Two novel series of (salen)ruthenium(III) complexes bearing guanidine and amidine axial ligands were synthesized, characterized, and evaluated for anticancer activity. In vitro cytotoxicity tests demonstrate that these complexes are cytotoxic against various cancer cell lines and the leading complexes have remarkable cancer-cell selectivity. A detailed study of the guanidine complex 7 and the amidine complex 13 reveals two distinguished modes of action. Complex 7 weakly binds to DNA and induces DNA damage, cell cycle arrest, and typical apoptosis pathways in MCF-7 cells. In contrast, complex 13 induces paraptosis-like cell death hallmarked by massive vacuole formation, mitochondrial swelling, and ER stress, resulting in significant cytotoxicity against human breast cancer cells. Our results provide an extraordinary example of tuning the mechanism of action of (salen)ruthenium(III) anticancer complexes by modifying the structure of the axial ligands.

Upconversion nanoparticles (UCNPs) with the capacity to emit high-energy visible or UV light under low-energy near-infrared excitation have been extensively explored for biomedical applications including imaging and photodynamic therapy (PDT) against cancer. Enhanced cellular uptake and controlled subcellular localization of a UCNP-based PDT system are desired to broaden the biomedical applications of the system and to increase its PDT effect. Herein, we build a multimodal nanoplatform with enhanced therapeutic efficiency based on 808 nm excited NaYbF4:Nd@NaGdF4:Yb/Er@NaGdF4 core–shell–shell nanoparticles that have a minimized overheating effect. The photosensitizer pyropheophorbide a (Ppa) is loaded onto the nanoparticles capped with biocompatible polymers, and the nanoplatform is functionalized with transcriptional activator peptides as targeting moieties. Significantly increased cellular uptake of the nanoparticles and dramatically elevated photocytotoxicity are achieved. Remarkably, colocalization of Ppa with mitochondria, a crucial subcellular organelle as a target of PDT, is proven and quantified. The subsequent damage to mitochondria caused by this colocalization is also confirmed to be significant. Our work provides a comprehensively improved UCNP-based nanoplatform that maintains great biocompatibility but shows higher photocytotoxicity under irradiation and superior imaging capabilities, which increases the biomedical values of UCNPs as both nanoprobes and carriers of photosensitizers toward mitochondria for PDT.

Graphitic carbon nanocubes (GCNCs) were prepared by pyrolysis of ZIF-8 nanocubes. The GCNCs resemble the structure of N-doped graphite and exhibit a high photothermal conversion efficiency of 40.4%. In vitro tests demonstrate that the GCNCs are highly biocompatible and induce an effective photothermal therapy effect under 808 nm irradiation. Our study provides a facile strategy for preparing functional carbon nanomaterials of prescribed size, morphology, and porous structure for bioapplications.

Platinum-based antineoplastic drugs are among the first-line chemotherapeutic agents against a variety of solid tumors, but toxic side-effects and drug resistance issues limit their clinical optimization. Novel strategies and platforms to conquer cisplatin resistance are highly desired. Herein, we assembled a multimodal nanoplatform utilizing 808 nm-excited and biocompatible core–shell–shell upconversion nanoparticles (UCNPs) [NaGdF4:Yb/Nd@NaGdF4:Yb/Er@NaGdF4] that were covalently loaded with not only photosensitizers (PSs), but also Pt(IV) prodrugs, which were rose bengal (RB) and c,c,t-[Pt(NH3)2Cl2(OCOCH2CH2NH2)2], respectively. The UCNPs had the capability to convert near infrared (NIR) light to visible light, which was further utilized by RB to generate singlet oxygen. At the same time, the nanoplatform delivered the Pt(IV) prodrug into cancer cells. Thus, this upconversion nanoplatform was able to carry out combined and simultaneous photodynamic therapy (PDT) and Pt chemotherapy. The nanoplatform was well characterized and the energy transfer efficiency was confirmed. Compared with free cisplatin or UCNPs loaded with RB only, our nanoplatform showed significantly improved cytotoxicity upon 808 nm irradiation in both cisplatin-sensitive and -resistant human ovarian cancer cells. A mechanistic study showed that the nanoparticles efficiently delivered the Pt(IV) prodrug into cancer cells, resulting in Pt-DNA damage, and that the nanoplatform generated cellular singlet oxygen to kill cancer cells. We, therefore, provide a comprehensive strategy to use UCNPs for combined Pt chemotherapy and PDT against cisplatin resistance, and our nanoplatform can also be used as a theranostic tool due to its NIR bioimaging capacity.

A nanohybrid is assembled by ratiometrically co-loading Pt(IV) prodrugs and photosensitizers into layered double hydroxide nanoparticles. The nanohybrid shows synergistic cell-killing effects and is significantly active against the proliferation of cisplatin-resistant human cancer cells with nanomolar IC50 values. Profound mechanistic investigations confirm its action mode of combined chemo- and photodynamic therapy.

