First-In-Class Thiosemicarbazone Metal Complexes Targeting the Sigma-2 Receptor (S2R) as an Innovative Strategy against Pancreatic Cancer.

Pancreatic cancer, with its increasing incidence and lowest 5-year survival rate, is predicted to become the second leading cause of cancer deaths by 2030. Current clinical trials have shown limited improvement, highlighting the need for new therapies. The sigma-2 receptor (S2R), with roles in tumor progression, is a target for novel thiosemicarbazones (TSCs).

Interactions with DNA Models of the Oxaliplatin Analog (-1,3-DACH)PtCl.

It is generally accepted that adjacent guanine residues in DNA are the primary target for platinum antitumor drugs and that differences in the conformations of the Pt-DNA adducts can play a role in their antitumor activity. In this study, we investigated the effect of the carrier ligand -1,3-diaminocyclohexane (-1,3-DACH) upon formation, stability, and stereochemistry of the (-1,3-DACH)PtG and (-1,3-DACH)Pt(d(GpG)) adducts (G = 9-EthlyGuanine, guanosine, 5'- and 3'-guanosine monophosphate; d(GpG) = deoxyguanosil(3'-5')deoxyguanosine). A peculiar feature of the -1,3-DACH carrier ligand is the steric bulk of the diamine, which is asymmetric with respect to the Pt-coordination plane.

Surface-Engineered Cesium Lead Bromide Perovskite Nanocrystals for Enabling Photoreduction Activity.

In recent years, colloidal lead halide perovskite (LHP) nanocrystals (NCs) have exhibited such intriguing light absorption properties to be contemplated as promising candidates for photocatalytic conversions. However, for effective photocatalysis, the light harvesting system needs to be stable under the reaction conditions propaedeutic to a specific transformation. Unlike photoinduced oxidative reaction pathways, photoreductions with LHP NCs are challenging due to their scarce compatibility with common hole scavengers like amines and alcohols.

Cytotoxic pathways activated by multifunctional thiosemicarbazones targeting sigma-2 receptors in breast and lung carcinoma cells.

Background: Multifunctional thiosemicarbazones (TSCs) able to bind sigma receptors and chelate metals are considered as a promising avenue for the treatment of pancreatic cancer due to the encouraging results obtained on in vitro and in vivo models. Here, we assessed the biochemical mechanism of these TSCs also on lung (A549) and breast (MCF7) cancer cells.

Methods: The density of sigma-2 receptors in normal (BEAS-2B and MCF10A) and in lung and breast (A549 and MCF7) cancer cells was evaluated by flow cytometry.

The mechanism of antiproliferative activity of the oxaliplatin pyrophosphate derivative involves its binding to nuclear DNA in cancer cells.

(1R,2R-diaminocyclohexane)(dihydropyrophosphato) platinum(II), also abbreviated as RRD2, belongs to a class of potent antitumor platinum cytostatics called phosphaplatins. Curiously, several published studies have suggested significant mechanistic differences between phosphaplatins and conventional platinum antitumor drugs. Controversial findings have been published regarding the role of RRD2 binding to DNA in the mechanism of its antiproliferative activity in cancer cells.

Special Issue "Cisplatin in Cancer Therapy: Molecular Mechanisms of Action 3.0".

The year 2023 marks the 45th year since FDA approval of cisplatin as an anticancer drug, and, at present, it is widely used against a spectrum of human tumors, including early-stage ovarian cancer, non-small cell lung cancer (typically developed by smokers), head and neck, and advanced bladder cancer [...

Cisplatin and zoledronic acid: two drugs combined in a Pt(II) complex with potential antitumor activity towards bone tumors and metastases.

Treatment of primary bone malignancies comprises surgery, radiotherapy, chemotherapy, and analgesics. Platinum-based chemotherapeutics, such as cisplatin, are commonly used for the treatment of bone cancer but, despite their success, outcomes are limited by toxicity and resistance. Recently, dinuclear Pt complexes with a bridging geminal bisphosphonate ligand proved to be endowed with selective accumulation in bone tumors or metastases leading to improved efficacy and reduced systemic toxicity.

Improvement of Kiteplatin Efficacy by a Benzoato Pt(IV) Prodrug Suitable for Oral Administration.

Kiteplatin, [PtCl(-1,4-DACH)] (DACH = diaminocyclohexane), contains an isomeric form of the oxaliplatin diamine ligand -1,2-DACH and has been proposed as a valuable drug candidate against cisplatin- and oxaliplatin-resistant tumors, in particular, colorectal cancer. To further improve the activity of kiteplatin, it has been transformed into a Pt(IV) prodrug by the addition of two benzoato groups in the axial positions. The new compound, ,,-[PtCl(OBz)(-1,4-DACH)] (; OBz = benzoate), showed cytotoxic activity at nanomolar concentration against a wide panel of human cancer cell lines.

