Nanocannabinoides como terapia frente a glioma / Nannocannabinoids for brain tumor drug delivery

Las patologías cerebrales representan un desafío terapéutico por la restricción al paso de fármacos a través de la barrera hematoencefálica. Por ello, actualmente se persigue diseñar transportadores de fármacos capaces de atravesar de manera eficiente el endotelio cerebral tras su administración intravenosa. Sin embargo, el impacto traslacional de la nanomedicina es aún discreto. Sin duda, la transición de un desarrollo empírico hacia un diseño racional adecuado a las necesidades terapéuticas concretas en cada caso aumentará las posibilidades de éxito.Bajo esta premisa y aprovechando tanto el tropismo cerebral como la actividad antiproliferativa del cannabidiol, y a fin de contribuir al diseño racional de nanocápsulas dirigidas para el tratamiento de gliomas, hemos evaluado la influencia de distintos parámetros en su comportamiento in vitro e in vivo. Efectivamente, hemos demostrado que tanto el paso a través de barrera hematoencefálica como la captación por células de glioma, así como la velocidad de liberación de fármacos pueden modularse variando su tamaño de partícula. El método térmico de inversión de fases posibilita la obtención de nanocápsulas bajo demanda en términos de tamaño gracias al modelo matemático lineal en una variable aquí descrito.Además, hemos desarrollado una novedosa estrategia de vectorización con cannabidiol (que incluso supera a otras que ya se encuentran en ensayos clínicos). Asimismo, las nanocápsulas sirven como transportadores de liberación prolongada del cannabidiol, superando así sus problemas de formulación que venían limitando su potencial terapéutico.En conjunto, las nanocápsulas lipídicas, cargadas y funcionalizadas con cannabidiol, constituyen prometedores candidatos para el tratamiento de gliomas. (AU)

Brain diseases are a major health challenge as brain drug delivery is truly hindered by the blood-brain barrier. Therefore, targeted drug nanocarriers arise as an alternative to achieve efficient transport across the brain endothelium following minimally-invasive intravenous injection. However, the global translational impact of nanomedicine remains modest. Certainly, the transition from empirical development towards a rational design tailored to the specific disease needs is likely to improve the chances of success.Under this assumption and taking advantage of both the natural brain tropism and the antiproliferative activity of cannabidiol, to contribute to the rational design of targeted nanocapsules for glioma therapy, we have thoroughly screened the influence of distinct parameters on their in vitro and in vivo behaviour. Effectively, we have demonstrated that both the brain and glioma targeting ability and the drug release rate can be tailored by varying the particle size of the nanocapsules. This fine size-tailoring can be achieved by the phase inversion temperature method thanks to the hereindescribed linear univariate mathematical model as a function of the oily phase/surfactant mass ratio.Moreover, we have introduced, on the one hand, a pioneering brain tumor targeting strategy with cannabidiol (with better targeting properties than other strategies that have already reached the clinical trials stage) and, on the other hand, nanocapsules as extendedrelease carriers of cannabidiol to overcome the formulation problems that have traditionally constrained its therapeutic potential.Altogether, small lipid nanocapsules loaded and functionalized with cannabidiol arise as promising dually-targeted candidates for intravenous treatment of glioma. (AU)

Limitations and Challenges in the Stability of Cysteamine Eye Drop Compounded Formulations.

Accumulation of cystine crystals in the cornea of patients suffering from cystinosis is considered pathognomonic and can lead to severe ocular complications. Cysteamine eye drop compounded formulations, commonly prepared by hospital pharmacy services, are meant to diminish the build-up of corneal cystine crystals. The objective of this work was to analyze whether the shelf life proposed for six formulations prepared following different protocols used in hospital pharmacies is adequate to guarantee the quality and efficacy of cysteamine eye drops. The long-term and in-use stabilities of these preparations were studied using different parameters: content of cysteamine and its main degradation product cystamine; appearance, color and odor; pH and viscosity; and microbiological analysis. The results obtained show that degradation of cysteamine was between 20% and 50% after one month of storage in the long-term stability study and between 35% and 60% in the in-use study. These data confirm that cysteamine is a very unstable molecule in aqueous solution, the presence of oxygen being the main degradation factor. Saturation with nitrogen gas of the solutions offers a means of reducing cysteamine degradation. Overall, all the formulae studied presented high instability at the end of their shelf life, suggesting that their clinical efficacy might be dramatically compromised.