A nanoplatform targeting DNA and p53 simultaneously is assembled. Layered double hydroxide nanoparticles are co-loaded with a Pt(IV) prodrug and a p53 activator. Once inside cells, cisplatin is released to attack genomic DNA and kill cancer cells; simultaneously, the p53 activator results in active p53, a key protein involved in the apoptotic pathways initiated by platinum drugs. The anticancer efficacy of cisplatin is significantly improved through this synergistic application.

Complexation of cisplatin with a p53 activator as a single anticancer agent resulted in synergistically improved cytotoxicity in p53 wild-type but not p53 null human cancer cells. Mechanistic investigation was carried out on this dual-targeting Pt(IV) prodrug, chalcoplatin. The prodrug effectively entered cancer cells and arrested the cell cycle at the S and G2/M phases, distinctive of that from cisplatin. Chalcoplatin significantly induced p53 activation as well as the subsequent apoptosis pathways. This unique mode of action renders chalcoplatin remarkably cytotoxic and makes this compound among the first examples of a Pt(IV) prodrug that directly interacts with the downstream pathway after the formation of Pt–DNA lesions.

Platinum(IV)-based anticancer prodrugs have attracted much attention due to their relative inertness under physiological conditions, being activated inside cells, and their capacity for functionalization with a variety of small-molecule or macromolecule moieties. Novel asymmetric platinum(IV) compounds synthesized through expedient and unique methods are desired. Here we utilize N-bromosuccinimide (NBS) and carry out oxidative bromination on platinum(II) drugs, namely cisplatin, carboplatin, and oxaliplatin, to obtain asymmetric and mono-bromo platinum(IV) prodrugs. Different solvents are used to obtain various compounds, and the compounds are further functionalized. Di-bromo compounds are also obtained through NBS-directed oxidative bromination in ethanol. The crystal structures of representative compounds are discussed, and the reduction potentials of some compounds are examined. A cytotoxicity test shows that the mono- and di-bromo platinum(IV) compounds are active against human ovarian cancer cells. Our study enriches the family of asymmetric platinum(IV) prodrugs and provides with a convenient strategy to obtain brominated platinum(IV) complexes.

•A salicylanilide–Pt conjugate, SA–Pt, was synthesized and biologically evaluated.•The complexes showed identical cytotoxicities compared with cisplatin.•SA–Pt entered cells efficiently, arrested cell cycle, and triggered apoptosis.•SA–Pt weakly inhibited transcription, indicating a distinct mechanism of action.Cationic monofunctional platinum(II)-based anticancer agents with a general formula of cis-[Pt(NH3)2(N-donor)Cl]+ have recently drawn significant attention due to their unique mode of action, distinctive anticancer spectrum, and promising antitumor activity both in vitro and in vivo. Understanding the mechanism of action of novel monofunctional platinum compounds through rational drug design will aid in the further development of active agents. In this study, we synthesized and evaluated a monofunctional platinum-based anticancer agent SA–Pt containing a bulky salicylanilide moiety. The antiproliferative activity of SA–Pt was close to that of cisplatin. Mechanism studies revealed that SA–Pt entered HeLa cells more efficiently than cisplatin, blocked the cell cycle at the S-phase, and induced apoptosis. The compound bound to DNA as effectively as cisplatin, but did not block RNA polymerase II-mediated transcription as strongly as cisplatin, indicating that once the compound formed Pt-DNA lesions, the salicylanilide group was more easily recognized and removed. This study not only enriches the family of monofunctional platinum-based anticancer agents but also guides the design of more potent monofunctional platinum complexes.A unique monofunctional Pt(II) anticancer agent (SA–Pt) containing a bulky salicylanilide moiety was synthesized. SA–Pt showed cytotoxicity against a panel of human cancer cells. The compound entered HeLa cells more efficiently than cisplatin, induced apoptosis, but had a weaker transcription inhibitory effect.

A new organocatalytic transfer hydrogenation strategy for the asymmetric synthesis of 1,1-diarylethanes is described. Under mild conditions, a range of 1,1-diarylethanes substituted with an o-hydroxyphenyl or indole unit could be obtained with excellent efficiency and enantioselectivity. We also extended the protocol to an unprecedented asymmetric hydroarylation of 1,1-diarylalkenes with indoles for the synthesis of a range of highly enantioenriched 1,1,1-triarylethanes bearing acyclic all-carbon quaternary stereocenters. These diaryl- and triarylethanes exhibit impressive cytotoxicity against a number of human cancer cell lines. Preliminary mechanistic studies combined with DFT calculations provided important insight into the reaction mechanism.

