Simultaneous Administration of Bevacizumab with Bee-Pollen Extract-Loaded Hybrid Protein Hydrogel NPs Is a Promising Targeted Strategy against Cancer Cells.

Bevacizumab (Bev) a humanized monoclonal antibody that fights vascular endothelial growth factor A (VEGF-A). It was the first specifically considered angiogenesis inhibitor and it has now become the normative first-line therapy for advanced non-small-cell lung cancer (NSCLC). In the current study, polyphenolic compounds were isolated from bee pollen (PCIBP) and encapsulated (EPCIBP) inside moieties of hybrid peptide-protein hydrogel nanoparticles in which bovine serum albumin (BSA) was combined with protamine-free sulfate and targeted with folic acid (FA). The apoptotic effects of PCIBP and its encapsulation (EPCIBP) were further investigated using A549 and MCF-7 cell lines, providing significant upregulation of Bax and caspase 3 genes and downregulation of Bcl2, HRAS, and MAPK as well. This effect was synergistically improved in combination with Bev. Our findings may contribute to the use of EPCIBP simultaneously with chemotherapy to strengthen the effectiveness and minimize the required dose.

Natural Compounds as Promising Adjuvant Agents in The Treatment of Gliomas.

In humans, glioblastoma is the most prevalent primary malignant brain tumor. Usually, glioblastoma has specific characteristics, such as aggressive cell proliferation and rapid invasion of surrounding brain tissue, leading to a poor patient prognosis. The current therapy-which provides a multidisciplinary approach with surgery followed by radiotherapy and chemotherapy with temozolomide-is not very efficient since it faces clinical challenges such as tumor heterogeneity, invasiveness, and chemoresistance. In this respect, natural substances in the diet, integral components in the lifestyle medicine approach, can be seen as potential chemotherapeutics. There are several epidemiological studies that have shown the chemopreventive role of natural dietary compounds in cancer progression and development. These heterogeneous compounds can produce anti-glioblastoma effects through upregulation of apoptosis and autophagy; allowing the promotion of cell cycle arrest; interfering with tumor metabolism; and permitting proliferation, neuroinflammation, chemoresistance, angiogenesis, and metastasis inhibition. Although these beneficial effects are promising, the efficacy of natural compounds in glioblastoma is limited due to their bioavailability and blood-brain barrier permeability. Thereby, further clinical trials are necessary to confirm the in vitro and in vivo anticancer properties of natural compounds. In this article, we overview the role of several natural substances in the treatment of glioblastoma by considering the challenges to be overcome and future prospects.

Recent Overview of Resveratrol's Beneficial Effects and Its Nano-Delivery Systems.

Natural polyphenols have a wide variety of biological activities and are taken into account as healthcare materials. Resveratrol is one such natural polyphenol, belonging to a group known as stilbenoids (STBs). Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is mainly found in grapes, wine, nuts, and berries. A wide range of biological activities has been demonstrated by resveratrol, including antimicrobial, antioxidant, antiviral, antifungal, and antiaging effects, and many more are still under research. However, as with many other plant-based polyphenol products, resveratrol suffers from low bioavailability once administered in vivo due to its susceptibility to rapid enzyme degradation by the body's innate immune system before it can exercise its therapeutic influence. Therefore, it is of the utmost importance to ensure the best use of resveratrol by creating a proper resveratrol delivery system. Nanomedicine and nanodelivery systems utilize nanoscale materials as diagnostic tools or to deliver therapeutic agents in a controlled manner to specifically targeted locations. After a brief introduction about polyphenols, this review overviews the physicochemical characteristics of resveratrol, its beneficial effects, and recent advances on novel nanotechnological approaches for its delivery according to the type of nanocarrier utilized. Furthermore, the article summarizes the different potential applications of resveratrol as, for example, a therapeutic and disease-preventing anticancer and antiviral agent.

Biomechanics of Cell Membrane.

This Special Issue is focused on measuring and characterizing the mechanical and adhesive properties of cells and membranes [...].

Acute Cytotoxic Effects on Morphology and Mechanical Behavior in MCF-7 Induced by TiO2NPs Exposure.

