the excellent anticancer efficacy of these prodrugs, underscoring the encouraging outlook of this strategy for effective cancer therapy.

Fluorinated Gadolinium Chelate-Grafted Nanoconjugates for Contrast-Enhanced T1-Weighted 1H and pH-Activatable 19F Dual-Modal MRI.

Magnetic resonance imaging (MRI) is one of the most popular imaging techniques, which offers an ionization-free noninvasive means for imaging deep tissues with high resolution. Conventional 1H MRI is well versed in providing detailed anatomical information but suffers from low contrast for tracking biomarkers because of the abundance of water in living bodies. 19F MRI with negligible endogenous background interference enables highly sensitive detection of biomolecular targets and has drawn extensive attention from the biomedical research community recently. However, this imaging technique only acquires the "hot spot" signals of exogenous 19F nucleus-containing imaging probes. 1H/19F MRI dual-modal imaging is expected to compensate for the limitations of either single-modal imaging and accomplish synergistic morphological and physiological imaging. Herein, we report a highly biocompatible nanoconjugate composed of pH-responsive 19F nucleus-bearing Gd3+ chelates, which enables significant contrast enhancement for T1-weighted 1H MRI and permits pH-responsive activation of 19F signals for 19F MRI, providing both clear anatomical details of living bodies and the biorelevant molecular information with low background interference. This nanoconjugate facilitates sensitive and accurate detection of tumors with contrast-enhanced T1-weighted 1H and pH-activatable 19F dual-modal imaging on a single MRI scanner.

Reversible redox-responsive 1H/19F MRI molecular probes.

Herein we report a pair of redox-responsive manganese complexes Mn(iii)/(ii)-N,N'-bis(2-hydroxy-4-trifluoromethylbenzyl)ethylenediamine-N,N'-diacetate (HTFBED, L1), which are water soluble and biologically interconvertible, as reversible redox-responsive probes in 1H/19F MRI for detecting and imaging biological redox species, offering a means to access valuable redox information associated with various diseases.

Cascaded Multiresponsive Self-Assembled 19F MRI Nanoprobes with Redox-Triggered Activation and NIR-Induced Amplification.

Molecular probes featuring promising capabilities including specific targeting, high signal-to-noise ratio, and in situ visualization of deep tissues are in great demand for tumor diagnosis and therapy. 19F magnetic resonance imaging (MRI) techniques incorporating stimuli-responsive probes are anticipated to be highly beneficial for specific detection and imaging of tumors because of negligible background and deep tissue penetration. Herein, we report a cascaded multiresponsive self-assembled nanoprobe, which enables sequential redox-triggered and near-infrared (NIR) irradiation-induced 19F MR signal activation/amplification for sensing and imaging. Specifically, we designed and synthesized a cascaded multiresponsive 19F-bearing nanoprobe based on the self-assembly of amphiphilic redox-responsive 19F-containing polymers and NIR-absorbing indocyanine green (ICG) molecules. It could realize the activation of 19F signals in the reducing tumor microenvironment and subsequent signal amplification via the photothermal process. This stepwise two-stage activation/amplification of 19F signals was validated by 19F NMR and MRI both in vitro and in vivo. The multiresponsive 19F nanoprobes capable of cascaded 19F signal activation/amplification and photothermal effect exertion can provide accurate sensing and imaging of tumors.

A fluorinated bihydrazide conjugate for activatable sensing and imaging of hypochlorous acid by 19F NMR/MRI.

Hypochlorous acid (HClO) is one of the most important reactive oxygen species (ROS) and plays a vital role in many physiological and pathological processes. The comprehensive exploration of mechanistic details and the potential clinical translation necessitate the development of reliable probes for prompt and accurate detection of HClO in complex biological environments. Herein we report a fluorinated bihydrazide conjugate as a 19F NMR/MRI probe with a "turn-on" character for the detection of HClO. This probe could selectively respond to HClO, leading to a significant recovery of 19F signals for 19F NMR/MRI. Activatable sensing and imaging of HClO were achieved with SMMC-7721 cells and nude mice, which demonstrates that this small molecular conjugate could serve as a selective probe for real-time sensing and imaging of HClO in biological systems.

Versatile Octapod-Shaped Hollow Porous Manganese(II) Oxide Nanoplatform for Real-Time Visualization of Cargo Delivery.

