Microfluidic preparation and in vitro evaluation of iRGD-functionalized solid lipid nanoparticles for targeted delivery of paclitaxel to tumor cells

Solid lipid nanoparticles (SLNs) can combine the advantages of different colloidal carriers and prevent some of their disadvantages. The production of nanoparticles by means of microfluidics represents a successful platform for industrial scale-up of nanoparticle manufacture in a reproducible way. The realisation of a microfluidic technique to obtain SLNs in a continuous and reproducible manner encouraged us to create surface functionalised SLNs for targeted drug release using the same procedure. A tumor homing peptide, iRGD, owning a cryptic C-end Rule (CendR) motif is responsible for neuropilin-1 (NRP-1) binding and for triggering extravasation and tumor penetration of the peptide. In this study, the Paclitaxel loaded-SLNs produced by microfluidics were functionalized with the iRGD peptide. The SLNs proved to be stable in aqueous medium andwere characterized by a Z-average under 150 nm, a polydispersity index below 0.2, a zeta-potential between -20 and -35 mV and a drug encapsulation efficiency around 40%. Moreover, in vitro cytotoxic effects and cellular uptake have been assessed using 2D and 3D tumour models of U87 glioblastoma cell lines. Overall, these results demonstrate that the surface functionalization of SLNs with iRGD allow better cellular uptake and cytotoxicity ability.Peer reviewe

Induced expression of P-gp and BCRP transporters on brain endothelial cells using transferrin functionalized nanostructured lipid carriers:A first step of a potential strategy for the treatment of Alzheimer's disease

P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) are two transporters expressed in human neural stem/progenitor cells and at the Blood-Brain Barrier (BBB) level with decreased activity in the early stage of Alzheimer's disease (AD). Both proteins, have a protective role for the embryonic stem cells in the early developmental step, maintaining them in an undifferentiated state, and limit the access of exogenous and endogenous agents to the brain. Recently, MC111 selected from a P-gp/BCRP ligands library was investigated as multitarget strategy for AD treatment, considering its ability to induce the expression and activity of both proteins. However, MC111 clinical use could be limited for the ubiquitous physiological expression of efflux transporters and its moderate toxicity towards endothelial cells. Therefore, a selective MC111 delivery system based on nanostructured lipid carriers (NLC) functionalized with transferrin were developed. The results proved the formation of NLC with average size about 120 nm and high drug encapsulation efficiency (EE% greater than 50). In vitro studies on hCMEC/D3 cells revealed that the MC111 was selectively released by NLC at BBB level and then inducing the activity and expression of BCRP and P-gp, involved in the clearance of amyloid p peptide on brain endothelial cells

Preparation of cetyl palmitate-based PEGylated solid lipid nanoparticles by microfluidic technique

In recent years, several studies have shown that the use of solid lipid nanoparticles (SLN) as a colloidal drug delivery system was more advantageous than lipid emulsions, liposomes and polymeric nanoparticles. SLNs have numerous advantages of different nanosystems and rule out many of their drawbacks. Despite the numerous advantages of SLNs, translation from the preclinical formulation to the industrial scale-up is limited. In order to provide a reproducible and reliable method of producing nanoparticles, and thus, obtain an industrial scale-up, several methods of synthesis of nanoparticles by microfluidic have been developed. Microfluidic technique allows a good control and a continuous online synthesis of nanosystems compared to synthesis in bulk, leading to a narrow size distribution, high batch-to-batch reproducibility, as well as to the industrial scale-up feasibility. This work described the optimization process to produce SLNs by microfluidics. The SLNs produced by microfluidics were characterized by complementary optical and morphological techniques and compared with those produced by bulk method. SLNs were loaded with paclitaxel and sorafenib, used as model drugs. The anti-cancer efficiency of the SLNs formulation was estimated with 2D and 3D tumour models of two different cell lines, and the cellular uptake was also studied with fluorescence-assisted measurements. Statement of significance In this work, we describe the production of a single step continuous production for solid lipid nanoparticles (SLNs) via glass capillary-based microfluidic-chip. Comparing to conventional bulk methods, the current synthesis method showed several advantages, including a continuous production with high yield, good reproducibility and precise control over the properties of SLNs, which are critical pre-conditions for its successful industrialization. The superiority of this microfluidic-based method was confirmed by an overall physicochemical characterization of the produced SLNs. The size of the SLNs was controlled by altering the microfluidic parameters, and SLNs with dimensions ca. 100 nm were feasibly fabricated through parameters optimization. The microfluidics production of SLNs offered a good encapsulation efficiency and drug loading degree for a sustained release manner . (c) 2020 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.Peer reviewe

