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The search for new antineoplastic agents is imperative, as cancer remains one of the most preeminent causes of death worldwide. Since the discovery of the therapeutic potential of cisplatin, the study of metallodrugs in cancer chemotherapy acquired increasing interest. Starting from cisplatin derivatives, such as oxaliplatin and carboplatin, in the last years, different compounds were explored, employing different metal centers such as iron, ruthenium, gold, and palladium. Nonetheless, metallodrugs face several drawbacks, such as low water solubility, rapid clearance, and possible side toxicity. Encapsulation has emerged as a promising strategy to overcome these issues, providing both improved biocompatibility and protection of the payload from possible degradation in the biological environment. In this respect, liposomes, which are spherical vesicles characterized by an aqueous core surrounded by lipid bilayers, have proven to be ideal candidates due to their versatility. In fact, they can encapsulate both hydrophilic and hydrophobic drugs, are biocompatible, and their properties can be tuned to improve the selective delivery to tumour sites exploiting both passive and active targeting. In this review, we report the most recent findings on liposomal formulations of metallodrugs, with a focus on encapsulation techniques and the obtained biological results.

This review highlights significant advancements in antibody-drug conjugates (ADCs) equipped with metal-based and nature-inspired payloads, focusing on synthetic strategies for antibody conjugation. Traditional methods such us maleimide and succinimide conjugation and classical condensation reactions are prevalent for metallodrugs and natural compounds. However, emerging non-conventional strategies such as photoconjugation are gaining traction due to their milder conditions and, in an aspect which minimizes side reactions, selective formation of ADC. The review also summarizes the therapeutic and diagnostic properties of these ADCs, highlighting their enhanced selectivity and reduced side effects in cancer treatment compared to non-conjugated payloads. ADCs combine the specificity of monoclonal antibodies with the cytotoxicity of chemotherapy drugs, offering a targeted approach to the elimination of cancer cells while sparing healthy tissues. This targeted mechanism has demonstrated impressive clinical efficacy in various malignancies. Key future advancements include improved linker technology for enhanced stability and controlled release of cytotoxic agents, incorporation of novel, more potent, cytotoxic agents, and the identification of new cancer-specific antigens through genomic and proteomic technologies. ADCs are also expected to play a crucial role in combination therapies with immune checkpoint inhibitors, CAR-T cells, and small molecule inhibitors, leading to more durable and potentially curative outcomes. Ongoing research and clinical trials are expanding their capabilities, paving the way for more effective, safer, and personalized treatments, positioning ADCs as a cornerstone of modern medicine and offering new hope to patients.