The side effects induced by nanoparticle exposure at a cellular level are one of the priority research topics due to the steady increase in the use of nanoparticles (NPs). Recently, the focus on cellular morphology and mechanical behavior is gaining relevance in order to fully understand the cytotoxic mechanisms. In this regard, we have evaluated the morphomechanical alteration in human breast adenocarcinoma cell line (MCF-7) exposed to TiO2NPs at two different concentrations (25 and 50 µg/mL) and two time points (24 and 48 h). By using confocal and atomic force microscopy, we demonstrated that TiO2NP exposure induces significant alterations in cellular membrane elasticity, due to actin proteins rearrangement in cytoskeleton, as calculated in correspondence to nuclear and cytoplasmic compartments. In this work, we have emphasized the alteration in mechanical properties of the cellular membrane, induced by nanoparticle exposure.

Resveratrol-Induced Temporal Variation in the Mechanical Properties of MCF-7 Breast Cancer Cells Investigated by Atomic Force Microscopy.

Atomic force microscopy (AFM) combined with fluorescence microscopy has been used to quantify cytomechanical modifications induced by resveratrol (at a fixed concentration of 50 µM) in a breast cancer cell line (MCF-7) upon temporal variation. Cell indentation methodology has been utilized to determine simultaneous variations of Young's modulus, the maximum adhesion force, and tether formation, thereby determining cell motility and adhesiveness. Effects of treatment were measured at several time-points (0-6 h, 24 h, and 48 h); longer exposures resulted in cell death. Our results demonstrated that AFM can be efficiently used as a diagnostic tool to monitor irreversible morpho/nano-mechanical changes in cancer cells during the early steps of drug treatment.

Encapsulation of Thermo-Sensitive Lauric Acid in Silica Shell: A Green Derivate for Chemo-Thermal Therapy in Breast Cancer Cell.

Lauric acid is a green derivate that is abundant in some seeds such as coconut oil where it represents the most relevant fatty acid. Some studies have emphasized its anticancer effect due to apoptosis induction. In addition, the lauric acid is a Phase Change Material having a melting temperature of about 43.2 °C: this property makes it a powerful tool in cancer treatment by hyperthermal stress, generally induced at 43 °C. However, the direct use of lauric acid can have some controversial effects, and it can undergo degradation phenomena in the extracellular environment. For this reason, we have encapsulated lauric acid in a silica shell with a one-step and reproducible synthetic route in order to obtain a monodispersed SiO2@LA NPs with a good encapsulation efficiency. We have used these NPs to expose breast cancer cell lines (MCF-7) at different concentrations in combination with hyperthermal treatment. Uptake, viability, oxidative stress induction, caspases levels, and morphometric parameters were analyzed. These nanovectors showed double action in anticancer treatments thanks to the synergic effect of temperature and lauric acid activity.

Morphomechanical and structural changes induced by ROCK inhibitor in breast cancer cells.

The EMT phenomenon is based on tumour progression. The cells lose their physiologic phenotype and assumed a mesenchymal phenotype characterized by an increased migratory capacity, invasiveness and high resistance to apoptosis. In this process, RHO family regulates the activation or suppression of ROCK (Rho-associated coiled-coil containing protein kinase) which in turn regulates the cytoskeleton dynamics. However, while the biochemical mechanisms are widely investigated, a comprehensive and careful estimation of biomechanical changes has not been extensively addressed. In this work, we used a strong ROCK inhibitor, Y-27632, to evaluate the effects of inhibition on living breast cancer epithelial cells by a biomechanical approach. Atomic Force Microscopy (AFM) was used to estimate changes of cellular elasticity, quantified by Young's modulus parameter. The morphometric alterations were analyzed by AFM topographies and Confocal Laser Scanning Microscopy (CLSM). Our study revealed a significant modification in the Young's modulus after treatment, especially as regards cytoskeletal region. Our evidences suggest that the use of Y-27632 enhanced the cell rigidity, preventing cell migration and arrested the metastasization process representing a potential powerful factor for cancer treatment.

Transforming Growth Factor-ß Promotes Morphomechanical Effects Involved in Epithelial to Mesenchymal Transition in Living Hepatocellular Carcinoma.