In Situ Formation of Zwitterionic Ligands: Changing the Passivation Paradigms of CsPbBr Nanocrystals.

CsPbBr nanocrystals (NCs) passivated by conventional lipophilic capping ligands suffer from colloidal and optical instability under ambient conditions, commonly due to the surface rearrangements induced by the polar solvents used for the NC purification steps. To avoid onerous postsynthetic approaches, ascertained as the only viable stability-improvement strategy, the surface passivation paradigms of as-prepared CsPbBr NCs should be revisited. In this work, the addition of an extra halide source (8-bromooctanoic acid) to the typical CsPbBr synthesis precursors and surfactants leads to the formation of a zwitterionic ligand already before cesium injection.

Interaction of Copper Trafficking Proteins with the Platinum Anticancer Drug Kiteplatin.

The interaction of metallodrugs with proteins influences their mechanism of action and side effects. In the case of platinum drugs, copper transporters modulate sensitivity and resistance to these anticancer agents. To deepen the knowledge of the structural properties underlying the reactivity of platinum drugs with copper transporters, we studied the interaction of kiteplatin and two of its derivatives with the methionine-rich motif of copper importer Ctr1 and with the dithiol motif of the first domain of Menkes ATPase.

Effect of chirality on the anticancer activity of Pt(II) and Pt(IV) complexes containing 1,2 and 1,2 enantiomers of the -1,2-diamino-4-cyclohexene ligand (DACHEX), an analogue of diaminocyclohexane used in oxaliplatin.

Six enantiomerically pure, oxaliplatin-like, platinum compounds (two platinum(II) and four platinum(IV)), all containing unsaturated cyclic diamine -1,2-diamino-4-cyclohexene (DACHEX) as a substitute for the -1,2-diaminocyclohexane used in oxaliplatin, were investigated. The complexes were characterized by elemental analyses, ESI-MS, and H-NMR spectroscopy. For the four Pt(IV) complexes the electrochemical redox behaviour, investigated by cyclic voltammetry, showed that all complexes possess reduction potentials suitable for activation .

New Oxaliplatin-Pyrophosphato Analogs with Improved In Vitro Cytotoxicity.

Two new Pt(II)-pyrophosphato complexes containing the carrier ligands -1,3-diaminocyclohexane (-1,3-DACH) and -1,2-diamine-4-cyclohexene (1,2-DACHEX), variants of the 1,2-diaminocyclohexane ligand present in the clinically used Pt-drug oxaliplatin, have been synthesized with the aim of developing new potential antitumor drugs with high bone tropism. The complexes are more stable at physiological pH than in acid conditions, with Na[Pt(pyrophosphato)(-1,3-DACH)] () slightly more stable than [Pt(dihydrogenpyrophosphato)(1,2-DACHEX)] (). The greater reactivity at acidic pH ensures a greater efficacy at the tumor site.

Size-tunable and stable cesium lead-bromide perovskite nanocubes with near-unity photoluminescence quantum yield.

Stable cesium lead bromide perovskite nanocrystals (NCs) showing a near-unity photoluminescence quantum yield (PLQY), narrow emission profile, and tunable fluorescence peak in the green region can be considered the ideal class of nanomaterials for optoelectronic applications. However, a general route for ensuring the desired features of the perovskite NCs is still missing. In this paper, we propose a synthetic protocol for obtaining near-unity PLQY perovskite nanocubes, ensuring their size control and, consequently, a narrow and intense emission through the modification of the reaction temperature and the suitable combination ratio of the perovskite constituting elements.

Pt(iv) complexes based on cyclohexanediamines and the histone deacetylase inhibitor 2-(2-propynyl)octanoic acid: synthesis, characterization, cell penetration properties and antitumor activity.

The Pt(iv) complexes based on (SP-4-2)-dichlorido(cyclohexane-1,4-diamine)platinum(ii) (kiteplatin) and the histone deacetylase inhibitor 2-(2-propynyl)octanoic acid (POA) were investigated. Since POA contains a chiral carbon, all the possible Pt(iv) isomers were prepared and characterized, and their antiproliferative activity on six cancer cell lines was compared with that of the corresponding Pt(iv) complexes containing the cyclohexane-1R,2R-diamine equatorial ligand. To justify the very good antiproliferative activity (nanomolar IC), the polarity, lipophilicity, permeability, and cell accumulation of the complexes were studied.