Providing strategies to overcome the toxicity and side effects of platinum-based antineoplastic drugs is crucial for their future development. Here we describe a strategy of using low-cytotoxic and non-functionalized layered double hydroxide (LDH) nanoparticles (NPs) to increase the cancer-cell specificity as well as anticancer efficacy of a cisplatin prodrug. In our study, the prodrug is efficiently loaded into and protected by LDH. The Pt-loaded NPs exhibit much higher cytotoxicity than the prodrug against cancer cells. Moreover, the Pt-loaded NPs are much less active against certain types of normal cells. We further investigate the mechanisms behind these phenomena including cellular uptake, cell cycle arrest, and apoptosis induction. We find that LDH is able to significantly improve both the cellular uptake of Pt and genomic DNA platination in cancer cells, and the Pt-loaded NPs induce severe apoptosis in cancer but not normal cells. All of these findings imply that Pt-loaded LDH NPs have great potential to be further developed as anticancer nanomedicine.

•Platinated PARP-1 inhibitors have been designed, synthesized, and characterized.•Complex 3 showed identical spectrum of anticancer activity compared with cisplatin.•Complex 3 displayed an improved inhibitory effect against PARP-1.•Complex 3 was able to enter into cells well and bind to DNA effectively.•Complex 3 arrested cell cycle differently than cisplatin or parent inhibitor.Inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) have shown to be promising in clinical trials against cancer and other diseases, and lots of efforts have been put into the development of organic compounds as more potent PARP-1 inhibitors. Here we describe a strategy to conveniently obtain metal-based PARP-1 inhibitors with enhanced biological activities by conjugating platinum moiety with an original inhibitor, e.g., benzonaphthyridone. Based on the structure–activity relationship analysis of PARP-1 inhibitors, three platinated PARP-1 inhibitors were designed, and the complexes were synthesized and characterized. Complex 3 presented significantly enhanced cytotoxicity against a panel of human cancer cells and a 10-fold increased inhibitory effect against recombinant PARP-1 compared with the original PARP-1 inhibitor. Complex 3 was as cytotoxic as cisplatin and its spectrum of anticancer activity was identical to that of cisplatin. The complex was able to enter into cancer cells efficiently, bind to DNA well, and block cell cycle at G2/M phase, indicating that complex 3 is an effective anticancer agent with a distinct mechanism of action. Our study implies that the conjugation of platinum with PARP-1 inhibitors could be a valid strategy to obtain more potent anticancer agents with improved biological activities.

•Ruthenium(II)-arene complexes bearing PARP-1 inhibitors have been synthesized.•The complexes showed improved cytotoxicities compared with PARP-1 inhibitors.•Complex 3 inhibited PARP-1, bound to DNA, and inhibited transcription.Small-molecule inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) have currently drawn much attention as promising chemotherapeutic drug candidates, and there is a need to develop more potent PARP inhibitors with improved bioavailability. Here we report a strategy to improve the cytotoxicity of PARP inhibitors by conjugation with organometallic ruthenium(II)–arene compounds. We also report a systematic study to reveal the mechanism of action of these ruthenium–PARP inhibitor conjugates. The complexes have been synthesized and characterized spectroscopically. The improved antiproliferative activity from the as-prepared complexes in four human cancer cell lines has indicated their potential for further development as antitumor drugs. Cellular uptake study reveals that the most active complex 3 easily entered into cells. Target validation assays show that the complexes inhibited PARP-1 slightly better than the original PARP inhibitors, that complex 3 strongly bound to DNA and inhibited transcription, and that this complex arrested the cell cycle at the G0/G1 stage. This type of information could shed light on the design of the next generation of more active ruthenium–PARP inhibitor conjugates.Graphical abstractRuthenium–PARP inhibitor conjugates: Organometallic ruthenium(II)–arene complexes bearing PARP inhibitors showed increased cytotoxicity as promising anticancer agents. The complexes enter into cancer cells well and have multi-targeted properties: on one hand, they bind to DNA and inhibit transcription; on the other hand, they inhibit the catalytic activity of PARP.

A novel approach to design bimetallic anticancer drug candidates with the capability to combat both drug resistance and tumor metastasis is reported. These water-soluble bifunctional Pt(IV)–Ru(II) heterodinuclear complexes with a unique mode of action display up to 2-orders of magnitude enhanced cytotoxicity in cisplatin-resistant cells and significantly impede cancer cell migration.

Complexation of cisplatin with a p53 activator as a single anticancer agent resulted in synergistically improved cytotoxicity in p53 wild-type but not p53 null human cancer cells. Mechanistic investigation was carried out on this dual-targeting Pt(IV) prodrug, chalcoplatin. The prodrug effectively entered cancer cells and arrested the cell cycle at the S and G2/M phases, distinctive of that from cisplatin. Chalcoplatin significantly induced p53 activation as well as the subsequent apoptosis pathways. This unique mode of action renders chalcoplatin remarkably cytotoxic and makes this compound among the first examples of a Pt(IV) prodrug that directly interacts with the downstream pathway after the formation of Pt–DNA lesions.