The epithelial mesenchymal transition (EMT) is a physiological multistep process involving epithelial cells acquiring a mesenchymal-like phenotype. It is widely demonstrated that EMT is linked to tumor progression and metastasis. The transforming growth factor (TGF)-ß pathways have been widely investigated, but its role in the hepatocarcinoma EMT is still unclear. While the biochemical pathways have been extensively studied, the alteration of biomechanical behavior correlated to cellular phenotype and motility is not yet fully understood. To better define the involvement of TGF-ß1 in the metastatic progression process in different hepatocarcinoma cell lines (HepG2, PLC/PRF/5, HLE), we applied a systematic morphomechanical approach in order to investigate the physical and the structural characteristics. In addition, we evaluated the antitumor effect of LY2157299, a TGF-ßR1 kinase inhibitor, from a biomechanical point of view, using Atomic Force and Confocal Microscopy. Our approach allows for validation of biological data, therefore it may be used in the future as a diagnostic tool to be combined with conventional biomolecular techniques.

Polymeric Nano-Micelles as Novel Cargo-Carriers for LY2157299 Liver Cancer Cells Delivery.

LY2157299 (LY), which is very small molecule bringing high cancer diffusion, is a pathway antagonist against TGFß. LY dosage can be diluted by blood plasma, can be captured by immune system or it might be dissolved during digestion in gastrointestinal tract. The aim of our study is to optimize a "nano-elastic" carrier to avoid acidic pH of gastrointestinal tract, colon alkaline pH, and anti-immune recognition. Polygalacturonic acid (PgA) is not degradable in the gastrointestinal tract due to its insolubility at acidic pH. To avoid PgA solubility in the colon, we have designed its conjugation with Polyacrylic acid (PAA). PgA-PAA conjugation has enhanced their potential use for oral and injected dosage. Following these pre-requisites, novel polymeric nano-micelles derived from PgA-PAA conjugation and loading LY2157299 are developed and characterized. Efficacy, uptake and targeting against a hepatocellular carcinoma cell line (HLF) have also been demonstrated.

Hybrid polymeric-protein nano-carriers (HPPNC) for targeted delivery of TGFß inhibitors to hepatocellular carcinoma cells.

TGFß1 pathway antagonists have been considered promising therapies to attenuate TGFß downstream signals in cancer cells. Inhibiting peptides, as P-17 in this study, are bound to either TGFß1 or its receptors, blocking signal transduction. However, for efficient use of these TGFß1antagonist as target therapeutic tools, improvement in their delivery is required. Here, a plasmid carrying specific shDNA (SHT-DNA), small interfering RNA (siRNA), and the peptide (P-17) were loaded separately into folic acid (FA)-functionalized nano-carriers made of Bovine Serum Albumin (BSA). The two building blocks of the carrier, (BSA and FA) were used because of the high affinity of albumin for liver and for the overexpression of folate receptors on the membrane of hepatocellular carcinoma cells. The empty and the encapsulated carriers were thoroughly investigated to characterize their structure, to evaluate the colloidal stability and the surface functionalization. The entrapment of SHT-DNA, siRNA and P-17, respectively, was demonstrated by morphological and quantitative analysis. Finally, cellular studies were performed to assess the targeting efficiency of the hybrid carriers. These vectors were used because of the high affinity of albumin for liver and for the overexpression of folate receptors on the membrane hepatocellular carcinoma cells. The empty and the encapsulated carriers were thoroughly investigated to characterize their structure, to evaluate the colloidal stability and the surface functionalization. The entrapment of SHT-DNA, siRNA and P-17, respectively, was demonstrated by morphological and quantitative analysis. A novel fabrication of Hybrid Polymeric-Protein Nano-Carriers (HPPNC) for delivering TGF ß1 inhibitors to HCC cells has been developed. SHT-DNA, siRNA and P-17 have been successfully encapsulated. TGF ß1 inhibitors-loaded HPPNC were efficiently uptaken by HLF cells.

Thiophene-based fluorescent probes with low cytotoxicity and high photostability for lysosomes in living cells.

