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.
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.
Lysosomes play a critical role in the autophagy process. The impairment of lysosomes can affect the degradation of autophagic cargo, leading to the blockage of autophagy at the lysosomal stage and ...subsequent cell death. Herein, two phosphorescent Re(i) tricarbonyl complexes (Re1 and Re2) bearing β-carboline derivatives have been synthesized and characterized. Both complexes show pH-dependent phosphorescence, which can be used to specifically image the lysosomes. Cytotoxicity assay shows that they exhibit high anticancer activity and are able to overcome cross-resistance to cisplatin. Re2 can induce autophagy, which is blocked at the lysosomal stage due to lysosomal dysfunction, such as the decrease of cathepsin B activity, subsequently leading to both autophagy and apoptosis dependent cell death. In vivo studies revealed that it could significantly inhibit tumor growth.
Copper complexes have long been considered as a promising class of anticancer or antibacterial therapeutics. In this paper, two novel copper(II) complexes containing a β-carboline derivative and ...amino acids, namely Cu(1-Im-βc)(L-Val)ClO
·0.5H
O (Cu1) and Cu(1-Im-βc)(L-Phe)ClO
·0.5H
O (Cu2), where 1-Im-βc = 1-(2-imidazolyl)-β-carboline, L-Val = L-valine, and L-Phe = L-phenylalanine, were designed and synthesized. The complexes were characterized by elemental analysis, infrared spectroscopy, molar conductivity measurements, and mass spectrometry to determine their spatial structures and compositions. Both complexes bind to DNA by insertion. The complexes also show a good affinity for human serum albumin (HSA). In addition, the antitumor activity of the two complexes against lung cancer cells (A549), cervical cancer cells (HeLa), and breast cancer cells (MBA-MD-231) is significantly superior to that of the traditional antitumor drug, cisplatin. Finally, the anticancer mechanism results show that the complexes can induce apoptosis in HeLa cells, which is associated with mitochondrial damage, oxidative stress caused by reactive oxygen species (ROS) production, and activation of the caspase protein family. This study demonstrates that the introduction of aromatic heterocyclic alkaloid ligands with a broad spectrum of biological activities and water-soluble amino acid ligands into copper complexes can regulate their amphiphilic properties and biological activity, so as to obtain highly efficient copper-based therapeutics.
Cisplatin resistance in tumor cells is known mainly due to the reduced accumulation of platinum ions by efflux, detoxification by intracellular GSH, and nucleotide excision repair machinery-mediated ...nuclear DNA repair. In this work, theranostic Pt(IV)-NPs, which are precisely self-assembled by biotin-labeled Pt(IV) prodrug derivative and cyclodextrin-functionalized IR780 in a 1:1 molecular ratio, have been developed for addressing all these hurdles via mitochondria-targeted chemotherapy solely or chemophotothermal therapy. In these nanoparticles, IR780 as a small-molecule dye acts as a mitochondria-targeting ligand to make Pt(IV)-NPs relocate finally in the mitochondria and release cisplatin. As demonstrated by in vitro and in vivo experiments, Pt(IV)-NPs can markedly facilitate cancer-specific mitochondrial targeting, inducing mitochondrial dysfunction and mitochondrial DNA (mtDNA) damage, thus greatly increasing the Pt accumulation, reducing the GSH levels, and avoiding DNA repair machinery in cisplatin-resistant cancer cells (A549R), finally resulting in significant inhibition of A549R tumor growth on animal models by chemotherapy solely. Upon near-infrared irradiation, mitochondria-targeted chemophotothermal synergistic therapy can be realized, further overcoming cisplatin resistance and even eliminating A549R tumors completely. Moreover, such novel Pt(IV)-NPs integrate multimodal targeting (cancer and mitochondria targeting), imaging (near-infrared imaging and photoacoustic imaging), and therapeutic (chemo- and photothermal therapy) moieties in a constant ratio (1:1:1) into a single, reproducible, and structurally homogeneous entity, avoiding nonuniform drug loading and premature leakage as well as the discrete steps of imaging and therapy, which thus is more beneficial for precise therapeutics and future clinical translation.
