Due to the progressive ageing of the human population, the number of cancer cases is increasing. For this reason, there is an urgent need for new treatments that can prolong the lives of cancer patients or ensure them a good quality of life. Although significant progress has been made in the treatment of cancer in recent years and the survival rate of patients is increasing, limitations in the use of conventional therapies include the frequent occurrence of side effects and the development of resistance to chemotherapeutic agents. These limitations are prompting researchers to investigate whether combining natural agents with conventional drugs could have a positive therapeutic effect in cancer treatment. Several natural bioactive compounds, especially polyphenols, have been shown to be effective against cancer progression and do not exert toxic effects on healthy tissues. Many studies have investigated the possibility of combining polyphenols with conventional drugs as a novel anticancer strategy. Indeed, this combination often has synergistic benefits that increase drug efficacy and reduce adverse side effects. In this review, we provide an overview of the studies describing the synergistic effects of curcumin, a polyphenol that has been shown to have extensive cytotoxic functions against cancer cells, including combined treatment. In particular, we have described the results of recent preclinical and clinical studies exploring the pleiotropic effects of curcumin in combination with standard drugs and the potential to consider it as a promising new tool for cancer therapy.

Purpose: Dimethyl fumarate (DMF), the first-line oral therapy for relapsing-remitting multiple sclerosis, is rapidly metabolized into monomethyl fumarate. The DMF oral administration provokes gastrointestinal discomfort causing treatment withdrawal. The present study aimed to develop an innovative formulation for DMF nasal administration. Lipid-polymer hybrid nanoparticles (LPNs) were developed to improve DMF stability, limiting gastrointestinal side effects and increasing brain bioavailability by nose-to-brain targeting application. Methods: DMF-loaded and unloaded LPNs with or without hyaluronic acid (HA) were prepared using the nanoprecipitation via magnetic/mechanical stirring technique. Particle morphology and surface properties were evaluated; drug content, viscosity, and mucoadhesion were determined. Physico-chemical stability of LPNs and DMF in the LPNs was also explored. In vitro DMF permeation experiments were performed utilizing the PermeaPad^®. The cytotoxicity and cellular uptake studies were performed using RPMI 2650 and SK-N-BE2 cell lines. DMF nose-to–brain delivery was evaluated by intranasally administering DMF-loaded LPNs to rats. Results: LPNs with average sizes of 120– 250 nm and a negative zeta potential − 17.3 to − 43 mV were obtained, primarily influenced by the presence of HA. HA assured drug stability up to 60 days and promoting the in vitro permeation of DMF compared to the free-DMF. HA greatly improved the viscosity and mucoadhesive properties. LPNs with and without HA did not exhibit any cytotoxicity and showed a rapid cell uptake starting from 15 min to 2 h with a best internalization after 1 h of treatment in both epithelial and neuronal cell lines. Nasal administration of DMF-loaded LPNs allowed to quantify up to about 12 μg/mL of DMF in the rat cerebrospinal fluid. Conclusion: The results highlight the role of HA in improving LPNs properties and performance as carrier of DMF for nasal administration. In particular, LPNs appear able to enter neurons and monolayers of epithelial cells, allowing to promote the nose-to-brain DMF delivery.

Despite its potential against several carcinomas, the pharmacological efficacy of silibinin (SLB) is hampered by poor solubility, absorption, and oral bioavailability. To face these issues, we developed polylactic-co-glycolic acid (PLGA) nanoparticles (NPs) coated with hydrophilic polyethene oxide (PEO) for controlled and targeted SLB delivery. NPs were produced at two different SLB loadings and presented a spherical shape with smooth surfaces and stable size in water and cell culture medium. The encapsulation efficiencies were found to be >84%, and thermal analysis revealed that the SLB was present in an amorphous state within the NPs. In vitro SLB release experiments revealed that at the lowest SLB loading, desorption of the active molecule from the surface or nanoporosities of the NPs mainly dictates release. In contrast, at the highest SLB loading, diffusion primarily regulates release, with negligible contributions from other mechanisms. Cell experiments showed that, compared with the free drug, SLB loaded in the produced NPs significantly increased the bioactivity against H1299, H1975, and H358 cells.