Quimioterapia nanométrica a base de cannabinoides para el tratamiento de tumores ginecológicos / Cannabinoid based chemo-nanotherapy for the treatment of gynecological

El cannabidiol está despertando un creciente interés como agente antitumoral. Sin embargo, no se ha estudiado su efecto en cáncer de ovario, uno de los tumores más agresivos en mujeres. En el presente trabajo se ha evaluado, por primera vez, el potencial uso del cannabidiol en solución y encapsulado en nanopartículas funcionalizadas con ácido fólico en cáncer de ovario, ya que estos tumores sobre expresan los receptores de ácido fólico, permitiendo una acumulación selectiva de estas nanoformulaciones en las células tumorales. El cannabidiol en solución inhibe la proliferación y migración de las células SKOV-3. En terapia de combinación, aumenta significativamente la eficacia antitumoral del paclitaxel, presentando un efecto sensibilizador y sinérgico. En los modelos in ovo, la administración previa de cannabidiol en solución seguido de su coadministración con paclitaxel muestra un efecto inhibitorio sobre el crecimiento tumoral significativamente superior al paclitaxel en monoterapia. Las nanopartículas desarrolladas son eficazmente internalizadas por las células SKOV-3, presentando las nanopartículas con ácido fólico una captación más rápida. Aunque en los estudios de eficacia antitumoral in vitro las nanopartículas funcionalizadas no presentan una actividad antiproliferativa superior al cannabidiol en solución o a las nanopartículas no funcionalizadas, en los modelos in ovo su eficacia antitumoral es significativamente superior, indicando que el desarrollo de nanopartículas funcionalizadas con ácido fólico es una buena estrategia para vectorizar el cannabidiol a tumores de ovario. Por último, las nanopartículas de cannabidiol potencian el efecto antitumoral del paclitaxel, presentando las formulaciones funcionalizadas con ácido fólico una mayor eficacia que el cannabidiol en solución

Cannabidiol has become in a potential anticancer agent. Nevertheless, it has not been evaluated in ovarian cancer, one of the most aggressive tumors in women. In this work, the potential use of cannabidiol in solution and encapsulated into polymeric nanoparticles coated with folic acid was evaluated for the first time for the treatment of ovarian cancer. Ovarian tumors over-express folic acid receptors and folic-acid-coated nanoformulations trend to be selectively accumulated at tumor site. Cannabidiol in solution administered as monotherapy inhibits the proliferation and migration of SKOV-3 cells. In combination therapy, it significantly increases the antitumor efficacy of paclitaxel, showing a sensitizer and synergistic effect. In ovo, the previous administration of cannabidiol in solution followed by its co-administration with paclitaxel, shows a significantly higher inhibitory effect on ovarian tumor growth than single paclitaxel. The developed nanoparticles are efficiently uptaken by SKOV-3 cells, showing folic acid coated formulations a faster internalization. Although coated formulations do not exhibit a higher in vitro antiproliferative effect compared to cannabidiol in solution or non-coated formulations, in ovo its antitumoral efficacy is significantly higher. This indicates that folic acid-coated nanoparticles represent a good strategy to target cannabidiol to ovarian tumors. Finally, cannabidiol-loaded nanoparticles improve the in vitro antiproliferative effect of paclitaxel, showing folic acid-coated-formulations a better efficacy than cannabidiol in solution

PLGA Nanoparticles for the Intraperitoneal Administration of CBD in the Treatment of Ovarian Cancer: In Vitro and In Ovo Assessment.

The intraperitoneal administration of chemotherapeutics has emerged as a potential route in ovarian cancer treatment. Nanoparticles as carriers for these agents could be interesting by increasing the retention of chemotherapeutics within the peritoneal cavity. Moreover, nanoparticles could be internalised by cancer cells and let the drug release near the biological target, which could increase the anticancer efficacy. Cannabidiol (CBD), the main nonpsychotropic cannabinoid, appears as a potential anticancer drug. The aim of this work was to develop polymer nanoparticles as CBD carriers capable of being internalised by ovarian cancer cells. The drug-loaded nanoparticles (CBD-NPs) exhibited a spherical shape, a particle size around 240 nm and a negative zeta potential (-16.6 ± 1.2 mV). The encapsulation efficiency was high, with values above 95%. A controlled CBD release for 96 h was achieved. Nanoparticle internalisation in SKOV-3 epithelial ovarian cancer cells mainly occurred between 2 and 4 h of incubation. CBD antiproliferative activity in ovarian cancer cells was preserved after encapsulation. In fact, CBD-NPs showed a lower IC50 values than CBD in solution. Both CBD in solution and CBD-NPs induced the expression of PARP, indicating the onset of apoptosis. In SKOV-3-derived tumours formed in the chick embryo model, a slightly higher-although not statistically significant-tumour growth inhibition was observed with CBD-NPs compared to CBD in solution. To sum up, poly-lactic-co-glycolic acid (PLGA) nanoparticles could be a good strategy to deliver CBD intraperitoneally for ovarian cancer treatment.

