**2.1. General**

However, this amount could be lower if the boron delivery system is concentrated in or near the cell nucleus; (c) retention of 10B in tumor during the BNCT process; (d) rapid clearance from blood and healthy tissues; (e) and adequate lipophilicity especially for glioma treatment where the drug should be able to cross blood-brain barrier (BBB) [17]. Furthermore, like any drug in medicinal chemistry, the 10B-loaded agent must meet the following requirements: (f) absence of systemic toxicity, (g) chemical and metabolic stability, and (h) appropriate water solubility.

After the first efforts, during the 1940s and 1950s (see Section 1.1.), the lack of selectivity and low boron tumor accumulation observed for the simplest boron salts (**Figure 1**) used until the moment prevented their application in BNCT clinical trials. However, around the 1960s, the first studies of the two compounds currently in clinical began, both 10B-enriched, the polyhedral borane BSH (**Figure 1**) and L-4-dihydroxyborylphenylalanine, known as L-boronophenylalanine (L-BPA; **Figure 3**) [18], which could be accumulated into desired tis-

Due to BSH is a small hydrophilic molecule (**Figure 1**), it does not cross the intact BBB. It only penetrates into the brain passively when the BBB is disrupted [10], as it is observed in the GBM. Although BSH has been applied for the treatment of GBM in infusions with no toxic effects, the efficacy has been limited due to low observed tumor:brain (3:1) and tumor:blood (0.9–2.5:1) ratios [19]. The main structural advantage of BSH compared to L-BPA is that BSH contains 12 times more B per molecule yielding a higher number of events after neutron capture than in L-BPA. BSH has been studied in different therapeutic schedules, combined or not with other small molecules, like L-BPA, or vehicles looking for the improvement of the

**Figure 3.** (A) Currently, available boronic acid for treatment of GBM trough BNCT. (B) L-BPA-F complex. (C) Esterification

**1.3. Boron neutron capture therapy: current therapeutic agents**

sues for its structural analogy to some biomolecules.

208 Glioma - Contemporary Diagnostic and Therapeutic Approaches

of L-BPA with ethylene glycol.

From a medicinal chemistry point of view, different strategies have been studied in order to identify new and more selective molecules to glioma cells, with adequate ability to cross the BBB, with higher tumor concentration in the path of the neutron beam and drug-like properties. The third-generation products, which potentially may accumulate into glioma for its structural analogy to some biomolecules, could be classified [15] in (a) macromolecular species and (b) low molecular weight molecules. In reference to the first group, we could mention monoclonal and bispecific antibodies, epidermal growth factor, and encapsulating agents such as boron-containing nanovehicles (liposomes). Here, we will discuss compounds belonging to the second group, like polyhedral boron cluster derivatives, boronic acid derivatives, and other boron-containing small molecules (e.g., oxaborolanes, dioxaborolanes, and azaboro-heterocycles, among others).
