Hypoxia and the acidic microenvironment play a vital role in tumor metastasis and angiogenesis, generally compromising the chemotherapeutic efficacy. This provides a tantalizing angle for the design ...of platinum(IV) prodrugs for the effective and selective killing of solid tumors. Herein, two carbonic anhydrase IX (CAIX)‐targeting platinum(IV) prodrugs have been developed, named as CAIXplatins. Based on their strong affinity for and inhibition of CAIX, CAIXplatins can not only overcome hypoxia and the acidic microenvironment, but also inhibit metabolic pathways of hypoxic cancer cells, resulting in a significantly enhanced therapeutic effect on hypoxic MDA‐MB‐231 tumors both in vitro and in vivo compared with cisplatin/oxaliplatin, accompanied with excellent anti‐metastasis and anti‐angiogenesis activities. Furthermore, the cancer selectivity indexes of CAIXplatins are 70–90 times higher than those of cisplatin/oxaliplatin with effectively alleviated side‐effects.
Tumor microenvironment and metabolism regulation can be achieved by targeting carbonic anhydrase IX with platinum(IV) prodrugs, termed CAIXplatins. This strategy could be used to treat hypoxic and aggressive tumors. The advantages of CAIXplatins in comparison to cisplatin/oxaliplatin include the greatly increased cancer selectivity index, enhanced therapeutic efficiency, reduced level of side‐effects, as well as the excellent anti‐angiogenesis activity.
G‐quadruplex DNA show structural polymorphism, leading to challenges in the use of selective recognition probes for the accurate detection of G‐quadruplexes in vivo. Herein, we present a tripodal ...cationic fluorescent probe, NBTE, which showed distinguishable fluorescence lifetime responses between G‐quadruplexes and other DNA topologies, and fluorescence quantum yield (Φf) enhancement upon G‐quadruplex binding. We determined two NBTE‐G‐quadruplex complex structures with high Φf values by NMR spectroscopy. The structures indicated NBTE interacted with G‐quadruplexes using three arms through π–π stacking, differing from that with duplex DNA using two arms, which rationalized the higher Φf values and lifetime response of NBTE upon G‐quadruplex binding. Based on photon counts of FLIM, we detected the percentage of G‐quadruplex DNA in live cells with NBTE and found G‐quadruplex DNA content in cancer cells is 4‐fold that in normal cells, suggesting the potential applications of this probe in cancer cell detection.
G4 imaging: A tripodal cationic fluorescence probe, NBTE, was used for the visualization (based on fluorescence lifetime) and quantification (based on photon counts) of G‐quadruplex DNA in live cells by fluorescence lifetime imaging microscopy (FLIM). Structural studies provided a structural basis for the DNA‐topology‐based fluorescence response of NBTE.
During autophagy, the intracellular components are captured in autophagosomes and delivered to lysosomes for degradation and recycling. Changes in lysosomal trafficking and contents are key events in ...the regulation of autophagy, which has been implicated in many physiological and pathological processes. In this work, two iridium(III) complexes (LysoIr1 and LysoIr2) are developed as theranostic agents to monitor autophagic lysosomes. These complexes display lysosome‐activated phosphorescence and can specifically label lysosomes with high photostability. Simultaneously, they can induce autophagy potently without initiating an apoptosis response. We demonstrate that LysoIr2 can effectively implement two functions, namely autophagy induction and lysosomal tracking, in the visualization of autophagosomal–lysosomal fusion. More importantly, they display strong two‐photon excited fluorescence (TPEF), which is favorable for live cell imaging and in vivo applications.
Kill Two Birds with One Stone: Two iridium(III) complexes can specifically image lysosomes and induce an autophagic response in live cells. The combination of these two intriguing properties makes them ideal theranostic agents to track lysosomal changes during autophagic processes. Additionally, these complexes display strong two‐photon excited fluorescence, which is favorable for live cell imaging and in vivo applications.
The development and malignancy of cancer cells are closely related to the changes of the epigenome. In this work, a mitochondria‐targeted rhenium(I) complex (DFX‐Re3), integrating the clinical iron ...chelating agent deferasirox (DFX), has been designed. By relocating iron to the mitochondria and changing the key metabolic species related to epigenetic modifications, DFX‐Re3 can elevate the methylation levels of histone, DNA, and RNA. As a consequence, DFX‐Re3 affects the events related to apoptosis, RNA polymerases, and T‐cell receptor signaling pathways. Finally, it is shown that DFX‐Re3 induces immunogenic apoptotic cell death and exhibits potent antitumor activity in vivo. This study provides a new approach for the design of novel epigenetic drugs that can recode the cancer epigenome by intervening in mitochondrial metabolism and iron homeostasis.