This study aimed to develop hybrid nanoparticles (LPNs) using hyaluronic acid (HA) of different molecular weights for intranasal delivery of silibinin (SLB) to glioma tumors. LPNs were prepared using low, medium, and high molecular weight HA. Blank LPNs measured approximately 100 nm, whereas SLB-LPNs were about 160 nm. Cryo-TEM confirmed a spherical morphology with an internal multilayer bilayer structure, and the membrane thickness ranged between 8 and 16 nm. Zeta potential was approximately -44.4 mV due to the presence of HA. Isothermal titration calorimetry indicated improved stability and an amorphous structure of SLB within LPNs, particularly when using low molecular weight HA. The drug content and encapsulation efficiency were about 100 % and 60 %, respectively. In vitro, about 85 % of SLB was released over 24 h, significantly higher and prolonged than Free-SLB (only 20 % in 1 h). Cellular uptake in RPMI 2650 cells was increased (about 2-fold) compared to control, while cytotoxicity assays in T98-G glioblastoma cells showed a 50 % reduction in viability after 72 h of treatment with SLB-LPNs. These findings underscore the crucial role of HA molecular weight in optimizing LPNs performance for brain-targeted delivery and highlight their promising potential for intranasal glioma therapy.

Cancer is one of the main diseases causing one-third of the worldwide death every year. The recent progresses achieved in chemotherapy have increased patients' survival, however, drug efficacy is limited by the occurrence of serious side effects and the development of drug resistance. To overcome these problems, research interests, aim to develop alternative therapies based on the use of polyphenols, such as curcumin. Polyphenols are effective against different cancers and in combination with standard drugs, display synergism enhancing anticancer effects. Malignant mesothelioma (MM) is an aggressive cancer associated with exposure to asbestos fibers for which to date, neither surgical nor chemotherapy, based on the use of cisplatin and other platinum drugs, result in a favorable prognosis. We previously reported that daily administration of a curcumin standardized extract exerted anticancer effects in MM in vitro and in vivo. The efficacy of this formulation has been tested in several clinical trials in combination to standard drugs. Since curcumin is known to increase cisplatin sensitivity in different cancer, here we evaluated the ability of this formulation in enhancing cisplatin sensitivity in MM. The effect of combined treatment was evaluated in 2D and 3D cultures by using two MM cell lines, MSTO-211H and Ist-Mes2, that are sensitive or less responsive to the piroxicam/cisplatin combined treatment respectively. Results indicate that this treatment determines a dramatic apoptotic increase linked to a concomitant inactivation of Nrf2, a transcription factor with a key role in carcinogenesis, and of NUPR1, a transcriptional regulator involved in drug chemoresistance.

Obesity is a multifactorial disease associated with a chronic imbalance between energy intake and energy consumption, as well as the ingestion of high-fat foods. It is widely reported that the Mediterranean Diet (MD), a dietary regimen rich in vegetables, fruits, fiber and complex polyunsaturated lipids, can positively act on obesity onset. These aliments contain bioactive molecules that exert beneficial effects on two traits often associated with obesity: lipid accumulation and imbalance in oxidative homeostasis. Additionally, they can act on metabolic pathways linked to obesity through the cross-kingdom activity of plant miRNAs. In this review, we provide an overview of the studies describing the anti-obesogenic effect of plant-based foods typical of the Mediterranean Diet. We describe the results of recent studies that link the effect of lipid reduction with the ingestion of bioactive molecules or plant miRNAs typical of MD foods. We also report how advances in bioinformatic analyses have elucidated the role of plant-derived miRNAs in metabolic homeostasis, revealing how the cross-kingdom interaction results in the anti-obesogenic action of the MD. These findings shed light on the molecular mechanisms through which the MD dietary pattern exerts its metabolic effects, suggesting new perspectives on MD nutrition-based strategies as novel therapeutic approaches for obesity.