The clinical application of nanomaterials for chemodynamic therapy (CDT), which generate multiple reactive oxygen species (ROS), presents significant challenges. These challenges arise due to insufficient levels of endogenous hydrogen peroxide and catalytic ions necessary to initiate Fenton reactions. As a result, sophisticated additional delivery systems are required. In this study, a novel bimetallic copper (II) pentacyanonitrosylferrate (Cu(II)NP, Cu[Fe(CN) 5 NO]) material was developed to address these limitations. This material functions as a multiple ROS generator at tumoral sites by self-inducing hydrogen peroxide and producing peroxynitrite (ONOO - ) species. The research findings demonstrate that this material exhibits low toxicity towards normal liver organoids, yet shows potent antitumoral effects on High Grade Serous Ovarian Cancer (HGSOC) organoid patients, regardless of platinum resistance. Significantly, this research introduces a promising therapeutic opportunity by proposing a single system capable of replacing the need for H 2 O 2 , additional catalysts, and NO-based delivery systems. This innovative system exhibits remarkable multiple therapeutic mechanisms, paving the way for potential advancements in clinical treatments., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: Chemodynamic therapy (CDT) holds great promise in achieving cancer therapy through Fenton and Fenton-like reactions, which generate highly toxic reactive species. However, CDT is limited by the lower amount of catalyst ions that can decompose already existing intracellular H 2 O 2 and produce reactive oxygen species (ROS) to attain a therapeutic outcome., Objectives: To overcome these limitations, a tailored approach, which utilizes dual metals cations (Ag + , Fe 2+ ) based silver pentacyanonitrosylferrate or silver nitroprusside (AgNP) were developed for Fenton like reactions that can specifically kill cancer cells by taking advantage of tumor acidic environment without used of any external stimuli., Methods: A simple solution mixing procedure was used to synthesize AgNP as CDT agent. AgNP were structurally and morphologically characterized, and it was observed that a minimal dose of AgNP is required to destroy cancer cells with limited effects on normal cells. Moreover, comprehensive in vitro studies were conducted to evaluate antitumoral mechanism., Results: AgNP have an effective ability to decompose endogenous H 2 O 2 in cells. The decomposed endogenous H 2 O 2 generates several different types of reactive species ( • OH, O 2 •- ) including peroxynitrite (ONOO - ) species as apoptotic inducers that kill cancer cells, specifically. Cellular internalization data demonstrated that in short time, AgNP enters in lysosomes, avoid degradation and due to the acidic pH of lysosomes significantly generate high ROS levels. These data are further confirmed by the activation of different oxidative genes. Additionally, we demonstrated the biocompatibility of AgNP on mouse liver and ovarian organoids as an ex vivo model while AgNP showed the therapeutic efficacy on patient derived tumor organoids (PDTO)., Conclusion: This work demonstrates the therapeutic application of silver nitroprusside as a multiple ROS generator utilizing Fenton like reaction. Thereby, our study exhibits a potential application of CDT against HGSOC (High Grade Serous Ovarian Cancer), a deadly cancer through altering the redox homeostasis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Production and hosting by Elsevier B.V.)

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) is a member of a family of peptidyl-prolyl isomerases that specifically recognizes and binds phosphoproteins, catalyzing the rapid cis-trans isomerization of phosphorylated serine/threonine-proline motifs, which leads to changes in the structures and activities of the targeted proteins. Through this complex mechanism, PIN1 regulates many hallmarks of cancer including cell autonomous metabolism and the crosstalk with the cellular microenvironment. Many studies showed that PIN1 is largely overexpressed in cancer turning on a set of oncogenes and abrogating the function of tumor suppressor genes. Among these targets, recent evidence demonstrated that PIN1 is involved in lipid and glucose metabolism and accordingly, in the Warburg effect, a characteristic of tumor cells. As an orchestra master, PIN1 finely tunes the signaling pathways allowing cancer cells to adapt and take advantage from a poorly organized tumor microenvironment. In this review, we highlight the trilogy among PIN1, the tumor microenvironment and the metabolic program rewiring., Competing Interests: Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The modularity and ease of synthesis of carbene-metal-amide (CMA) complexes based on the coinage metals (Au, Ag, Cu) and N-heterocyclic carbenes (NHCs) as ancillary ligands pave the way for the expansion of their applications beyond photochemistry and catalysis. Herein, we further improve the synthesis of such compounds by circumventing the use of toxic organic solvents which were previously required for their purification, and we expand their scope to include complexes incorporating carbolines as the amido fragments. The novel complexes are screened both in vitro and ex vivo, against several cancer cell lines and high-grade serous ovarian cancer (HGSOC) tumoroids, respectively. Excellent cytotoxicity values are obtained for most complexes, while the structural variety of the CMA library screened thus far, provides promising leads for future developments. Variations of all three components (NHC, metal, amido ligand), enable the establishment of trends regarding cytotoxicity and selectivity towards cancerous over normal cells., (© 2022 Wiley-VCH GmbH.)