Quercetin and Its Nano-Formulations for Brain Tumor Therapy—Current Developments and Future Perspectives for Paediatric Studies

The development of efficient treatments for tumors affecting the central nervous system (CNS) remains an open challenge. Particularly, gliomas are the most malignant and lethal form of brain tumors in adults, causing death in patients just over 6 months after diagnosis without treatment. The current treatment protocol consists of surgery, followed using synthetic drugs and radiation. However, the efficacy of these protocols is associated with side effects, poor prognosis and with a median survival of fewer than two years. Recently, many studies were focused on applying plant-derived products to manage various diseases, including brain cancers. Quercetin is a bioactive compound derived from various fruits and vegetables (asparagus, apples, berries, cherries, onions and red leaf lettuce). Numerous in vivo and in vitro studies highlighted that quercetin through multitargeted molecular mechanisms (apoptosis, necrosis, anti-proliferative activity and suppression of tumor invasion and migration) effectively reduces the progression of tumor cells. This review aims to summarize current developments and recent advances of quercetin’s anticancer potential in brain tumors. Since all reported studies demonstrating the anti-cancer potential of quercetin were conducted using adult models, it is suggested to expand further research in the field of paediatrics. This could offer new perspectives on brain cancer treatment for paediatric patients

Exploring the Microfluidic Production of Biomimetic Hybrid Nanoparticles and Their Pharmaceutical Applications

: Nanomedicines have made remarkable advances in recent years, addressing the limitations of traditional therapy and treatment methods. Due to their improved drug solubility, stability, precise delivery, and ability to target specific sites, nanoparticle-based drug delivery systems have emerged as highly promising solutions. The successful interaction of nanoparticles with biological systems, on the other hand, is dependent on their intentional surface engineering. As a result, biomimetic nanoparticles have been developed as novel drug carriers. In-depth knowledge of various biomimetic nanoparticles, their applications, and the methods used for their formulation, with emphasis on the microfluidic production technique, is provided in this review. Microfluidics has emerged as one of the most promising approaches for precise control, high reproducibility, scalability, waste reduction, and faster production times in the preparation of biomimetic nanoparticles. Significant advancements in personalized medicine can be achieved by harnessing the benefits of biomimetic nanoparticles and leveraging microfluidic technology, offering enhanced functionality and biocompatibility

Accuracy Assessment of Numerical Dosimetry for the Evaluation of Human Exposure to Electric Vehicle Inductive Charging Systems

In this article, we discuss numerical aspects related to the accuracy and the computational efficiency of numerical dosimetric simulations, performed in the context of human exposure to static inductive charging systems of electric vehicles. Two alternative numerical methods based on electric vector potential and electric scalar potential formulations, respectively, are here considered for the electric field computation in highly detailed anatomical human models. The results obtained by the numerical implementation of both approaches are discussed in terms of compliance assessment with ICNIRP guidelines limits for human exposure to electromagnetic fields. In particular, different strategies for smoothing localized unphysical outliers are compared, including novel techniques based on statistical considerations. The outlier removal is particularly relevant when comparison with basic restrictions is required to define the safety of electromagnetic fields exposure. The analysis demonstrates that it is not possible to derive general conclusions about the most robust method for dosimetric solutions. Nevertheless, the combined use of both formulations, together with the use of an algorithm for outliers removal based on a statistical approach, allows to determine final results to be compared with reference limits with a significant level of reliability

Cyclodextrin-based supramolecular deep eutectic solvent (CycloDES): A vehicle for the delivery of poorly soluble drugs

