The history of small extracellular vesicles and their implication in cancer drug resistance

Small extracellular vesicles (EVs) in the last 20 years are demonstrated to possess promising properties as potential new drug delivery systems, biomarkers, and therapeutic targets. Moreover, EVs are described to be involved in the most important steps of tumor development and progression including drug resistance. The acquired or intrinsic capacity of cancer cells to resist chemotherapies is one of the greatest obstacles to overcome to improve the prognosis of many patients. EVs are involved in this mechanism by exporting the drugs outside the cells and transferring the drug efflux pumps and miRNAs in recipient cells, in turn inducing drug resistance. In this mini-review, the main mechanisms by which EVs are involved in drug resistance are described, giving a rapid and clear overview of the field to the readers

The importance of being CAFs (in cancer resistance to targeted therapies)

In the last two decades, clinical oncology has been revolutionized by the advent of targeted drugs. However, the efficacy of these therapies is significantly limited by primary and acquired resistance, that relies not only on cell-autonomous mechanisms but also on tumor microenvironment cues. Cancer-associated fibroblasts (CAFs) are extremely plastic cells of the tumor microenvironment. They not only produce extracellular matrix components that build up the structure of tumor stroma, but they also release growth factors, chemokines, exosomes, and metabolites that affect all tumor properties, including response to drug treatment. The contribution of CAFs to tumor progression has been deeply investigated and reviewed in several works. However, their role in resistance to anticancer therapies, and in particular to molecular therapies, has been largely overlooked. This review specifically dissects the role of CAFs in driving resistance to targeted therapies and discusses novel CAF targeted therapeutic strategies to improve patient survival

Self-Therapeutic Nanomaterials for Cancer Therapy: A Review

Cancer is a commonly lethal disease that causes many deaths every year around the world. Many strategies have been applied to treat cancer, such as surgery, radiation, and chemotherapy, but all of these therapeutic approaches are limited. Nanotechnology could provide a tremendous platform to boost the efficacy of therapeutic systems from the bench to clinical applications. The current trend of using nanomaterials for therapeutic applications is limited to drug delivery and external stimuli-responsive systems. However, several nanomaterials can reduce the growth of aggressive tumors through their self-therapeutic properties. In this review, we discuss the self-therapeutic nanomaterials that can kill cancer cells without the need for any external stimulation (heat, light, radiation, or a magnetic field) or the loading of any extra therapeutic compounds. These nanomaterials can produce reactive oxygen species, act as deoxygenating agents, or produce free radicals at tumor sites. Self-therapeutic peptide-based and other organic nanomaterials that are used to inhibit multidrug resistance (MDR) proteins, e.g., P-glycoprotein (P-gp), are also discussed. This review discusses the possible mechanisms of action of self-therapeutic nanomaterials for cancer inhibition, highlighting critical and future aspects

α/β-Hydrolase Domain (ABHD) Inhibitors as New Potential Therapeutic Options against Lipid-Related Diseases

Much of the experimental evidence in the literature has linked altered lipid metabolism to severe diseases such as cancer, obesity, cardiovascular pathologies, diabetes, and neurodegenerative diseases. Therefore, targeting key effectors of the dysregulated lipid metabolism may represent an effective strategy to counteract these pathological conditions. In this context, α/β-hydrolase domain (ABHD) enzymes represent an important and diversified family of proteins, which are involved in the complex environment of lipid signaling, metabolism, and regulation. Moreover, some members of the ABHD family play an important role in the endocannabinoid system, being designated to terminate the signaling of the key endocannabinoid regulator 2-arachidonoylglycerol. This Perspective summarizes the research progress in the development of ABHD inhibitors and modulators: design strategies, structure-activity relationships, action mechanisms, and biological studies of the main ABHD ligands will be highlighted

The history of nanoscience and nanotechnology: From chemical-physical applications to nanomedicine

Nanoscience breakthroughs in almost every field of science and nanotechnologies make life easier in this era. Nanoscience and nanotechnology represent an expanding research area, which involves structures, devices, and systems with novel properties and functions due to the arrangement of their atoms on the 1-100 nm scale. The field was subject to a growing public awareness and controversy in the early 2000s, and in turn, the beginnings of commercial applications of nanotechnology. Nanotechnologies contribute to almost every field of science, including physics, materials science, chemistry, biology, computer science, and engineering. Notably, in recent years nanotechnologies have been applied to human health with promising results, especially in the field of cancer treatment. To understand the nature of nanotechnology, it is helpful to review the timeline of discoveries that brought us to the current understanding of this science. This review illustrates the progress and main principles of nanoscience and nanotechnology and represents the pre-modern as well as modern timeline era of discoveries and milestones in these fields

