## 5 Strategies to Enhance the Delivery of Therapeutic Agents across the BBB
### Polymeric Nanoparticles  
Polymeric nanoparticles (NPs) are particles of nanometric size (1-1000 nm) composed of a solid core, and have been widely exploited to cross the BBB due to their properties for drug delivery, such as high loading capacity, high stability, controlled drug release and targeting efficiency [5].  
Polymeric NPs can be produced using either synthetic or natural polymers (more limited in terms of their synthesis and processing). According to their morphology, polymeric NPs are classified in two distinct categories, namely, nanospheres and nanocapsules (Figure 5). In nanospheres, the drug is molecularly dispersed throughout the polymeric network or is placed onto the surface of the polymeric core, while in the case of nanocapsules, the drug molecules are solubilized in an oil or aqueous core which is surrounded by a polymeric layer [59].  
Moreover, the properties of these NPs can be tailored by the introduction of third party components [73] in order to increase their half-life, to reach the BBB more easily, and to increase drug bioavailability into the brain for the treatment of neurological disorders such as AD [69].  
The selection of the type of polymer for the production of such NPs is based on several criteria and factors, namely, the desired size for a particular application, physicochemical properties of the drug to be loaded within the polymeric core, surface characteristics and required functionality, degree of biodegradability and biocompatibility, and drug release profile of the final formulation [74]. Several natural and synthetic polymers have been used to prepare NPs for brain delivery [75].  
Poly (butyl cyanoacrylate) (PBCA) NPs were the first polymer-based DDS used to deliver drugs to the CNS [76]. Unfortunately, despite many advantages they possess, such as biocompatibility and biodegradability, PBCA NPs have not yet been launched in clinical use. One of the major limitations of these particles is their poor drug loading capacity, in particular for hydrophobic molecules. Besides, the burst release of the drug from PBCA-NPs has also been pointed out as a shortcoming in most of the in vitro release studies describing the use of PBCA-NPs [77]. Moreover, it has been seen recently that PBCA NPs could present potential toxicity, which could be attributed to faster degradation and a more rapid release of degradation products [78]. However, other authors have demonstrated that they can induce oxidative stress, ferrotosis and necrosis [79].  
Alternatively, several types of polymeric NPs with high positive charge have been reported to cross the BBB due to their electrostatic interaction with brain endothelial cells (negatively charged). Chitosan (CS) is a naturally occurring polysaccharide that possesses  
Figure 5: Schematic representation of nanospheres and nanocapsules with the drug entrapped or adsorbed onto the surface of nanoparticles (based on [72]).  
high biodegradability, low toxicity and good biocompatibility, which has the ability to efficiently form NPs [80]. However, it shows low solubility in neutral and alkaline pH, thereby requiring production methods adapted to the physicochemical properties of the drug in question, such as the careful choice of a specific chitosan (e.g., molecular weight and degree of acetylation) and possible chemical modification [81].  
Polyesters (e.g., poly (lactic acid) (PLA), poly (glycolic acid) (PGA), poly(lactic-co-glycolic acid) (PLGA)) have also been widely used for parenteral administration of drugs [75].