Background: The progression of ovarian cancer seems to be related to HDAC1, HDAC3, and HDAC6 activity. A possible strategy for improving therapies for treating ovarian carcinoma, minimizing the preclinical screenings, is the repurposing of already approved pharmaceutical products as inhibitors of these enzymes., Objective: This work was aimed to implement a computational strategy for identifying new HDAC inhibitors for ovarian carcinoma treatment among approved drugs., Method: The CHEMBL database was used to construct training, test, and decoys sets for performing and validating HDAC1, HDAC3 and HDAC6 3D-QSAR models obtained by using the FLAP program. Docking and MD simulations were used in combination with the generated models to identify novel potential HDAC inhibitors. Cell viability assays and Western blot analyses were performed on normal and cancer cells for a direct evaluation of the anti-proliferative activity and an in vitro estimation of HDAC inhibition of the compounds selected through in silico screening., Result: The best quantitative prediction was obtained for the HDAC6 3D-QSAR model. The screening of approved drugs highlighted a new potential use as HDAC inhibitors for some compounds, in particular nitrofuran derivatives, usually known for their antibacterial activity and frequently used as antimicrobial adjuvant therapy in cancer treatment. Experimental evaluation of these derivatives highlighted a significant antiproliferative activity against cancer cell lines overexpressing HDAC6, and an increase in acetylated alpha-tubulin levels., Conclusion: Experimental results support the hypothesis of potential direct interaction of nitrofuran derivatives with HDACs. In addition to the possible repurposing of already approved drugs, this work suggests the nitro group as a new zinc-binding group, able to interact with the catalytic zinc ion of HDACs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

ATP citrate lyase (ACLY) is an important enzyme that catalyzes the conversion of citrate to acetyl-CoA in normal cells, facilitating the de novo fatty acid synthesis. Lipids and fatty acids were found to be accumulated in different types of tumors, such as brain, breast, rectal and ovarian cancer, representing a great source of energy for cancer cell growth and metabolism. Since ACLY-mediated conversion of citrate to acetyl-CoA constitutes the basis for fatty acid synthesis, ACLY seems to be quite an unexplored and promising therapeutic target for anticancer drug design. A pharmacophore-based virtual screening (VS) protocol with the aid of hierarchical docking, consensus docking (CD), molecular dynamics (MD) simulations and ligand-protein binding free energy calculations led to the identification of compound VS1, which showed a moderate but promising inhibitory activity, demonstrating to be 2.5 times more potent than reference inhibitor 2-hydroxycitrate. These results validate the reliability of our VS workflow and pave the way for the design of novel and more potent ACLY inhibitors.Communicated by Ramaswamy H. Sarma.

