Josefa Alvarez-Fuentes

Background and Purpose: Atherosclerosis, a chronic inflammatory disease characterised by lipid accumulation and endothelial dysfunction, remains a leading cause of cardiovascular morbidity and mortality. While cannabinoid 2 (CB ₂ ) receptor agonists show therapeutic promise in preclinical studies, their systemic application is hindered by poor bioavailability and off‐target effects. Consequently, targeted delivery systems are essential to enhance therapeutic efficacy and mitigate adverse effects. Experimental Approach: This study presents a targeted nanotherapeutic strategy for localising the CB ₂ receptor agonist directly at atherosclerotic lesions. Poly(lactic‐co‐glycolic acid) (PLGA) nanoparticles (NPs), encapsulating the selective agonist JWH‐133 and functionalised with a VCAM‐1 binding peptide (VBP) for selective binding to vascular cell adhesion molecule‐1 (VCAM‐1) (VBP‐JWH‐133‐NPs), were developed. In vivo experiments were conducted in both male and female apolipoprotein E‐deficient (ApoE ^−/− ) mice to assess the anti‐inflammatory and lipid‐modulating effects of the nanotherapy. Serum lipid profiles, aortic plaque burden and key inflammatory markers were analysed. Key Results: VBP‐JWH‐133‐NPs significantly reduced foam cell‐rich depositions and modulate systemic inflammatory markers in both sexes, demonstrating superior anti‐atherogenic efficacy compared with free JWH‐133. The therapeutic benefits are notably more pronounced in male mice, which exhibit greater initial plaque area and lipid deposition. Conclusion and Implications: These findings underscore the potential of VBP‐JWH‐133‐NPs as an efficient and superior delivery system for cannabinoid therapies in atherosclerosis. By addressing sex as a biological variable, this approach offers a nuanced strategy for developing more effective and precise cardiovascular interventions.

During the past two decades the development of drug delivery systems (DDSs) has been a revolutionary cue for the advancement of conventional approaches of drug administration in medicine and thus has opened new frontiers such as micromedicine and nanomedicine. These frontiers encompass therapeutic, diagnostic, as well as theranostic approaches and have witnessed seminal growth in the recent past [1]. Micro-/nanotechnology that enables the fabrication of fine and ultrafine structures (e.g., particles, fibers, wires, etc., onthe nanom eter scale) using diverse materials has played a pivotal role in the development of these frontier areas. The success of micro-/nanomedicine is governed to a great extent by the availability of polymeric m aterial which can be used for human applications. Till date, multiple polymeric m aterials have been approved by the United States Food and Drug Administration (US FDA) [2] for their application as DDSs, which largely include polyesters, polyacrylates, polyanhydrides, polyamides, and polycarbonates. Among these, polyesters represent a major class where multiple polyester-based DDSs have been approved by the US FDA for application in humans [3, 4], including polylactic acid (PLA), polyglycolic acid (PGA), polylacticco-glycolic acid (PLGA), polydioxanone, polycaprolactone (PCL), and poly(trimethyl carbonate) [3, 5, 67]. Further, the potential of polyester-based polymers as versatile DDSs has been demonstrated by their ability to encapsulate diverse therapeutic molecules/cargo (e.g., synthetic drugs, proteins, or deoxyribonucleic acid [DNA]) inside the polymer matrix [8, 9]. In contrast to the administration of a free drug, encapsulation of a drug inside polyester-based particulate DDSs not only ensures its protection in hostile environments and desirable release kinetics, but can also improve its bioavailability and thus facilitate high payload delivery [2]. Currently there are more than 10 polyester-based DDSs available commercially in the m arket [9]. For example, two of the PLGA-based DDSs are Zoladex® (PLGA/goserelin acetate), which is used for the treatm ent of prostate cancer, and Lupron Depot® (PLGA/leuprolide acetate), which is used for the treatm ent o f prostate cancer and endometriosis [10]. Due to their desirable properties, polyester-based m aterials show high potential for the development of future DDSs employing DNA, small interfering ribonucleic acid (siRNA), messenger ribonucleic acid (mRNA), aptamer, and other novel synthetic/peptide-based therapeutic molecules. While existing polyester-based DDSs have shown good success, innovations in polymer chemistry combined with the discovery of novel therapeutic molecules are continuously fueling the development of newer biodegradable, biocompatible, tissue-specific, stimuli-responsive (pH, temperature, pressure, light, ionic concentration, and catalytic based) polyester-based DDSs [11].