Regulation of tumor hypoxia and redox homeostasis is a promising strategy for cancer therapy. Nanocatalytic medicine has played more and more important roles in this field because it can cleverly ...convert the efficiency and selectivity of catalysis into high therapeutic efficiency. Herein, we developed a platinum(
iv
)-ruthenium hybrid prodrug, named as
Pt-Ru
, for efficient chemo-catalytic synergistic therapy of hypoxic tumors. The ruthenium hybridization endowed the Pt(
iv
) prodrug with multi-enzyme catalytic activity, that is, mimicking catalase (CAT) to generate O
2
in situ
, mimicking peroxidase (POD) to produce reactive oxygen species, and mimicking glutathione peroxidase (GPx) to deplete GSH, thus effectively overcoming tumor hypoxia and cisplatin resistance. As a result,
Pt-Ru
treatment led to a superior anticancer efficacy to cisplatin both
in vitro
and
in vivo
. This work suggested redox homeostasis regulation as a tantalizing angle for developing the next generation of platinum drugs.
Regulation of tumor hypoxia and redox homeostasis is a promising strategy for cancer therapy.
Harsh photothermal temperatures, long-term body retention of nanoagents, elevated ROS and inflammation induction all threaten the normal tissues, thus hindering the translation of photothermal ...therapy (PTT) from bench to clinical practice. To resolve these problems, we have developed a disassembled theranostic nanodrug Qu-FeIIP based on the quercetin coordination. Herein, quercetin is not only the heat shock protein (Hsp 70) inhibitor but also the skeleton of Qu-FeIIP, realizing near-infrared light induced low-temperature PTT (45 °C) to ablate tumor completely without heat stress to normal tissues. Owing to the ROS scavenging ability of quercetin, Qu-FeIIP effectively reduces intracellular ROS and in vivo inflammatory factors (TNF-α, IL-6, IFN-γ) levels. Simultaneously, quercetin-Fe coordination is weakened when scavenging ROS, which triggers the Qu-FeIIP disassembling, resulting in effective clearance of nanoparticles from main organs 168 h post intravenous injection. Additionally, the photoacoustic and magnetic resonance dual-imaging capability of Qu-FeIIP offers excellent spatial resolution and imaging depth not only for precise tumor diagnosis but also for monitoring the nanodrug disassembling in vivo. Thus, Qu-FeIIP intrinsically integrates precise diagnosis, excellent low-temperature PTT efficacy, ROS elimination and anti-inflammatory action, dynamic disassembly and renal clearance ability into a single nanodrug, which is very promising for future clinical cancer treatment.
Personalized in situ tumor vaccination is a promising immunotherapeutic modality. Currently, seeking immunogenic cell death (ICD) to generate in situ tumor vaccines is still mired by insufficient ...immunogenicity and an entrenched immunosuppressive tumor microenvironment (TME). Herein, a series of tetrazine-functionalized ruthenium(II) sonosensitizers have been designed and screened for establishing a bioorthogonal-activated in situ tumor vaccine via oncolytic pyroptosis induction. Based on nanodelivery-augmented bioorthogonal metabolic glycoengineering, the original tumor is selectively remolded to introduce artificial target bicycle 6.1.0 nonyne (BCN) into cell membrane. Through specific bioorthogonal ligation with intratumoral BCN receptors, sonosensitizers can realize precise membrane-anchoring and synchronous click-activation in desired tumor sites. Upon ultrasound (US) irradiation, the activated sonosensitizers can intensively disrupt the cell membrane with dual type I/II reactive oxygen species (ROS) generation for a high-efficiency sonodynamic therapy (SDT). More importantly, the severe membrane damage can eminently evoke oncolytic pyroptosis to maximize tumor immunogenicity and reverse immunosuppressive TME, ultimately eliciting powerful and durable systemic antitumor immunity. The US-triggered pyroptosis is certified to effectively inhibit the growths of primary and distant tumors, and suppress tumor metastasis and recurrence in “cold” tumor models. This bioorthogonal-driven tumor-specific pyroptosis induction strategy has great potential for the development of robust in situ tumor vaccines.