Reported here is a mitochondria‐targeted ReI complex, DFX‐Re3, that can relocate iron to the mitochondria and change the metabolites related to epigenetics. DFX‐Re3 can elevate the methylation levels of histone/DNA/RNA, affect RNA polymerase activities, and induce immunogenic apoptosis. This study provides a new approach to the design of epigenetic drugs for recoding the cancer epigenome by intervening in mitochondrial metabolism and iron homeostasis.
Elucidation of relationship among chemical structure, cellular uptake, localization, and biological activity of anticancer metal complexes is important for the understanding of their mechanisms of ...action. Organometallic rhenium(I) tricarbonyl compounds have emerged as potential multifunctional anticancer drug candidates that can integrate therapeutic and imaging capabilities in a single molecule. Herein, two mononuclear phosphorescent rhenium(I) complexes (Re1 and Re2), along with their corresponding dinuclear complexes (Re3 and Re4), were designed and synthesized as potent anticancer agents. The subcellular accumulation of Re1–Re4 was conveniently analyzed by confocal microscopy in situ in live cells by utilizing their intrinsic phosphorescence. We found that increased lipophilicity of the bidentate ligands could enhance their cellular uptake, leading to improved anticancer efficacy. The dinuclear complexes were more potent than the mononuclear counterparts. The molecular anticancer mechanisms of action evoked by Re3 and Re4 were explored in detail. Re3 with a lower lipophilicity localizes to lysosomes and induces caspase‐independent apoptosis, whereas Re4 with higher lipophilicity specially accumulates in mitochondria and induces caspase‐independent paraptosis in cancer cells. Our study demonstrates that subcellular localization is crucial for the anticancer mechanisms of these phosphorescent rhenium(I) complexes.
Directing by design: The anticancer mechanisms of phosphorescent rhenium(I) tricarbonyl polypyridine complexes are found to be closely associated with their organelle‐specific localizations (see figure).
Stimuli-activatable photosensitizers (PSs) are highly desirable for photodynamic therapy (PDT) to selectively demolish tumor cells. On the other hand, lysosomes are emerging as attractive anticancer ...targets. Herein, four cyclometalated iridium(iii)-β-carboline complexes with pH-responsive singlet oxygen (
O
) production and lysosome-specific imaging properties have been designed and synthesized. Upon visible light (425 nm) irradiation, they show highly selective phototoxicities against cancer cells. Notably, complex
(Ir(N^C)
(N^N)(PF
) in which N^C = 2-phenylpyridine and N^N = 1-(2-benzimidazolyl)-β-carboline) displays a remarkably high phototoxicity index (PI = IC
in the dark/IC
in light) of >833 against human lung carcinoma A549 cells. Further studies show that
-mediated PDT induces caspase-dependent apoptosis through lysosomal damage. The pH-responsive phosphorescence of complex
can be utilized to monitor the lysosomal integrity upon PDT, which provides a reliable and convenient method for
monitoring of therapeutic effect and real-time assessment of treatment outcome. Our work provides a strategy for the construction of highly effective multifunctional subcellular targeted photodynamic anticancer agents through rational structural modification of phosphorescent metal complexes.
Phosphorescent metal complexes are a new kind of multifunctional antitumor compounds that can integrate imaging and antitumor functions in a single molecule. In this minireview, we summarize the ...recent research progress in this field, concentrating on the theranostic applications of phosphorescent iridium(
iii
), ruthenium(
ii
) and rhenium(
i
) complexes. The molecular design that affords these complexes with tumour- or subcellular organelle-targeting properties is elucidated. The potential of these complexes to induce and monitor the dynamic behavior of subcellular organelles and the changes in microenvironment during the process of therapy is demonstrated. Moreover, the potential and advantages of applying new technologies, such as super-resolution imaging and phosphorescence lifetime imaging, are also described. Finally, the challenges faced in the development of novel theranostic metallo-anticancer complexes for possible clinical translation are proposed.
The recent development in phosphorescent iridium, ruthenium and rhenium complexes as theranostic anticancer agents is summarized.