Bone tumor-targeted delivery of theranostic Pt-bisphosphonate complexes promotes killing of metastatic tumor cells.

Platinum-based drugs such as cisplatin are very potent chemotherapeutics, whereas radioactive platinum (Pt) is a rich source of low-energy Auger electrons, which kills tumor cells by damaging DNA. Auger electrons damage cells over a very short range. Consequently, Pt-based radiopharmaceuticals should be targeted toward ​tumors to maximize radiotherapeutic efficacy and minimize Pt-based systemic toxicity.

Selenium-doped hydroxyapatite nanoparticles for potential application in bone tumor therapy.

In the present study we have studied the incorporation and release of selenite ions (SeO) in hydroxyapatite nanoparticles for the treatment of bone tumors. Two types of selenium-doped hydroxyapatite (HASe) nanoparticles (NPs) with a nominal Se/(P + Se) molar ratio ranging from 0.01 up to 0.

PEGylated solid lipid nanoparticles for brain delivery of lipophilic kiteplatin Pt(IV) prodrugs: An in vitro study.

Here, polyethylene glycol (PEG)-stabilized solid lipid nanoparticles (SLNs) containing Pt(IV) prodrugs derived from kiteplatin were designed and proposed as novel nanoformulations potentially useful for the treatment of glioblastoma multiforme. Four different Pt(IV) prodrugs were synthesized, starting from kiteplatin by the addition of two carboxylate ligands with different length of the alkyl chains and lipophilicity degree, and embedded in the core of PEG-stabilized SLNs composed of cetyl palmitate. The SLNs were extensively characterized by complementary optical and morphological techniques.

Targeting of radioactive platinum-bisphosphonate anticancer drugs to bone of high metabolic activity.

Platinum-based chemotherapeutics exhibit excellent antitumor properties. However, these drugs cause severe side effects including toxicity, drug resistance, and lack of tumor selectivity. Tumor-targeted drug delivery has demonstrated great potential to overcome these drawbacks.

Platinum(IV) Complexes of -1,2-diamino-4-cyclohexene: Prodrugs Affording an Oxaliplatin Analogue that Overcomes Cancer Resistance.

Six platinum(IV) compounds derived from an oxaliplatin analogue containing the unsaturated cyclic diamine -1,2-diamino-4-cyclohexene (DACHEX), in place of the 1,2-diaminocyclohexane, and a range of axial ligands, were synthesized and characterized. The derivatives with at least one axial chlorido ligand demonstrated solvent-assisted photoreduction. The electrochemical redox behavior was investigated by cyclic voltammetry; all compounds showed reduction potentials suitable for activation in vivo.

Insights into the role of the lead/surfactant ratio in the formation and passivation of cesium lead bromide perovskite nanocrystals.

This study aims at rationalizing the effects of the lead/surfactant ratio on the structural evolution of cesium lead-bromide perovskite nanocrystals (NCs), ascertaining how their shape and surface composition can be modulated by suitably adjusting the ligand amount (an equivolumetric mixture of oleic acid and oleyl amine) relatively to lead bromide. The tailoring of the reaction conditions allows the obtainment of blue-emitting CsPbBr3 nanoplatelets in the presence of ligand excess, while green-emitting nanocubes are achieved under low-surfactant conditions. An insight into the NC's shape evolution dictated by the different reaction conditions suggests that the generation of CsPbBr3 nanoplatelets is controlled by the dimensions of [(RNH3)2(PbBr4)]n layers formed before the injection of cesium oleate.

A minimal structural variation can overcome tumour resistance of oxaliplatin: the case of 4,5-dehydrogenation of the cyclohexane ring.

A new family of anticancer compounds has been derived from oxaliplatin by inserting a double-bond between carbons 4 and 5 of the 1,2-diaminocyclohexane ring. Testing against a panel of human tumour cell lines including cervical (A431), ovarian (2008), and colon carcinomas (HCT-15 and LoVo), and two oxaliplatin-resistant clones (LoVo OXP and LoVo MDR) has shown that the new compounds have, in general, equal if not better cytotoxic activity and are able to overcome the oxaliplatin-resistance. Moreover, the oxalato derivative induced lipid droplets increase in LoVo OXP cells thus suggesting the involvement of metabolism stress in its mechanism of action.

Quantitative imaging of platinum-based antitumor complexes in bone tissue samples using LA-ICP-MS.

There is a need for effective medication against bone metastases because todays drugs are not able to penetrate the bone and reach the affected areas. To analyze if current or future platinum-containing drugs are able to achieve this, a quantitative imaging method is urgently needed. In this study, the platinum distribution in thin sections of mice tibia was determined using laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) in a spatially resolved manner.