Micelles: Polymeric and Lipidic
Micelles are self-assembly aggregates with 5-50 nm of amphiphilic agents (lipidic or polymeric] which occur above a well-defined concentration which is called the critical micelle concentration (CMC). Unlike liposomes or POs which are vesicles containing an aqueous core, micelles possess hydrophilic portions turned towards aqueous surroundings and a hydrophobic core made of the hydrophobic portions of the amphiphilic agents (Fig. 4.1) . As described before, although using the same type of amphiphilic constituents, whether an amphiphile is assembled in a micelle or in a vesicle, it depends on several parameters, such as concentration, molecular weight, geometry of the amphiphilic block copolymers or amphiphilic lipids or the ratio of the different blocks.
Like vesicles, micellar drug carriers have also been particularly attractive in studies of BBB penetration and brain drug delivery for their tuneable self-assembly, high drug-loading capacity, good biocompatibility, increased brain drug accumulation and extended circulation half-life. Moreover, their surface can also be decorated with targeting ligands which will actively direct the ONCs to the corresponding BBB endothelial cell receptors and facilitate transcytosis of drug across the BBB . Some illustrative examples of the use of micelles for brain drug delivery in different CNS diseases and glioma are presented in Table 4.2.
Nanoparticles: Lipid Nanoparticles and Polymeric Nanoparticles
Another important lipid-based ONC is lipid nanoparticles which are colloidal dispersions containing a solid lipid matrix in which hydrophobic therapeutic agents can be effectively carried. These ONCs present a size distribution ranging from 10 to 1000 nm. The term 'lipid nanoparticles' includes two types of nanoparticles which differ in their inner lipidic structure because of the composition and organisation of the lipids in the solid matrix: solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs)
 (Fig. 4.1). SLNs are an alternative of submicron-sized oil-inwater (o/w) emulsions, where the liquid lipid (oil) is replaced by a solid lipid (e.g. glyceiyl behenate, tripalmitin, stearic acid, glyceryl monostearate [GMS], cetyl palmitate, tristearin, tripalmitate [TP], glyceryl palmitostearate, glyceril trimyristate), which remains in the solid state at room temperature. In contrast, the lipid matrix of NLCs is composed of a mixture of liquid and solid lipids, that is, a solid matrix which entraps liquid lipid nanocompartments, and is also solid at room temperature . Some examples of liquid lipids include octyldodecanol, Miglyol® 812 (caprylic/capric triglycerides), oleic acid and propylene glycol monocaprylate. Although NLCs contain a liquid lipid, these nanoparticles remain in the solid state at room temperature by setting the proportion of liquid lipids in the formulation . The use of functional lipids in ONCs can enhance the dissolution and bioavailability of poorly water-soluble drugs, while the solid matrix allows the controlled release of encapsulated molecules and protects them from degradation, thus increasing the long-term stability of the system .
To enhance brain uptake of therapeutic agents, lipid nanoparticles are considered highly attractive colloidal systems because of their general properties [120-126]:
- • Biocompatibility, biodegradability generating natural degradation by-products
- • Non-immunogenicity, nonthrombogenicity and noninflammatory because of the use of physiological lipids and generally recognised as safe (GRAS) excipients
- • Physical stability in the circulatory system
- • Natural tendency to cross the BBB by endocytosis or by transcytosis mechanism of endothelial cells  lining blood capillaries in the brain or permeate the tight junctions between cells because of their lipophilic nature and small size
- • Possibility of surface functionalisation to target the BBB
- • Use of excipients which are regulatory-approved and do not induce drug alterations (e.g. protein denaturation, chemical degradation)
- • Ease of manufacturing/scaling up at an industrial scale cost- effectively with reproducibility in drug loading
- • Capacity to encapsulate a wide variety of biologically active compounds
Despite the development of lipid matrices being described several decades ago, nowadays lipid nanoparticles are gaining a special interest for therapeutic brain delivery because of the increasing availability of lipophilic excipients with well-known safety profiles which offer the possibility of modulating release profiles [127, 128]. In vitro studies have shown that lipid nanoparticles are less toxic than polymeric ones . In addition, these nanosystems can present high physicochemical stability; for example, Blasi et al.  demonstrated that SLNs composed of cetyl palmitate are stable when stored at 4°C for four years. These authors reinforced the potential of lipid nanoparticles as ONCs for brain drug delivery based on long-term physicochemical stability and the in vivo safety profile.
The use of both lipid nanoparticles (i.e. SLNs and NLCs) has been widely investigated to mediate targeting of therapeutic agents for different brain pathologies (e.g. neurodegenerative, psychotic disorders or tumours) and overcome the constraints on the transport of therapeutics across the BBB. These ONCs have already demonstrated their high value in improving the delivery of therapeutics to the brain, crossing the BBB more easily. Some examples of these studies are explored in the next sections.