Precise quantitative measurement of viscosity at the subcellular level presents great challenges. Two-photon phosphorescence lifetime imaging microscopy (TPPLIM) can reflect micro-environmental ...changes of a chromophore in a quantitative manner. Phosphorescent iridium complexes are potential TPPLIM probes due to their rich photophysical properties including environment-sensitive long-lifetime emission and high two-photon absorption (TPA) properties. In this work, a series of iridium(iii) complexes containing rotatable groups are developed as mitochondria-targeting anticancer agents and quantitative viscosity probes. Among them,
(Ir(ppy-CHO)
(dppe)PF
; ppy-CHO: 4-(2-pyridyl)benzaldehyde; dppe:
-1,2-bis(diphenylphosphino)ethene) shows satisfactory TPA properties and long lifetimes (up to 1 μs). The emission intensities and lifetimes of
are viscosity-dependent, which is mainly attributed to the configurational changes in the diphosphine ligand as proved by
H NMR spectra.
displays potent cytotoxicity, and mechanism investigations show that it can accumulate in mitochondria and induce apoptotic cell death. Moreover,
can induce mitochondrial dysfunction and monitor the changes in mitochondrial viscosity simultaneously in a real-time and quantitative manner
TPPLIM. Upon
treatment, a time-dependent increase in viscosity and heterogeneity is observed along with the loss of membrane potential in mitochondria. In summary, our work shows that multifunctional phosphorescent metal complexes can induce and precisely detect microenvironmental changes simultaneously at the subcellular level using TPPLIM, which may deepen the understanding of the cell death mechanisms induced by these metallocompounds.
G‐quadruplexes (G4s) are prevalent in oncogenes and are potential antitumor drug targets. However, binding selectivity of compounds to G4s still faces challenges. Herein, we report a platinum(II) ...complex (Pt1), whose affinity to G4‐DNA is activated by adaptive binding and selectivity controlled by binding kinetics. The resolved structure of Pt1/VEGF‐G4 (a promoter G4) shows that Pt1 matches 3′‐G‐tetrad of VEGF‐G4 through Cl−‐dissociation and loop rearrangement of VEGF‐G4. Binding rate constants are determined by coordination bond breakage/formation, correlating fully with affinities. The selective rate‐determining binding step, Cl−‐dissociation upon G4‐binding, is 2–3 orders of magnitude higher than dsDNA. Pt1 potently targets G4 in living cells, effectively represses VEGF expression, and inhibits vascular growth in zebrafish. We show adaptive G4‐binding activation and controlled by kinetics, providing a complementary design principle for compounds targeting G4 or similar biomolecules.
A PtII compound was synthesized and adaptively bound G‐quadruplex DNA through kinetic control. The solution structure of the complex was solved. It was further proved that the compound can target G‐quadruplex in living cells, repress VEGF expression in cancer cells and inhibit blood vessels growth in zebrafish.
Ruthenium complexes are promising photosensitizers (PSs), but their clinical applications have many limitations. Here, a multifunctional nano‐platform PDA‐Pt‐CD@RuFc formed by platinum‐decorated and ...cyclodextrin (CD)‐modified polydopamine (PDA) nanoparticles (NPs) loaded with a ferrocene‐appended ruthenium complex (RuFc) is reported. The NPs can successfully deliver RuFc to the tumor sites. The release of RuFc from the NPs can be triggered by low pH, photothermal heating, and H2O2. The combined photodynamic and photothermal therapy (PDT‐PTT) mediated by PDA‐Pt‐CD@RuFc NPs can overcome the hypoxic environment of tumors from several aspects. First, the platinum NPs can catalyze H2O2 to produce O2. Second, vasodilation caused by photothermal heating can sustain the oxygen supplement. Third, PDT exerted by RuFc can also occur through the non‐oxygen‐dependent Fenton reaction. Due to the presence of PDA, platinum NPs, and RuFc, the nanosystem can be used in multimodal imaging including photothermal, photoacoustic, and computed tomography imaging. The NPs can be excited by the near‐infrared two‐photon light source. Moreover, the combined treatment can improve the tumor microenvironments to obtain an optimized combined therapeutic effect. In summary, this study presents a tumor‐microenvironment‐adaptive strategy to optimize the potential of ruthenium complexes as PSs from multiple aspects.
A multifunctional nanocomposite for ruthenium‐based photosensitizers that can successfully adapt to and remodel tumor microenvironments is developed. The release of the photosensitizer can be triggered by low pH, photothermal heating, and H2O2. The as‐fabricated nanoparticles can accumulate in tumor tissues and show great potential for combined therapy with multimodal imaging capacities.
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