Nanocannabinoides como terapia frente a glioma / Nannocannabinoids for brain tumor drug delivery

Brain diseases are a major health challenge as brain drug delivery is truly hindered by the blood-brain barrier. Therefore, targeted drug nanocarriers arise as an alternative to achieve efficient transport across the brain endothelium following minimally-invasive intravenous injection. However, the global translational impact of nanomedicine remains modest. Certainly, the transition from empirical development towards a rational design tailored to the specific disease needs is likely to improve the chances of success. Under this assumption and taking advantage of both the natural brain tropism and the antiproliferative activity of cannabidiol, to contribute to the rational design of targeted nanocapsules for glioma therapy, we have thoroughly screened the influence of distinct parameters on their in vitro and in vivo behaviour. Effectively, we have demonstrated that both the brain and glioma targeting ability and the drug release rate can be tailored by varying the particle size of the nanocapsules. This fine size-tailoring can be achieved by the phase inversion temperature method thanks to the hereindescribed linear univariate mathematical model as a function of the oily phase/surfactant mass ratio. Moreover, we have introduced, on the one hand, a pioneering brain tumor targeting strategy with cannabidiol (with better targeting properties than other strategies that have already reached the clinical trials stage) and, on the other hand, nanocapsules as extendedrelease carriers of cannabidiol to overcome the formulation problems that have traditionally constrained its therapeutic potential. Altogether, small lipid nanocapsules loaded and functionalized with cannabidiol arise as promising dually-targeted candidates for intravenous treatment of glioma

Las patologías cerebrales representan un desafío terapéutico por la restricción al paso de fármacos a través de la barrera hematoencefálica. Por ello, actualmente se persigue diseñar transportadores de fármacos capaces de atravesar de manera eficiente el endotelio cerebral tras su administración intravenosa. Sin embargo, el impacto traslacional de la nanomedicina es aún discreto. Sin duda, la transición de un desarrollo empírico hacia un diseño racional adecuado a las necesidades terapéuticas concretas en cada caso aumentará las posibilidades de éxito. Bajo esta premisa y aprovechando tanto el tropismo cerebral como la actividad antiproliferativa del cannabidiol, y a fin de contribuir al diseño racional de nanocápsulas dirigidas para el tratamiento de gliomas, hemos evaluado la influencia de distintos parámetros en su comportamiento in vitro e in vivo. Efectivamente, hemos demostrado que tanto el paso a través de barrera hematoencefálica como la captación por células de glioma, así como la velocidad de liberación de fármacos pueden modularse variando su tamaño de partícula. El método térmico de inversión de fases posibilita la obtención de nanocápsulas bajo demanda en términos de tamaño gracias al modelo matemático lineal en una variable aquí descrito. Además, hemos desarrollado una novedosa estrategia de vectorización con cannabidiol (que incluso supera a otras que ya se encuentran en ensayos clínicos). Asimismo, las nanocápsulas sirven como transportadores de liberación prolongada del cannabidiol, superando así sus problemas de formulación que venían limitando su potencial terapéutico. En conjunto, las nanocápsulas lipídicas, cargadas y funcionalizadas con cannabidiol, constituyen prometedores candidatos para el tratamiento de gliomas

Size-Tailored Design of Highly Monodisperse Lipid Nanocapsules for Drug Delivery.