Providing strategies to overcome the toxicity and side effects of platinum-based antineoplastic drugs is crucial for their future development. Here we describe a strategy of using low-cytotoxic and non-functionalized layered double hydroxide (LDH) nanoparticles (NPs) to increase the cancer-cell specificity as well as anticancer efficacy of a cisplatin prodrug. In our study, the prodrug is efficiently loaded into and protected by LDH. The Pt-loaded NPs exhibit much higher cytotoxicity than the prodrug against cancer cells. Moreover, the Pt-loaded NPs are much less active against certain types of normal cells. We further investigate the mechanisms behind these phenomena including cellular uptake, cell cycle arrest, and apoptosis induction. We find that LDH is able to significantly improve both the cellular uptake of Pt and genomic DNA platination in cancer cells, and the Pt-loaded NPs induce severe apoptosis in cancer but not normal cells. All of these findings imply that Pt-loaded LDH NPs have great potential to be further developed as anticancer nanomedicine.

Platinum(IV)-based anticancer prodrugs have attracted much attention due to their relative inertness under physiological conditions, being activated inside cells, and their capacity for functionalization with a variety of small-molecule or macromolecule moieties. Novel asymmetric platinum(IV) compounds synthesized through expedient and unique methods are desired. Here we utilize N-bromosuccinimide (NBS) and carry out oxidative bromination on platinum(II) drugs, namely cisplatin, carboplatin, and oxaliplatin, to obtain asymmetric and mono-bromo platinum(IV) prodrugs. Different solvents are used to obtain various compounds, and the compounds are further functionalized. Di-bromo compounds are also obtained through NBS-directed oxidative bromination in ethanol. The crystal structures of representative compounds are discussed, and the reduction potentials of some compounds are examined. A cytotoxicity test shows that the mono- and di-bromo platinum(IV) compounds are active against human ovarian cancer cells. Our study enriches the family of asymmetric platinum(IV) prodrugs and provides with a convenient strategy to obtain brominated platinum(IV) complexes.

Platinum-based antineoplastic drugs are among the first-line chemotherapeutic agents against a variety of solid tumors, but toxic side-effects and drug resistance issues limit their clinical optimization. Novel strategies and platforms to conquer cisplatin resistance are highly desired. Herein, we assembled a multimodal nanoplatform utilizing 808 nm-excited and biocompatible core–shell–shell upconversion nanoparticles (UCNPs) [NaGdF4:Yb/Nd@NaGdF4:Yb/Er@NaGdF4] that were covalently loaded with not only photosensitizers (PSs), but also Pt(IV) prodrugs, which were rose bengal (RB) and c,c,t-[Pt(NH3)2Cl2(OCOCH2CH2NH2)2], respectively. The UCNPs had the capability to convert near infrared (NIR) light to visible light, which was further utilized by RB to generate singlet oxygen. At the same time, the nanoplatform delivered the Pt(IV) prodrug into cancer cells. Thus, this upconversion nanoplatform was able to carry out combined and simultaneous photodynamic therapy (PDT) and Pt chemotherapy. The nanoplatform was well characterized and the energy transfer efficiency was confirmed. Compared with free cisplatin or UCNPs loaded with RB only, our nanoplatform showed significantly improved cytotoxicity upon 808 nm irradiation in both cisplatin-sensitive and -resistant human ovarian cancer cells. A mechanistic study showed that the nanoparticles efficiently delivered the Pt(IV) prodrug into cancer cells, resulting in Pt-DNA damage, and that the nanoplatform generated cellular singlet oxygen to kill cancer cells. We, therefore, provide a comprehensive strategy to use UCNPs for combined Pt chemotherapy and PDT against cisplatin resistance, and our nanoplatform can also be used as a theranostic tool due to its NIR bioimaging capacity.

A nanohybrid is assembled by ratiometrically co-loading Pt(IV) prodrugs and photosensitizers into layered double hydroxide nanoparticles. The nanohybrid shows synergistic cell-killing effects and is significantly active against the proliferation of cisplatin-resistant human cancer cells with nanomolar IC50 values. Profound mechanistic investigations confirm its action mode of combined chemo- and photodynamic therapy.

A nanoplatform targeting DNA and p53 simultaneously is assembled. Layered double hydroxide nanoparticles are co-loaded with a Pt(IV) prodrug and a p53 activator. Once inside cells, cisplatin is released to attack genomic DNA and kill cancer cells; simultaneously, the p53 activator results in active p53, a key protein involved in the apoptotic pathways initiated by platinum drugs. The anticancer efficacy of cisplatin is significantly improved through this synergistic application.