# Formulation of Boron Encapsulated Smart Nanocapsules for Targeted Drug Delivery to the Brain
## 1 Introduction
### Boron Neutron Capture Therapy  
Boron Neutron Capture Therapy (BNCT) is a targeted chemo-radiotherapeutic technique. It is a two-step approach (Figure 1) that involves the selective delivery of boronated agents to tumours and their subsequent irradiation with epithermal neutrons that have energy between 0.5 eV and 10 keV, which results in a nuclear fission reaction that selectively destroys cancer cells.  
Figure 1: BNCT steps: selective delivery of 10B-drugs to tumour cells is followed by irradiation with slow neutrons (1n), leading to tissue repair. (Adapted from [PERSON] et al. [20]).  
The first step is the selective uptake of a therapeutic dose of the drug by the cancer cells; this is critical for the success of the BNCT treatment. The second step involves irradiating the area of interest with a neutron beam to form 11B, which undergoes nuclear fission, releasing the radiating energy that leads to a high probability of local tumour cell death by direct DNA damage [20]. Accordingly, the nuclear reaction of \({}^{10}\)B can be used for the selective destruction of malignant tumour cells without compromising nearby normal and healthy tissues [21]. The probability of capturing a neutron by a nuclide is defined as the \"neutron-capture cross section\" (\(\sigma_{\text{th}}\)); nuclides with large \(\sigma_{\text{th}}\) values are desirable for this purpose. \({}^{10}\)Boron (\(\sigma_{\text{th}}\) = 3838 barns) offers a good compromise between toxicity and stability, and its chemistry is highly versatile and well established. Moreover, as the oxygen enhancement ratio (i.e., the measure of the proportion of radiation doses that are needed to affect the same rate of cell survival under hypoxic or oxic conditions) of neutrons (1.6) is lower than that of X-rays (2.5-3.0); the use of neutron beams is preferred in treatments involving hypoxic cells [22].  
The predominant types of radiation released by the \({}^{10}\)B reaction are recoiling \({}^{7}\)Li nuclei and \(\alpha\) particles. It only takes a few alpha (\(\alpha\)) particles to kill a malignant cell. They are equally lethal to hypoxic and oxygenated cells as they are to nonproliferating cells [23]. Since the cytocidal effects of the capture reaction occur primarily in malignant cells that have accumulated a sufficient amount of \({}^{10}\)B, surrounding normal cells and tissues having low levels of \({}^{10}\)B are not subjected to the same amount of high Linear Energy Transfer (LET) radiation. Energetic alpha particles produced by the interaction of \({}^{10}\)B with neutrons have high LET, low oxygen enhancement ratio, and high relative biological effectiveness. These LET particles are lethal but--because of their size, energy, and short path lengths (4.5 to 10 \(\upmu\)m)--the effect is confined to the host cell [24].  
In recent years, the possibility of developing more selective targeting therapies such as BNCT has been explored. Early molecular designs were guided by BBB being more permeable because of the leaky vasculature of a carcinoma cell due to the requirement of higher amounts of nutrients for faster and more rapid growth. Healthy cells, on the contrary, have a more rigid and stable structure, only requiring nutrients for controlled growth. However, drug delivery to the brain was unsuccessful as clusters of tumour cells were protected by the normal healthy cell within the BBB and, therefore, not completely eradicating the tumour, resulting in tumour re-occurrence. Due to the more negatively surface charged mitochondrion present within the tumour cell, positively surface charged, lipophilic molecules in the form of DLCs can potentially be used to selectively deliver boron moieties and take advantage of these characteristics present within the tumour tissues.