The aim of this work was to develop a new class of deep eutectic solvent (DES) composed of a complexation agent, namely hydroxy-propyl-beta-cyclodextrin (HP beta CD), to exploit a synergic solubilization-enhancing approach. For this purpose, cyclodextrin-based supramolecular DES (CycloDES) were physical-chemical characterized and loaded with three different BCS class II model drugs, specifically Cannabidiol, Indomethacin, and Dexamethasone, evaluating the influence of different factors on the observed solubility and permeation compared with the only HP beta CD/drug complexation. Hence, CycloDESs were presented as a possible vehicle for drugs and represent a novel potential approach for solving BCS class II and IV solubility issues, demonstrating at least a 100-fold improvement in the investigated drug solubilities. Furthermore, CycloDESs demonstrated a significantly improved resistance to dilution preserving a high percentage of drug in solution (i.e. 93% for Indomethacin) when water is added to the DES if compared with a glucose-choline chloride DES, used as a standard. This evidence guarantees the solubilityenhancing effect useful for the delivery of BCS class II and IV drugs converting solid raw material to advantageous liquid vehicles bypassing the rate-determining dissolution step

Innovative Pharmaceutical Techniques for Paediatric Dosage Forms: A Systematic Review on 3D Printing, Prilling/Vibration and Microfluidic Platform

: The production of paediatric pharmaceutical forms represents a unique challenge within the pharmaceutical industry. The primary goal of these formulations is to ensure therapeutic efficacy, safety, and tolerability in paediatric patients, who have specific physiological needs and characteristics. In recent years, there has been a significant increase in attention towards this area, driven by the need to improve drug administration to children and ensure optimal and specific treatments. Technological innovation has played a crucial role in meeting these requirements, opening new frontiers in the design and production of paediatric pharmaceutical forms. In particular, three emerging technologies have garnered considerable interest and attention within the scientific and industrial community: 3D printing, prilling/vibration, and microfluidics. These technologies offer advanced approaches for the design, production, and customization of paediatric pharmaceutical forms, allowing for more precise dosage modulation, improved solubility, and greater drug acceptability. In this review, we delve into these cutting-edge technologies and their impact on the production of paediatric pharmaceutical forms. We analyse their potential, associated challenges, and recent developments, providing a comprehensive overview of the opportunities that these innovative methodologies offer to the pharmaceutical sector. We examine different pharmaceutical forms generated using these techniques, evaluating their advantages and disadvantages

Numerical Aspects in Dosimetric Analysis of Human Exposure to Wireless Power Transfer for Electric Vehicles

In this work, numerical aspects related to the accuracy of numerical dosimetric simulations, performed in the context of human exposure to wireless power transfer systems for electric vehicles, are discussed. Two alternative methods for electric field computation in highly detailed anatomical human models are applied, discussing results in the framework of the current regulations and guidelines. Different strategies for smoothing localized outliers are compared, including novel techniques based on statistical considerations

The Pharmaceutical Technology Approach on Imaging Innovations from Italian Research

Many modern therapeutic approaches are based on precise diagnostic evidence, where imaging procedures play an essential role. To date, in the diagnostic field, a plethora of agents have been investigated to increase the selectivity and sensitivity of diagnosis. However, the most common drawbacks of conventional imaging agents reside in their non-specificity, short imaging time, instability, and toxicity. Moreover, routinely used diagnostic agents have low molecular weights and consequently a rapid clearance and renal excretion, and this represents a limitation if long-lasting imaging analyses are to be conducted. Thus, the development of new agents for in vivo diagnostics requires not only a deep knowledge of the physical principles of the imaging techniques and of the physiopathological aspects of the disease but also of the relative pharmaceutical and biopharmaceutical requirements. In this scenario, skills in pharmaceutical technology have become highly indispensable in order to respond to these needs. This review specifically aims to collect examples of newly developed diagnostic agents connoting the importance of an appropriate formulation study for the realization of effective products. Within the context of pharmaceutical technology research in Italy, several groups have developed and patented promising agents for fluorescence and radioactive imaging, the most relevant of which are described hereafter