In Vivo Application of Carboranes for Boron Neutron Capture Therapy (BNCT): Structure, Formulation and Analytical Methods for Detection

Abstract

Carboranes have emerged as one of the most promising boron agents in boron neutron capture therapy (BNCT). In this context, in vivo studies are particularly relevant, since they provide qualitative and quantitative information about the biodistribution of these molecules, which is of the utmost importance to determine the efficacy of BNCT, defining their localization and (bio)accumulation, as well as their pharmacokinetics and pharmacodynamics. First, we gathered a detailed list of the carboranes used for in vivo studies, considering the synthesis of carborane derivatives or the use of delivery system such as liposomes, micelles and nanoparticles. Then, the formulation employed and the cancer model used in each of these studies were identified. Finally, we examined the analytical aspects concerning carborane detection, identifying the main methodologies applied in the literature for ex vivo and in vivo analysis. The present work aims to identify the current strengths and weakness of the use of carboranes in BNCT, establishing the bottlenecks and the best strategies for future applications.

Keywords: COSAN; anticancer treatments; boron agents; boron neutron capture therapy (BNCT); cancer; carboranes; chemical conjugates; delivery systems; in vivo; metallacarboranes.

Figure 12

Schematic representation of carboranes incorporated into drug delivery systems such as liposomes (carborane in the core (23) [173], in the bilayer (24) [171] and in both compartments (25) [165]), micelle (26) [175], nanogel (27) [85] and LDL (29) [140]. Created with BioRender.com.

Figure 13

Schematic representation of carboranes incorporated into drug delivery systems such as COFs (porphyrin-based (29) [192] and carborane-based (30) [182]), SWCNTs (31) [183], HMSN (32) [185] and magnetic nanoparticles (33) [188]. Created with Bio.Render.com.

Figure 1

Schematic representation of (A) nuclear fission reaction on ¹⁰B atom and (B) BNCT mode of action. Images created with BioRender.com.

Figure 2

Structures of borophenylalanine (BPA), BPA−fructose complex, mercaptoundecahydrododecaborate (BSH), closo-carborane (ortho-, meta-, and para-C₂B₁₀H₁₂), closo-dodecaborate anion (1-CB₁₁H₁₂⁻), nido-carbonane anion (nido-C₂B₉H₁₂⁻), COSAN ([3-3′]-Co(1,2-C₂B₉H₁₁)₂]⁻) and FESAN ([3-3′]-Fe(1,2-C₂B₉H₁₁)₂]⁻).

Figure 3

Structures of carboranyl-maltoside (1), cRDG-COS-carborane (2) and carborane-bearing pullulan (3).

Figure 4

Structures of deoxyuridine- (4), thymidine- (5), uracil- (6) and pyrimidine-carborane (7) derivatives.

Figure 5

Structures of sunitinib- (8), doxorubicin- (9), nitroimidazole- (10) and sulfonamide-carborane (11) derivatives.

Figure 6

Structures of CuTCPH, ZnTCPH and H2TCPH (12), BOPP (13), ZnB₄Pc phtalocyanin (14) and TPFC (15), containing carborane moieities.

Figure 7

Structures of magnevist-carborane (16) and COSAN-iodinated (17) derivatives.

Figure 8

Structures of phenylalanine-carborane derivative (18).

Figure 9

Structures of cRGD- (19), PSMA- (20) and TAT (GRKKRRQRRRPQ)- (21) carborane derivatives.

Figure 10

Structure of carborane-antibody conjugate (22).

Figure 11

Structure of β-cyclodextrins and carborane sulfonamide (23) [110]. Image created with BioRender.com.

Figure 14

Schematic representation of the techniques for carborane detection using gamma-ray emission measurements. Red circle represents the radionuclides. Created with BioRender.com.

Figure 15

Schematic representation of sample processing and measurements for boron detection using boron elemental analysis techniques. Created with BioRender.com.

Figure 16

Fluorescence-based analysis of carborane-bearing pullulan nanogels incorporating rhodamine-b as fluorescent dye. (a) The in-vivo biodistribution in mice 6 h (left) and 24 h (right) after injection of the carborane drug. (b) The ex vivo analysis of the tumor in organs and tumor of controls (top) and carborane-treated mice (bottom). Reprinted from ref [85] with permission from Elsevier.

Figure 17

An example of in vivo PET analysis of murine tumoral model after injection of COSAN-conjugated [⁶⁴Cu]-enriched AuNPs at different time intervals. [⁶⁴Cu]-based detection allowed imaging of the tumor morphology and localization of the carborane-based drug. Reprinted from ref [203] with permission from John Wiley and Sons.

Figure 18

Magnetic resonance imaging (MRI) analysis of liver metastases in Balb/c mice. The arrows identify the tumor in non-treated (a) and Gd-carboranes conjugate-treated (b) samples after in vivo BNCT treatment. Reprinted from ref [141] with permission from Elsevier.