# Formulation of Boron Encapsulated Smart Nanocapsules for Targeted Drug Delivery to the Brain
## 1 Introduction
### Mitochondrial Targeting  
Neoplastic cells are characterized by high metabolic activity, which opens the possibility of targeting cellular organelles, such as mitochondria, and offers the distinct advantage that both nondividing and dividing cancer cells can become accessible to the therapeutic agent [25]. Following the demonstration of the mitochondrial accumulation of lipophilic cations, fluorescent DLCs (Figure 2), such as rhodamine-123, are employed to visualize mitochondria and to estimate mitochondrial activity [26; 27].  
DLCs have been shown to accumulate selectively in tumour cells. The positively surface charged lipophilic properties that DLCs possess allow them to be selectively drawn towards the tumour cells due to a more negatively surface charged mitochondrial transmembrane potential, that is, due to the higher metabolic activity of cancer cells when compared to healthy cells [8; 13; 14; 15]. The resonance-stabilized delocalisation in their structure, combined with their inherent lipophilicity, leads to a decrease in cost associated with free energy change, which accompanies the diffusion of DLCs through the cell membranes. Henceforth, a larger accumulation (>100 fold) in the mitochondrial matrix of tumour cells is observed, [10; 16] in addition to the high difference (>5 fold) in the cytoplasmic and extracellular concentrations [16; 17]. These have, therefore, been used in the synthesis and development of selective target-specific anticancer agents that can be used in BNCT, [18] despite the structural modification of DLCs (e.g., by covalent bonding with boronated moieties) that might significantly affect their accumulation.  
Due to the complexity of the BBB, much effort has been made to use the nanodelivery-based systems for drug delivery. The main strategies are: [28].  
1. Delivery across the BBB through the manipulation of the drug via a prodrug or nanodelivery system.
2. Direct delivery to the brain: this can be performed through surgery or intra-cerebro-ventricular administration of a precalculated amount of drug to the brain. However, this is limited due to its invasive nature.
3. Delivery of drug intranasally: the most promising delivery route due to its practical, noninvasive, rapid, and simple nature.
4. Delivery of drug through the BBB via a two-component stimuli-responsive polymeric drug delivery system, which is enabled to release drug at a specified condition.  
The intranasal route is possible due to the brain being at its most leaky nature in that region. A review by [PERSON] et al. [29] showed that it was feasible to deliver, via this route, molecules such as small polar molecules, peptides, proteins, polysaccharides, vaccines, or DNA plasmid vaccines. More recently, a review published by [PERSON] et al. [30] had a more in depth look at the possible advantages and disadvantages for nasal drug delivery and its potential for future treatments. The advantages of intranasal delivery to the brain are clear; this route is noninvasive, rapid, and will attain higher patient compliance. However, some parts of the brain are difficult to reach via this route, and some pharmacophores are susceptible to nasal enzymatic degradation. Nanotechnology can be very helpful in overcoming some of these limitations.