Mitochondria-targeted photodynamic therapy (PDT) has recently been recognized as a promising strategy for effective cancer treatment. In this work, a mitochondria-targeted near-infrared (NIR) ...aggregation-induced emission (AIE)-active phosphorescent Ir(III) complex (Ir1) is reported with highly favourable mitochondria-targeted bioimaging and cancer PDT properties. Complex Ir1 has strong absorption in the visible light region (∼500 nm) and can effectively produce singlet oxygen (
O
) under green light (525 nm) irradiation. It preferentially accumulates in the mitochondria of human breast cancer MDA-MB-231 cells as revealed by colocalization analysis. Complex Ir1 displays high phototoxicity toward human breast cancer MDA-MB-231 cells and mouse breast cancer 4T1 cells. Complex Ir1 induces reactive oxygen species (ROS) production, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress in MDA-MB-231 cells upon photoirradiation, leading to apoptotic cell death. The favorable PDT performance of Ir1
has been further demonstrated in tumour-bearing mice. Together, the results suggest that Ir1 is a promising photosensitizer for mitochondria-targeted imaging and cancer phototherapy.
Metal copper complexes have attracted extensive attention as potential alternatives to platinum-based anticancer drugs due to their possible different modes of action. Herein, a new copper(II) ...gluconate complex, namely Cu(DPQ)(Gluc)·2H2O (CuGluc, DPQ = pyrazino2,3-f1,10phenanthroline), with good water-solubility and high anticancer activity was synthesized by using D-gluconic acid (Gluc-2H) as an auxiliary ligand. The complex was well characterized by single-crystal X-ray diffraction analysis, elemental analysis, molar conductivity, and Fourier transform infrared spectroscopy (FTIR). The DNA-binding experiments revealed that CuGluc was bound to DNA by intercalation with end-stacking binding. CuGluc could oxidatively cleave DNA, in which 1O2 and H2O2 were involved. In addition, CuGluc was bound to the IIA subdomain of human serum albumin (HSA) through hydrophobic interaction and hydrogen bonding, showing a good affinity for HSA. The complex showed superior anticancer activity toward several cancer cells than cisplatin in vitro. Further studies indicated that CuGluc caused apoptotic cell death in human liver cancer (HepG2) cells through elevated intracellular reactive oxygen species (ROS) levels, mitochondrial dysfunction, cell cycle arrest, and caspase activation. Interestingly, CuGluc also triggered the ferroptosis mechanism through lipid peroxide accumulation and inhibition of glutathione peroxidase 4 (GPX4) activity. More importantly, CuGluc significantly inhibited tumor growth in vivo, which may benefit from the combined effects of apoptosis and ferroptosis. This work provides a promising strategy to develop highly effective antitumor copper complexes by coordinating with the glucose metabolite D-gluconic acid and exploiting the synergistic effects of apoptosis and ferroptosis mechanisms.
A new copper(II) gluconate complex (CuGluc) with good water-solubility and high anticancer activity was synthesized and its structure was confirmed by single-crystal X-ray diffraction analysis. Interestingly, CuGluc triggers both apoptosis and ferroptosis in cancer cells. More importantly, CuGluc shows better antitumor activity than cisplatin in vivo. Display omitted
•A water-soluble Cu(II) complex has been synthesized and characterized.•The complex interacts with DNA by intercalation and shows a good affinity for HSA.•The complex triggers apoptosis and ferroptosis of cancer cells.•The complex shows potent in vivo antitumor activity.