Lysosomal storage diseases (LSDs) comprise a group of rare inherited chronic syndromes that cause deficiency of specific native enzymes within the lysosomes. The macromolecular compounds that are usually catabolized by lysosomal enzymes are accumulated within these organelles, causing progressive damage to tissues, skeleton and organs and, in several cases, the central nervous system (CNS). The damage caused by substrate accumulation finally results in physical deterioration, functional impairment and potential death. Up to date, the most promising therapy for most LSDs is enzyme-replacement therapy (ERT), which provides patients with the corresponding active enzyme. However, these enzymes do not have enough stability in blood, the treatment must be therefore periodically administrated by i.v. infusion under medical supervision, and immunogenicity issues are frequent. In addition, affected areas within the CNS, where the blood-brain barrier (BBB) is a major obstacle, cannot be reached by the enzymes. Nanotechnology can provide useful carriers to successfully protect and preserve enzymes, and transport them through the BBB towards brain locations. Several strategies based on targeting specific receptors on the BBB have led to nanoparticles that successfully carry sensitive molecules to the brain. Then, the main LSDs are described and a thorough review of nanotechnology strategies for brain delivery studied up to date is presented.

This article aimed to produce, characterize and evaluate different surface-modified naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (CB13) loaded poly(lactic-co-glycolic acid) nanoparticles in order to improve their oral absorption and in vivo biodistribution. Plain and surface-modified PLGA nanoparticles were successfully prepared using a nanoprecipitation method. Chitosan, Eudragit^® RS, lecithin and vitamin E were used as surface modifying agents. The NPs were evaluated in terms of mean diameter and size distribution, zeta potential, morphology, drug loading, drug release profiles, mucoadhesive properties, in vitro cell viability and uptake and in vivo biodistribution. Mean particle size distributions in the range of 253–344 nm, spherical shape and controlled zeta potential values were observed depending on the additive employed. High values of entrapment efficiency were obtained for all the formulations. Lecithin and vitamin E modified particles showed higher release rates when compared to the rest of formulations. A clear improvement in ex vivo mucoadhesion properties was observed in the case of chitosan- and Eudragit^® RS-modified nanoparticles. Chitosan-poly(lactic-co-glycolic acid) nanoparticles showed the highest uptake values on Caco-2 cells. Biodistribution assays proved that most of the particles were accumulated in liver and spleen. An important goal has been achieved in this investigation: CB13, a highly lipophilic drug with low water solubility, can reach the interior of cells more efficiently when it is included in these surface-modified polymeric carriers.

Peer reviewed article authored by (Martín-Banderas L, Álvarez-Fuentes J, Durán-Lobato M, Prados J, Melguizo C, Fernández-Arévalo M, Holgado MÁ). Read article or submit your manuscript for publishing.

Abstract: In the present work, a promising formulation of an inhaled powder based on tobramycin-loaded microparticles has been reported. Biodegradable microparticles with controlled diameters in the range of 1-5 μm and narrow size distribution were synthesized by Flow Focusing® technology. Particles production was planned and optimized with the aid of a well-established mathematic model. Close agreements between theoretical an experimental sizes were obtained. To deliver a high payload of tobramycin to the lungs, the influence of surfactant concentration, polymer-drug ratio and initial drug concentration were investigated. For chosen formulations, drug delivery profiles were also studied. In some cases, it was found a controlled drug delivery for more than ten days, which could represent an important advance in the treatment of chronic lung infections. Other particles factors affecting deposit of an aerosol in the lung were also studied, such as surface charge and density.