BACKGROUND: Selective imaging of lysosomes by fluorescence microscopy using specific fluorescent probes allows the study of biological processes and it is potentially useful also for diagnosis. Lysosomes are involved in numerous physiological processes, such as bone and tissue remodeling, plasma membrane repair, and cholesterol homeostasis, along with cell death and cell signaling. Despite the great number of dyes available today on the market, the search for new fluorescent dyes easily up-taken by cells, biocompatible and bearing bright and long-lasting fluorescence is still a priority. METHODS: Two thiophene-based fluorescent dyes, TC1 and TC2, were synthetized as lysosome-specific probes. RESULTS: The new dyes showed high selectivity for fluorescent staining and imaging of lysosomes and disclosed high photostability, low toxicity and pH insensitivity in the range 2-10. CONCLUSIONS: The TC dyes exhibited high co-localization coefficients (>95%) and moderate quantum yields. They showed high biocompatibility and long-term retention, important features for biological applications. GENERAL SIGNIFICANCE: The results of the present work disclose a new class of organic dyes with potential wide applications as specific and efficient lysosome probes in the study of various biological processes.

The rationale for targeting TGF-ß in chronic liver diseases.

BACKGROUND: Transforming growth factor (TGF)-ß is a pluripotent cytokine that displays several tissue-specific biological activities. In the liver, TGF-ß is considered a fundamental molecule, controlling organ size and growth by limiting hepatocyte proliferation. It is involved in fibrogenesis and, therefore, in worsening liver damage, as well as in triggering the development of hepatocellular carcinoma (HCC). TGF-ß is known to act as an oncosuppressor and also as a tumour promoter in HCC, but its role is still unclear. DESIGN: In this review, we discuss the potential role of TGF-ß in regulating the tumoural progression of HCC, and therefore the rationale for targeting this molecule in patients with HCC. RESULTS: A considerable amount of experimental preclinical evidence suggests that TGF-ß is a promising druggable target in patients with HCC. To support this hypothesis, a phase II clinical trial is currently ongoing using a TGF-ß pathway inhibitor, and results will soon be available. CONCLUSIONS: The identification of new TGF-ß related biomarkers will help to select those patients most likely to benefit from therapy aimed at inhibiting the TGF-ß pathway. New formulations that may provide a more controlled and sustained delivery of the drug will improve the therapeutic success of such treatments.

From nature to nanomedicine: bioengineered metallic nanoparticles bridge the gap for medical applications.

The escalating global challenge of antimicrobial resistance demands innovative approaches. This review delves into the current status and future prospects of bioengineered metallic nanoparticles derived from natural sources as potent antimicrobial agents. The unique attributes of metallic nanoparticles and the abundance of natural resources have sparked a burgeoning field of research in combating microbial infections. A systematic review of the literature was conducted, encompassing a wide range of studies investigating the synthesis, characterization, and antimicrobial mechanisms of bioengineered metallic nanoparticles. Databases such as PubMed, Scopus, Web of Science, ScienceDirect, Springer, Taylor & Francis online and OpenAthen were extensively searched to compile a comprehensive overview of the topic. The synthesis methods, including green and sustainable approaches, were examined, as were the diverse biological sources used in nanoparticle fabrication. The amalgamation of metallic nanoparticles and natural products has yielded promising antimicrobial agents. Their multifaceted mechanisms, including membrane disruption, oxidative stress induction, and enzyme inhibition, render them effective against various pathogens, including drug-resistant strains. Moreover, the potential for targeted drug delivery systems using these nanoparticles has opened new avenues for personalized medicine. Bioengineered metallic nanoparticles derived from natural sources represent a dynamic frontier in the battle against microbial infections. The current status of research underscores their remarkable antimicrobial efficacy and multifaceted mechanisms of action. Future prospects are bright, with opportunities for scalability and cost-effectiveness through sustainable synthesis methods. However, addressing toxicity, regulatory hurdles, and environmental considerations remains crucial. In conclusion, this review highlights the evolving landscape of bioengineered metallic nanoparticles, offering valuable insights into their current status and their potential to revolutionize antimicrobial therapy in the future.