3D dynamic cultures of HGSOC organoids to model innovative and standard therapies

High-grade serous ovarian cancer (HGSOC) needs new technologies for improving cancer diagnosis and therapy. It is a fatal disease with few options for the patients. In this context, dynamic culture systems coupling with patient-derived cancer 3D microstructures could offer a new opportunity for exploring novel therapeutic approaches. In this study, we optimized a passive microfluidic platform with 3D cancer organoids, which allows a standardized approach among different patients, a minimum requirement of samples, multiple interrogations of biological events, and a rapid response. The passive flow was optimized to improve the growth of cancer organoids, avoiding the disruption of the extracellular matrix (ECM). Under optimized conditions of the OrganoFlow (tilting angle of 15° and an interval of rocking every 8 min), the cancer organoids grow faster than when they are in static conditions and the number of dead cells is reduced over time. To calculate the IC 50 values of standard chemotherapeutic drugs (carboplatin, paclitaxel, and doxorubicin) and targeted drugs (ATRA), different approaches were utilized. Resazurin staining, ATP-based assay, and DAPI/PI colocalization assays were compared, and the IC 50 values were calculated. The results showed that in the passive flow, the IC 50 values are lower than in static conditions. FITC-labeled paclitaxel shows a better penetration of ECM under passive flow than in static conditions, and cancer organoids start to die after 48 h instead of 96 h, respectively. Cancer organoids are the last frontiers for ex vivo testing of drugs that replicate the response of patients in the clinic. For this study, organoids derived from ascites or tissues of patients with Ovarian Cancer have been used. In conclusion, it was possible to develop a protocol for organoid cultures in a passive microfluidic platform with a higher growth rate, faster drug response, and better penetration of drugs into ECM, maintaining the samples' vitals and collecting the data on the same plate for up to 16 drugs

Discovery and optimization of benzoylpiperidine derivatives as new reversible, potent and selective MAGL inhibitors

The serine hydrolase monoacylglycerol lipase (MAGL) is the main responsible of the degradation of 2-arachidonoylglycerol, an endocannabinoid implicated in several physiological processes. Moreover, MAGL is involved in the formation of pro-tumorigenic signaling molecules. MAGL inhibition is considered a valid therapeutic approach to treat several pathological conditions, including several types of cancer.[1] So far, only a limited number of MAGL inhibitors have been discovered and most of them are characterized by an irreversible mechanism of action, determining the occurrence of undesired effects. In this study we identified a reversible MAGL inhibitor by a structure-based virtual screening analysis. With the aim of identifying more potent and selective MAGL inhibitors, chemical modifications were introduced to the original compound to improve both potency and selectivity.[2] The structural optimization led to the obtainment of nanomolar inhibitors (Figure 1), which are selective over other hydrolases and cannabinoid receptors. These new inhibitors exert an appreciable antiproliferative activity in cancer cells and are able to inhibit MAGL in in vivo assays. [1] Mulvihill MM, Nomura DK, Life Sci. 2013; 92(8-9):492-497. [2] Granchi C, Rizzolio F, Palazzolo S, Carmignani S, Macchia M, Saccomanni G, Manera C, Martinelli A, Minutolo F, Tuccinardi T, J Med Chem. 2016; 59(22):10299-10314

Recent advances of electrochemical and optical enzyme-free glucose sensors operating at physiological conditions

Diabetes is a pathological condition that requires the continuous monitoring of glucose level in the blood. Its control has been tremendously improved by the application of point-of-care devices. Conventional enzyme-based sensors with electrochemical and optical transduction systems can successfully measure the glucose concentration in human blood, but they suffer from the low stability of the enzyme. Non-enzymatic wearable electrochemical and optical sensors, with low-cost, high stability, point-of-care testing and online monitoring of glucose levels in biological fluids, have recently been developed and can help to manage and control diabetes worldwide. Advances in nanoscience and nanotechnology have enabled the development of novel nanomaterials that can be implemented for the use in enzyme-free systems to detect glucose. This review summarizes recent developments of enzyme-free electrochemical and optical glucose sensors, as well as their respective wearable and commercially available devices, capable of detecting glucose at physiological pH conditions without the need to pretreat the biological fluids. Additionally, the evolution of electrochemical glucose sensor technology and a couple of widely used optical detection systems along with the glucose detection mechanism is also discussed. Finally, this review addresses limitations and challenges of current non-enzymatic electrochemical, optical, and wearable glucose sensor technologies and highlights opportunities for future research directions