Nanomedicine employs nanotechnologies to develop innovative applications, and more specifically nano-objects in the field of human health, through exploitation of the physical, chemical and biological properties of materials at the nanoscale. The use of nanovehicles capable of transporting and releasing the active therapeutic payload into target cells, particularly in the case of cancer or inflammatory diseases, can also enhance diagnosis. Therefore, nanomedicines improve the benefit/risk ratio of drugs by increasing their bioavailability, selectivity, and efficacy in the target tissue, while reducing the necessary doses and hence diminishing untoward toxicity to healthy tissues. Overcoming multidrug resistance (MDR) to antitumor agents is a central goal of cancer research and therapeutics, making it possible to treat these diseases more accurately and effectively. The adaptability of nanomedicines e.g. modulation of their components, surface functionalization, encapsulation of various active therapeutics as well as the possibility of combining several treatments using a single nanoparticle platform, are characteristics which are perfectly poised to address classical chemoresistance, a major obstacle towards curative cancer therapy. In this review, we discuss an assortment of nanomedicines along with those that should be developed in order to surmount cancer MDR; these include exosomes, natural compounds, lipid nanocapsules, prodrug self-assemblies, and gold nanoparticles., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Overcoming multidrug resistance represents a major challenge for cancer treatment. In the search for new chemotherapeutics to treat malignant diseases, drug repurposing gained a tremendous interest during the past years. Repositioning candidates have often emerged through several stages of clinical drug development, and may even be marketed, thus attracting the attention and interest of pharmaceutical companies as well as regulatory agencies. Typically, drug repositioning has been serendipitous, using undesired side effects of small molecule drugs to exploit new disease indications. As bioinformatics gain increasing popularity as an integral component of drug discovery, more rational approaches are needed. Herein, we show some practical examples of in silico approaches such as pharmacophore modelling, as well as pharmacophore- and docking-based virtual screening for a fast and cost-effective repurposing of small molecule drugs against multidrug resistant cancers. We provide a timely and comprehensive overview of compounds with considerable potential to be repositioned for cancer therapeutics. These drugs are from diverse chemotherapeutic classes. We emphasize the scope and limitations of anthelmintics, antibiotics, antifungals, antivirals, antimalarials, antihypertensives, psychopharmaceuticals and antidiabetics that have shown extensive immunomodulatory, antiproliferative, pro-apoptotic, and antimetastatic potential. These drugs, either used alone or in combination with existing anticancer chemotherapeutics, represent strong candidates to prevent or overcome drug resistance. We particularly focus on outcomes and future perspectives of drug repositioning for the treatment of multidrug resistant tumors and discuss current possibilities and limitations of preclinical and clinical investigations., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Inorganic nanoparticles (NPs) including those derived from metals (e.g., gold, silver), semiconductors (e.g., quantum dots), carbon dots, carbon nanotubes, or oxides (e.g., iron oxide), have been deeply investigated recently for diagnostic and therapeutic purposes in oncology. Compared to organic nanomaterials, inorganic NPs have several advantages and unique characteristics for better imaging and drug delivery. Still, only a limited number of inorganic NPs are translated into clinical practice., Method: In this review, we discuss the progression of inorganic NPs for cancer therapy and imaging, focusing our attention on opportunities, limitations and challenges for the main constituting nanomaterials, including metallic and magnetic NPs. In particular, the pre-clinical and clinical trials from the bench toward the clinic are here investigated., Results: Over the last few decades, the development of wide range of NPs with the ability to tune size, composition and functionality, has provided an excellent resource for nanomedicine. Inorganic NPs provide a great opportunity as drug carriers, due to the easy modification of targeting molecules, the control of drug release by different stimuli, and the effective delivery to target sites, thus resulting in having an improved therapeutic efficacy and in reducing side effects. Inorganic NPs are investigated in preclinical and clinical studies for the detection, diagnosis and treatment of many diseases. The stability of inorganic NPs offers a potential advantage over the traditional delivery methods. Inorganic NPs could enhance and improve current imaging and diagnostic techniques, such as MRI or PET. Even though, they have not yet been approved for drug delivery applications, their ability to respond to external stimuli is now widely investigated in clinic., Conclusion: The successful translation of inorganic NPs to the clinic requires the development of a simple, safe, cost-effective, ecofriendly mode of synthesis, and a better understanding of the safety mechanisms, biodistribution and the pharmacokinetics of NPs. However, more attention should be given to concerns on long-term toxicity, carcinogenesis, immunogenicity, inflammation and tissue damage. Although, some inorganic NPs, which were apparently promising in the preclinical phase, were found not to be successful when translated to the clinic, several encouraging NPs are currently being developed for treatment and cancer care and for a wide variety of other diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: The application of nanotechnology in the medical field is called nanomedicine. Nowadays, this new branch of science is a point of interest for many investigators due to the important advances in which we assisted in recent decades, in particular for cancer treatment. Cancer nanomedicine has been applied in different fields such as drug delivery, nanoformulation and nanoanalytical contrast reagents. Nanotechnology may overcome many limitations of conventional approaches by reducing the side effects, increasing tumor drug accumulation and improving the efficacy of drugs. In the last two decades, nanotechnology has rapidly developed, allowing for the incorporation of multiple therapeutics, sensing and targeting agents into nanoparticles (NPs) for developing new nanodevices capable to detect, prevent and treat complex diseases such as cancer., Method: In this review, we describe the main drug nanoformulations based on different types of organic NPs, the advantages that the new formulations present in comparison with their free drug counterparts and how nanodrugs have improved clinical care. We subdivided them into four main groups: polymeric NPs, liposomes, micelles and exosomes, a small subgroup that has only recently been used in clinical trials., Results: The application of nanotechnology to pharmaceutical science has allowed us to build up nanosystems based on at least two stage vectors (drug/nanomaterial), which often shown better pharmacokinetics (PK), bioavailability and biodistribution. As a result of these advantages, the nanomaterials accumulate passively in the tumor (due to the enhanced permeability and retention, effect, EPR), thereby decreasing the side effects of free drug. Recently, many new drug formulations have been translated from bench to bedside., Conclusion: It is important to underline that the translation of nanomedicines from the basic research phase to clinical use in patients is not only expensive and time-consuming, but that it also requires appropriate funding. After many years spent in the design of innovative nanomaterials, it is now the time for the research to take into consideration the biological obstacles that nanodrugs have to overcome. Barriers such as the mononuclear phagocyte system, intratumoral pressure or multidrug resistance are regularly encountered when a cancer patient is treated, especially in the metastatic setting., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Introduction: Monoacylglycerol lipase is a serine hydrolase that plays a major role in the degradation of the endocannabinoid 2-arachidonoylglycerol. Because of this key role, selective inactivation of MAGL represents an interesting approach to obtain desirable effects in several diseases. Furthermore, MAGL is upregulated in cancer cells and primary tumors and its inhibition in aggressive breast, ovarian, and melanoma cancer cells impairs cell migration, invasiveness, and tumorigenicity. Areas covered: This review covers patent literature on MAGL inhibitors and their applications published from 2013 to 2017. Expert opinion: MAGL inhibition has gained considerable importance in many therapeutic fields and one compound has been subjected to Phase I studies. Even if a reasonable number of patents have been recently reported, novel MAGL inhibitors are still required, especially novel chemical classes displaying a reversible mechanism of action.

