## 5 Strategies to Enhance the Delivery of Therapeutic Agents across the BBB
### PLGA Nanoparticles  
PLGA nanoparticles are associated with high cost of production and difficulty in scaling up [82]. Most recent studies have focused on the use of PLGA as a material for the synthesis of NPs to encapsulate a wide variety of drugs for the treatment of neurological disorders, including AD. Several in vitro studies have showed that the use of these polymeric NPs enhanced bioavailability in the brain, with reduced inflammation, oxidative stress and plaque load [83].  
Indeed, PLGA is one of the most widely used biodegradable copolymers because the cleavage of polymer chains by hydrolysis results in free lactic acid (LA) and glycolic acid (GA) [84] as showed in Figure 6. Given the fact that these two metabolite monomers are endogenous, and easily eliminated from the body via the Krebs cycle in the form of H\({}_{2}\)O and CO\({}_{2}\), a minimal systemic toxicity is associated with the use of PLGA for drug delivery [9]. Formulations composed of PLGA and its related homopolymers (i.e., poly (lactic acid) (PLA) and poly (glycolic acid) (PGA)) have been approved by the FDA and EMA for medical applications [85].  
PLGA NPs undergo degradation via hydrolysis of ester bonds to monomeric anions (lactate and glycolate). While L-lactate is converted into CO\({}_{2}\), which is then excreted through the lungs and converted to pyruvate entering the Krebs cycle, D-lactate is not metabolized before excretion. Glycolate is either directly excreted through the renal system or oxidized into glyoxylate, which is then converted into glycine, serine and pyruvate [73]. These can also enter the Krebs cycle where they are metabolized into CO\({}_{2}\) and H\({}_{2}\)O [9,84].  
PLGA is typically produced by a catalysed ring-opening copolymerization of lactic acid and glycolic acid [86]. As a copolymer of both, PLGA inherits the intrinsic properties of these monomers [73]. However, it is essential to understand the effects of the lactate/glycolate acids ratio and the molecular weight of PLGA copolymers on the degradation behaviour and the kinetics of drug delivery.  
The most important influencing factor for controlling the degradation rates of the PLGA matrix is the ratio between lactate/glycolate acids in the copolymer. Whereas an increase in the lactate/glycolate ratio results in higher hydrophobicity, leading to lower  
Figure 6: Hydrolysis of PLGA NPs (based on [5]).  
degradation and slower drug release kinetics [87], a higher content of glycolate contributes to increase the hydrophilic character of PLGA being more amorphous and thus leading to much faster degradation and drug release [88].  
Since the lactate/glycolate ratio can be easily changed during synthesis, several publications discuss its impact on release kinetics and degradation [89; 90; 91; 92]. It should be noted that most of the studied PLGA NPs are prepared with lactate/glycolate ratios of 50/50 or higher because PLGA 50/50 constitutes a suitable choice for medium-rapid drug release if only the effect of lactate/glycolate ratio is considered [88].  
In fact, the final molecular weight of PLGA also significantly influences the degradation and drug release kinetics of the resulting nanoparticles [73]. It has been seen that a lower molecular weight leads to higher degradation and shorter drug release rates because a decrease results in a less hydrophobic polymer, which increases the water absorption rate, hydrolysis, and polymeric erosion [93]. On the other hand, a lower molecular weight promotes drug diffusion, thereby accelerating drug release kinetics [88; 94].