DNA condensation with a boron-containing cationic peptide for modeling boron neutron capture therapy

Abstract

The amino acid derivative 4-borono-L-phenylalanine (BPA) has been used in the radiation medicine technique boron neutron capture therapy (BNCT). Here we have characterized its interaction with DNA when incorporated into a positively charged hexa-L-arginine peptide. This ligand binds strongly to DNA and induces its condensation, an effect which is attenuated at higher ionic strengths. The use of an additional tetra-L-arginine ligand enables the preparation of a DNA condensate in the presence of a negligible concentration of unbound boron. Under these conditions, Monte Carlo simulation indicates that >85% of energy deposition events resulting from thermal neutron irradiation derive from boron fission. The combination of experimental model systems and simulations that we describe here provides a valuable tool for accurate track structure modeling of the DNA damage produced by the high LET particles involved in BNCT.

Boronated Condensed DNA as a Heterochromatic Radiation Target Model

“…Such a decrease in ethidium fluorescence is evident in Figure . With the intercalating fluorescent dye BOBO-3, at a concentration large enough to be detectable by visible absorption, we found that the decrease in its fluorescence intensity produced by the ligand Ac-BPA-Arg 6 -NH 2 was not caused by its displacement from the DNA to which it had been bound before the addition of the ligand Figure reveals that this fluorescence attenuation does not take place at a lower concentration of BOBO-3.…”

“…In the absence of the ligand, DNA (10 μg mL –1 ) features a positive band at 270 nm and a negative band at 245 nm. The ligand alone (10 μmol L –1 ) exhibits a positive band at 220–230 nm at the absorption of its aromatic ring . The combination of DNA and the ligand at these concentrations produces large physical effects (Figures –); the CD spectrum under these conditions reveals a decrease in intensity of the positive band at 270 nm.…”

“…The ligand alone (10 μmol L −1 ) exhibits a positive band at 220−230 nm at the absorption of its aromatic ring. 38 The combination of DNA We also assessed the interaction between the ligand and DNA using the steady-state fluorescence intensity of the intercalating dimeric cyanine dye BOBO-3. 51 This dye was present at either 75 or 750 nmol L −1 (equivalent to 0.5 or 5% of the DNA base pair concentration).…”

“…To address the dosimetry of neutron capture on boron, we have reported 38 on the combination of computational simulation using the TOPAS Monte Carlo tool 39 with a radiation chemical experimental model system involving boron bound to a DNA target in an aqueous solution. This model system employs BPA linked to the N-terminus of a hexa-Larginine carrier.…”

Clinical Viability of Boron Neutron Capture Therapy for Personalized Radiation Treatment

“…In this way, many efforts are being made to include the chemical and biological aspects of the problem in MC calculations, such as the code developed within the Geant4-DNA Project [ 66 ] (TOPAS-nBio is a wrapper for the latter). A clear example of this is the work by Perry et al [ 67 ] to model the DNA damage produced by the high LET particles involved in BNCT. Anyway, these theoretical calculations must be compared with experimental verifications.…”