Lapatinib/Paclitaxel polyelectrolyte nanocapsules for overcoming multidrug resistance in ovarian cancer.

The sonication-assisted layer-by-layer (SLBL) technology was developed to combine necessary factors for an efficient drug-delivery system: (i) control of nanocolloid size within 100 - 300 nm, (ii) high drug content (70% wt), (iii) shell biocompatibility and biodegradability, (iv) sustained controlled release, and (v) multidrug-loaded system. Stable nanocolloids of Paclitaxel (PTX) and lapatinib were prepared by the SLBL method. In a multidrug-resistant (MDR) ovarian cancer cell line, OVCAR-3, lapatinib/PTX nanocolloids mediated an enhanced cell growth inhibition in comparison with the PTX-only treatment. A series of in vitro cell assays were used to test the efficacy of these formulations. The small size and functional versatility of these nanoparticles, combined with their ability to incorporate various drugs, indicates that lapatinib/PTX nanocolloids may have in vivo therapeutic applications.

Thinking about Enhanced Permeability and Retention Effect (EPR).

This invited editorial article aims at reporting progress about the enhanced permeability and retention effect (EPR for short), starting from a recent Special Issue in the Journal of Personalized Medicine (namely, "EPR Effect-Based Tumor Targeted Nanomedicine") and focusing specifically on one of these contributing articles, a review from Jun Wu entitled "The Enhanced Permeability and Retention (EPR) Effect: The Significance of the Concept and Methods to Enhance Its Application", which has recently acquired the rank of a highly cited paper [...].

Nano-Clays for Cancer Therapy: State-of-the Art and Future Perspectives.

To date, cancer continues to be one of the deadliest diseases. Current therapies are often ineffective, leading to the urgency to develop new therapeutic strategies to improve treatments. Conventional chemotherapeutics are characterized by a reduced therapeutic efficacy, as well as them being responsible for important undesirable side effects linked to their non-specific toxicity. In this context, natural nanomaterials such as clayey mineral nanostructures of various shapes (flat, tubular, spherical and fibrous) with adjustable physico-chemical and morphological characteristics are emerging as systems with extraordinary potential for the delivery of different therapeutic agents to tumor sites. Thanks to their submicron size, high specific surface area, high adsorption capacity, chemical inertia and multilayer organization of 0.7 to 1 nm-thick sheets, they have aroused considerable interest among the scientific community as nano systems that are highly biocompatible in cancer therapy. In oncology, the nano-clays usually studied are halloysite, bentonite, laponite, kaolinite, montmorillonite and sepiolite. These are multilayered minerals that can act as nanocarriers (with a drug load generally between 1 and 10% by weight) for improved stabilization, efficient transport and the sustained and controlled release of a wide variety of anticancer agents. In particular, halloysite, montmorillonite and kaolinite are used to improve the dissolution of therapeutic agents and to delay and/or direct their release. In this review, we will examine and expose to the scientific community the extraordinary potential of nano-clays as unique crystalline systems in the treatment of cancer.

Nanomedicine in Cancer Targeting and Therapy.

Currently, cancer represents a major cause of death in the world, despite all the progress made in developing new therapies [...].

AFM Characterization of Halloysite Clay Nanocomposites' Superficial Properties: Current State-of-the-Art and Perspectives.

Natural halloysite clay nanotubes (HNTs) are versatile inorganic reinforcing materials for creating hybrid composites. Upon doping HNTs with polymers, coating, or loading them with bioactive molecules, the production of novel nanocomposites is possible, having specific features for several applications. To investigate HNTs composites nanostructures, AFM is a very powerful tool since it allows for performing nano-topographic and morpho-mechanical measurements in any environment (air or liquid) without treatment of samples, like electron microscopes require. In this review, we aimed to provide an overview of recent AFM investigations of HNTs and HNT nanocomposites for unveiling hidden characteristics inside them envisaging future perspectives for AFM as a smart device in nanomaterials characterization.

Impact of Nanomaterials in Biological Systems and Applications in Nanomedicine Field.

The increasingly widespread use of engineered nanomaterials in many applications increases the need to understand the mechanisms behind their toxicity [...].