The empirical development of nanocarriers has unfortunately led to high attrition rates in clinical trials. This underpins the importance of the rational design of nanomedicines to achieve efficient disease-driven therapies. Since particle size certainly influences in vivo behaviour, rational disease-driven colloid design can only be achieved by determining the parameters that accurately control their size distribution. To this end, we have thoroughly revisited the parameters that drive the phase-inversion temperature nanoemulsification method to obtain kinetically stable and monodisperse lipid nanocapsules. Notably, we have evidenced that the major parameter driving nanocapsule formation is the oily phase/surfactant ratio and consequently, we have established a linear univariate mathematical model that predicts the particle size distribution for various oily phase-surfactant combinations (R² > 0 99). Furthermore, we have observed that the difference between the HLB values of the surfactants and the triglycerides utilized as oily phase correlates with the steepness of the slope of the linear mathematical model. This model will bring the implementation of size-tailored lipid drug carriers determined by pathophysiological features a step closer. Importantly, this model pioneeringly fits all data available in the literature on size distribution of colloids prepared by low-energy methods and that were originally evaluated following other parameters. Moreover, the nanocapsules have been obtained following a single-step process, with the ensuing potential for a future scale-up in an energetically-efficient manner. These findings will eventually enable nanomedicines to be obtained "on-demand" to meet disease-driven criteria in terms of particle size and will also increase their chances of success.

Cannabidiol Enhances the Passage of Lipid Nanocapsules across the Blood-Brain Barrier Both in Vitro and in Vivo.

Diseases affecting the central nervous system (CNS) should be regarded as a major health challenge due to the current lack of effective treatments given the hindrance to brain drug delivery imposed by the blood-brain barrier (BBB). Since efficient brain drug delivery should not solely rely on passive targeting, active targeting of nanomedicines into the CNS is being explored. The present study is devoted to the development of lipid nanocapsules (LNCs) decorated with nonpsychotropic cannabinoids as pioneering nonimmunogenic brain-targeting molecules and to the evaluation of their brain-targeting ability both in vitro and in vivo. Noticeably, both the permeability experiments across the hCMEC/D3 cell-based in vitro BBB model and the biodistribution experiments in mice consistently demonstrated that the highest brain-targeting ability was achieved with the smallest-sized cannabinoid-decorated LNCs. Importantly, the enhancement in brain targeting achieved with the conjugation of cannabidiol to LNCs outperformed by 6-fold the enhancement observed for the G-Technology (the main brain active strategy that has already entered clinical trials for the treatment of CNS diseases). As the transport efficiency across the BBB certainly determines the efficacy of the treatments for brain disorders, small cannabinoid-decorated LNCs represent auspicious platforms for the design and development of novel therapies for CNS diseases.

Lipid nanocapsules decorated and loaded with cannabidiol as targeted prolonged release carriers for glioma therapy: In vitro screening of critical parameters.

The therapeutic potential of cannabinoids has been truly constrained heretofore due to their strong psychoactive effects and their high lipophilicity. In this context, precisely due to the lack of psychoactive properties, cannabidiol (CBD), the second major component of Cannabis sativa, arises as the phytocannabinoid with the most auspicious therapeutic potential. Hence, the incorporation of CBD in lipid nanocapsules (LNCs) will contribute to overcome the dosing problems associated with cannabinoids. Herein, we have prepared LNCs decorated and loaded with CBD for glioma therapy and screened in vitro their critical parameters. On the one hand, we have encapsulated CBD into the oily core of LNCs to test their in vitro efficacy as extended-release carriers against the human glioblastoma cell line U373MG. The in vitro antitumor effect was highly dependent on the size of LNCs due to its pivotal role in the extent of CBD release. Effectively, a comparison between two differently-sized LNCs (namely, 20-nm and 50-nm sized carriers) showed that the smaller LNCs reduced by 3.0-fold the IC50 value of their 50-nm sized counterparts. On the other hand, to explore the potential of this phytocannabinoid to target any of the cannabinoid receptors overexpressed in glioma cells, we decorated the LNCs with CBD. This functionalization strategy enhanced the in vitro glioma targeting by 3.4-fold in comparison with their equally-sized undecorated counterparts. Lastly, the combination of CBD-loading with CBD-functionalization further reduced the IC50 values. Hence, the potential of these two strategies of CBD incorporation into LNCs deserves subsequent in vivo evaluation.

Targeting to macrophages: role of physicochemical properties of particulate carriers--liposomes and microspheres--on the phagocytosis by macrophages.

Heterogeneous functions of macrophages in human immune systems have renewed interest in targeting of drugs to these cells. Various carrier systems have emerged to deliver drugs to macrophages, albeit the efficacy, reliability and selectivity of these carriers are still in question. To date, the most extensively studied carriers are liposomes and microspheres. Various physicochemical properties of these carriers can alter their efficacy and specificity to a great extent. These properties include hydrophilicity, surface charge, composition, concentration, and presence of various ligands. In this review, a comprehensive evaluation of the literature has been carried out in order to show the role of these parameters in the design of carriers for targeting of drugs to macrophages.