Multifunctional nanoplatforms featuring promising properties including excellent loading efficiency, real-time monitoring, and improved cargo bioavailability and bioselectivity are in great demand by the biomedical research community. During the development of such nanoplatforms, stimuli-responsive nanoparticles (NPs) as a smart nanoplatform have recently received extensive attention. Herein, we report small-sized octapod-shaped hollow porous manganese(II) oxide (HPMO) NPs as a stimuli-responsive T1-activatable nanoplatform for tumor-specific cargo delivery and real-time monitoring. The HPMO NPs functionalized by zwitterionic dopamine sulfonate (ZDS) can act as a versatile platform to load organic dyes or chemotherapeutic drugs with high loading efficiency. The obtained Cargo@HPMO would decompose into paramagnetic Mn2+ ions and subsequently release cargoes in mild acidic conditions, especially in tumor microenvironment and lysosome. The released Mn2+ can enhance T1 magnetic resonance signal for real-time monitoring of the cargo delivery in vivo. This octapod-shaped Cargo@HPMO can act as a smart and versatile nanoplatform with pH-responsive multimodal imaging and site-specific drug delivery for the development of accurate diagnosis and effective therapy for cancer.

Targeted arsenite-loaded magnetic multifunctional nanoparticles for treatment of hepatocellular carcinoma.

Arsenic trioxide (ATO), an FDA-approved drug for acute promyelocytic leukemia, also has great potential for treatment of solid tumors. Drug delivery powered by recent advances in nanotechnology has boosted the efficacy of many drugs, which is enlightening for applications of ATO in treating solid tumors. Herein, we reported arsenite-loaded multifunctional nanoparticles that are capable of pH-responsive ATO release for treating hepatocellular carcinoma (HCC) and real-time monitoring via magnetic resonance imaging. We fabricated these nanoparticles (designated as magnetic large-pore mesoporous silica nanoparticle (M-LPMSN)-NiAsO x ) by loading nanoparticulate ATO prodrugs (NiAsO x ) into the pores of large-pore mesoporous silica nanoparticles (LPMSNs) that contain magnetic iron oxide nanoparticles in the center. The surface of these nanodrugs was modified with a targeting ligand folic acid (FA) to further enhance the drug efficacy. Releasing profiles manifest the responsive discharging of arsenite in acidic environment. In vitro experiments with SMMC-7721 cells reveal that M-LPMSN-NiAsO x -FA nanodrugs have significantly higher cytotoxicity than traditional free ATO and induce more cell apoptosis. In vivo experiments with mice bearing H22 tumors further confirm the superior antitumor efficacy of M-LPMSN-NiAsO x -FA over traditional free ATO and demonstrate the outstanding imaging ability of M-LPMSN-NiAsO x -FA for real-time tumor monitoring. These targeted arsenite-loaded magnetic mesoporous silica nanoparticles integrating imaging and therapy hold great promise for treatment of HCC, indicating the auspicious potential of LPMSN-based nanoplatforms.

Facile synthesis of aquo-cisplatin arsenite multidrug nanocomposites for overcoming drug resistance and efficient combination therapy.

Cisplatin (CDDP) and arsenic trioxide (ATO), two representative inorganic anticancer drugs, have been successful in the treatment against several kinds of malignancies. However, combination therapy with these two drugs in clinical application suffers from poor pharmacokinetics, serious side effects, and drug resistance of the tumor. Herein, we report a carrier-free aquo-cisplatin arsenite multidrug nanocomposite loaded with cisplatin and arsenic trioxide prodrugs simultaneously. This nanocomposite achieves a high loading capacity and pH-dependent controlled release of the drugs. Because of these features, this nanocomposite shows better in vitro toxicity against various carcinoma cell lines than either the single drug or free drug combination, promotes the synergistic effect of cisplatin and arsenic trioxide, and significantly inhibits the growth of tumors in vivo. Furthermore, cisplatin and arsenic trioxide in this nanocomposite can realize a coordination of both enhanced DNA damage and DNA repair interference within cisplatin-resistant cells, which results in overcoming the drug resistance effectively. Gene expression profiles demonstrate the reduced expression of proto-oncogenes and DNA damage repair related genes MYC, MET, and MSH2, along with the increase of tumor suppressor genes PTEN, VHL, and FAS after the nanocomposite treatment. This type of multidrug nanocomposite offers an alternative and promising strategy for combination therapy and overcoming drug resistance.