Advances in nanotechnology for drug delivery are fostering significant progress in medicine and diagnostics. The multidisciplinary nature of the nanotechnology field encouraged the development of innovative strategies and materials to treat a wide range of diseases in a highly specific way, which allows reducing the drug dosage and, consequently, improving the patient’s compliance. Due to their good biocompatibility, easy synthesis, and high versatility, inorganic frameworks represent a valid tool to achieve this aim. In this context, Mesoporous Silica Nanoparticles (MSNs) are emerging in the biomedical field. For their ordered porosity and high functionalizable surface, achievable with an inexpensive synthesis process and being non-hazardous to biological tissues, MSNs offer ideal solutions to host, protect, and transport drugs to specific target sites. Extensive literature exists on the use of MSNs as targeted vehicles for systemic (chemo) therapy and for imaging/diagnostic purposes. However, the aim of this review is to give an overview of the last updates on the potential applications of the MSNs for Topical Drug Delivery (TDD) and as drug delivery systems into the brain, discussing their performances and advantages in dealing with these intriguing biological barriers.

A mesoporous silica-based nanodevice bearing the antineoplastic drug bortezomib (BTZ), whose release is triggered in acidic environment and grafted with folic acid (FOL) as a targeting function (FOL-MSN-BTZ) was tested on folate receptor overexpressing (FR+) multiple myeloma (MM) cells and on FR negative (FR−) normal cells. FOL-MSN-BTZ efficacy studies were conducted by means of growth experiments, TEM, TUNEL assay and Western Blotting analysis (WB). Metabolic investigations were performed to assess cells metabolic response to MSNs treatments. FOL-MSN-BTZ exclusively killed FR+ MM cells, leading to an apoptotic rate that was comparable to that induced by free BTZ, and the effect was accompanied by metabolic dysfunction and oxidative stress. Importantly, FOL-MSN-BTZ treated FR− normal cells did not show any significant sign of injury or metabolic perturbation, while free BTZ was still highly toxic. Notably, the vehicle alone (MSN-FOL) did not affect any biological process in both tested cell models. These data show the striking specificity of FOL-MSN-BTZ toward FR+ tumor cells and the outstanding safety of the MSN-FOL vehicle, paving the way for a future exploitation of FOL-MSN-BTZ in MM target therapy.

Background: Resistance to endocrine treatments is a major clinical challenge in the management of estrogen receptor positive breast cancers. Although multiple mechanisms leading to endocrine resistance have been proposed, the poor outcome of this subgroup of patients demands additional studies. Methods: FoxO3a involvement in the acquisition and reversion of tamoxifen resistance was assessed in vitro in three parental ER+ breast cancer cells, MCF-7, T47D and ZR-75-1, in the deriving Tamoxifen resistant models (TamR) and in Tet-inducible TamR/FoxO3a stable cell lines, by growth curves, PLA, siRNA, RT-PCR, Western blot, Immunofluorescence, Transmission Electron Microscopy, TUNEL, cell cycle, proteomics analyses and animal models. FoxO3a clinical relevance was validated in silico by Kaplan–Meier survival curves. Results: Here, we show that tamoxifen resistant breast cancer cells (TamR) express low FoxO3a levels. The hyperactive growth factors signaling, characterizing these cells, leads to FoxO3a hyper-phosphorylation and subsequent proteasomal degradation. FoxO3a re-expression by using TamR tetracycline inducible cells or by treating TamR with the anticonvulsant lamotrigine (LTG), restored the sensitivity to the antiestrogen and strongly reduced tumor mass in TamR-derived mouse xenografts. Proteomics data unveiled novel potential mediators of FoxO3a anti-proliferative and pro-apoptotic activity, while the Kaplan–Meier analysis showed that FoxO3a is predictive of a positive response to tamoxifen therapy in Luminal A breast cancer patients. Conclusions: Altogether, our data indicate that FoxO3a is a key target to be exploited in endocrine-resistant tumors. In this context, LTG, being able to induce FoxO3a, might represent a valid candidate in combination therapy to prevent resistance to tamoxifen in patients at risk.

The ionic gelation technique allows us to obtain nanoparticles able to function as carriers for hydrophobic anticancer drugs, such as 5-fluoruracil (5-FU). In this study, reticulated chitosan– docosahexaenoic acid (Chi–DHAr) nanoparticles were synthesized by using a chemical reaction between amine groups of chitosan (Chi) and carboxylic acids of docosahexaenoic acid (DHA) and the presence of a link between Chi and DHA was confirmed by FT-IR, while the size and morphology of the obtained Chi-DHAr nanoparticles was evaluated with dynamic light scattering (DLS) and scanning electron microscopy (SEM), respectively. Drug-loading content (DLC) and drug-loading efficiency (DLE) of 5-FU in Chi-DHAr nanoparticles were 33.74 ± 0.19% and 7.9 ± 0.26%, respectively, while in the non-functionalized nanoparticles (Chir + 5FU), DLC, and DLE were in the ranges of 23.73 ± 0.14%, 5.62%, and 0.23%, respectively. The in vitro release profile, performed in phosphate buffer saline (PBS, pH 7.4) at 37 °C, indicated that the synthetized Chi–DHAr nanoparticles provided a sustained release of 5-FU. Based on the obtained regression coefficient value (R²), the first order kinetic model provided the best fit for both Chir and Chi-DHAr nanoparticles. Finally, cytotoxicity studies of chitosan, 5-FU, Chir, Chir + 5-FU, Chi-DHAr, and Chi-DHAr + 5-FU nanoparticles were conducted. Overall, Chi-DHAr nanoparticles proved to be much more biocompatible than Chir nanoparticles while retaining the ability to release the drug with high efficiency, especially towards specific types of cancerous cells.

Cancer is a major health burden worldwide. Although the plethora of molecular targets identified in the last decades and the deriving developed treatments, which significantly improved patients’ outcome, the occurrence of resistance to therapies remains the major cause of relapse and mortality. Thus, efforts in identifying new markers to be exploited as molecular targets in cancer therapy are needed. This review will first give a glance on the diagnostic and therapeutic significance of histone deacetylase (HDAC) and voltage gated ion channels (VGICs) in cancer. Nevertheless, HDAC and VGICs have also been reported as molecular targets through which antiepileptic drugs (AEDs) seem to exert their anticancer activity. This should be claimed as a great advantage. Indeed, due to the slowness of drug approval procedures, the attempt to turn to off-label use of already approved medicines would be highly preferable. Therefore, an updated and accurate overview of both preclinical and clinical data of commonly prescribed AEDs (mainly valproic acid, lamotrigine, carbamazepine, phenytoin and gabapentin) in breast, prostate, brain and other cancers will follow. Finally, a glance at the emerging attempt to administer AEDs by means of opportunely designed drug delivery systems (DDSs), so to limit toxicity and improve bioavailability, is also given.