The blood-brain barrier (BBB) prevents efficient drug delivery to the central nervous system. As a result, brain diseases remain one of the greatest unmet medical needs. Understanding the tridimensional structure of the BBB helps gain insight into the pathology of the BBB and contributes to the development of novel therapies for brain diseases. Therefore, 3D models with an ever-growing sophisticated complexity are being developed to closely mimic the human neurovascular unit. Among these 3D models, hydrogel-, spheroid- and organoid-based static BBB models have been developed, and so have microfluidic-based BBB-on-a-chip models. The different 3D preclinical models of the BBB, both in health and disease, are here reviewed, from their development to their application for permeability testing of nanomedicines across the BBB, discussing the advantages and disadvantages of each model. The validation with data from in vivo preclinical data is also discussed in those cases where provided.

Embolization with microspheres is a therapeutic strategy based on the selective occlusion of the blood vessels feeding a tumor. This procedure is intraarterially performed in the clinical setting for the treatment of liver cancer. The practice has evolved over the last decade through the incorporation of drug loading ability, biodegradability and imageability with the subsequent added functionality for the physicians and improved clinical outcomes for the patients. This review highlights the evolution of the embolization systems developed through the analysis of the marketed embolic microspheres for the treatment of malignant hepatocellular carcinoma, namely the most predominant form of liver cancer. Embolic microspheres for the distinct modalities of embolization (i.e., bland embolization, chemoembolization and radioembolization) are here comprehensively compiled with emphasis on material characteristics and their impact on microsphere performance. Moreover, the future application of the embolics under clinical investigation is discussed along with the scientific and regulatory challenges ahead in the field. STATEMENT OF SIGNIFICANCE: Embolization therapy with microspheres is currently used in the clinical setting for the treatment of most liver cancer conditions. The progressive development of added functionalities on embolic microspheres (such as biodegradability, imageability or drug and radiopharmaceutical loading capability) provides further benefit to patients and widens the therapeutic armamentarium for physicians towards truly personalized therapies. Therefore, it is important to analyze the possibilities that advanced biomaterials offer in the field from a clinical translational perspective to outline the future trends in therapeutic embolization.

Although colloidal carriers have been in the pipeline for nearly four decades, standardized methods for testing their drug-release properties remain to be established in pharmacopeias. The in vitro assessment of drug release from these colloidal carriers is one of the most important parameters in the development and quality control of drug-loaded nano- and microcarriers. This lack of standardized protocols occurs due to the difficulties encountered in separating the released drug from the encapsulated one. This review aims to compare the most frequent types of release testing methods (i.e., membrane diffusion techniques, sample and separate methods and in situ detection techniques) in terms of the advantages and disadvantages of each one and of the key parameters that influence drug release in each case.

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.