Inhibition of lactate dehydrogenase (LDH) represents an innovative approach to tackle cancer because this peculiar glycolytic metabolism is characteristic of most invasive tumor cells. An investigation into the biological properties of saffron extracts led to the discover of their LDH-inhibition properties. In particular, the most important saffron components, crocetin, was found to inhibit LDH (IC 50 = 54.9 ± 4.7 μM). This carotenoid was independently produced by chemical synthesis, and its LDH-inhibition properties manifested via its antiproliferative activity against two glycolytic cancer cell lines (A549 and HeLa, IC 50 = 114.0 ± 8.0 and 113.0 ± 11.1 μM, respectively). The results described in this article suggest that saffron may be a helpful alimentary component in the prevention of cancer that potentially contributes to the efficacy of approved cancer therapies.

DNA nanotechnology is an emerging and exciting field, and represents a forefront frontier for the biomedical field. The specificity of the interactions between complementary base pairs makes DNA an incredible building material for programmable and very versatile two- and three-dimensional nanostructures called DNA origami. Here, we analyze the DNA origami and DNA-based nanostructures as a drug delivery system. Besides their physical-chemical nature, we dissect the critical factors such as stability, loading capability, release and immunocompatibility, which mainly limit in vivo applications. Special attention was dedicated to highlighting the boundaries to be overcome to bring DNA nanostructures closer to the bedside of patients.

In the post-genomics era, metabolomics represents a new "omics" approach that in the last decade has received increased attention in the field of oncology. Metabolomics is based on the holistic study of the metabolic profile that characterizes a specific phenotype in a biological system. The metabolic profile provides a readout of the metabolic state of an individual that cannot be obtained directly from DNA genotyping, gene expression, or proteomic profiling analyses. The translational value of metabonomics in the oncology field has been demonstrated by the identification of diagnostic and prognostic biomarkers. The so-called pharmaco-metabolomic approach that is currently emerging aims to identify the individual metabolomic characteristics able to predict drug effectiveness and/or toxicity. This review presents the potential role of pharmaco-metabolomics in the future of anticancer pharmacology to achieve customized anticancer treatments and new, targeted therapeutic approaches., (Copyright © 2011 Wiley Periodicals, Inc.)

Cell cycle deregulation is one of the first steps that transform normal cells into tumor cells. CDKs are a family of proteins devoted to controlling cell cycle entry, progression and exit. Studies from animal models show a tissue-specific essentiality of the single CDKs. In cancer cells, mis-regulation of CDK function is a common event. For this reason the pioneer compound Flavopiridol was developed and many new drugs are currently under development. ATP and the last generation of non-ATP competitive inhibitors are now emerging as one of the most potentially powerful target therapies. Many clinical trials are ongoing, as either a single agent or in combination with the classical cytotoxic agents. In this review, we discuss new strategies and methods to design more potent, selective and specific CDK inhibitors, starting from evidence emerging from animal and cancer cell models.