Radiation therapy for cancer treatments can be improved by inclusion of gold nanoparticles. Due to its high atomic mass, gold (197 atomic mass units) – compared to carbon (12 amu), nitrogen (14 amu), oxygen (16 amu), phosphorous (31 amu) and sulfur (32 amu) of which the softer tissues are mainly made of – absorbs more radiation but concentrated in a smaller area thus erasing the cancer cells more efficiently. However, the impact of foreign atoms bonding to DNA on radiation therapy is unknown.
In radiation therapy using x-rays, the so called low energy electrons of 0-10 eV – created by interaction of x-rays with the tumors cells – cause cell DNA damage. But the gold nanoparticles can bind to DNA and can change the way DNA damages. Rosenberg and his colleagues report on the details in their recent paper (1) Well, how do x-rays create low energy electrons? How does the low energy electron damage DNA? Here is exactly what happens if you imagine looking at an atom of gold. Upon x-irradiation, an electron is kicked out of an atom in the cells or gold, as a photoelectron (primary); on its way out, the primary photoelectron collides with the nearby atoms removing more and more electrons (secondary) from them, while losing part of its energy. This process repeats multiple times for the primary and secondary electrons until their energy is too low (0-10 eV).
The low energy electrons are highly reactive and they can attach to cell DNA by occupying certain previously empty orbitals (unoccupied orbitals) of the DNA molecule. An unoccupied orbital, when occupied by electrons, weakens the bond between atoms associated and can eventually break the bond. Breaking of bond especially, at the backbone of DNA causes strand breaks – DNA damage. Higher concentration of low energy secondary electrons can cause multiple lesions thus destroying the cancer cells. Hence gold nanoparticles can boost the number of low energy electrons.
Previous research indicated local environment around DNA and bonding of DNA can impact the effectiveness of low energy electrons profoundly. For instance, binding of just two cisplatin molecules – an inorganic compound used in cancer therapy – to 3197 base pair plasmid increases the number of single strand breaks caused by 10 eV electrons by nearly four times (2). The orientation of DNA with respect to the gold surface affects the yield of hydroxide ion induced by low energy electrons (3). However, DNA-gold bond might affect the rate of hydroxide ion production but is unknown. DNA can bind with the gold nanoparticles through sulfur, nitrogen or phosphorous depending on its relative orientation. A bond – established between gold atom and sulfur for example – is due to sharing of their loosely bound outer electrons.
Rosenberg and his colleagues, in this paper, attempt to see what difference does it for the low energy secondary electrons attaching to a DNA molecule, when the DNA is bonded through nitrogen (Au-N) and when it is is bonded through sulfur (Au-S); the secondary electron is expected to occupy the unoccupied orbitals of DNA (3).
The authors first compared the degree of occupation in the unoccupied orbital localized on nitrogen atom of DNA in two different samples; they also compared the rate of DNA damage: In one sample DNA was bonded to gold through nitrogen that is part of DNA structure; in the second sample, the same DNA was first anchored to a external sulfur atom that then binds to gold atom. They created low energy secondary electrons using X-rays from a powerful source called synchrotron, a facility located at the Argonne National Laboratory. Simultaneously, the same X-radiation was used to move one of the tighly bound electrons from nitrogen – called core electron – to its unoccupied orbital. This technique, X-ray Absorption spectroscopy, mapped the density of unoccupied states localized on nitrogen atom. Once again, using the same x-rays, in a so-called x-ray photoelectron spectroscopy, authors identified if the bonds between certain atoms were broken by x-radiation.
They found the density of unoccupied orbital of nitrogen in DNA bonded through sulfur higher than that in DNA bonded through nitrogen. In laymen terms, the unoccupied orbital on nitrogen in S- bonded DNA is emptier than in N- bonded DNA. The DNA damage was also higher in S-bonded DNA compared to N-bonded DNA. This meant, lower the occupancy in an orbital, higher is the probability that secondary electron attaches to that orbital and greater will be DNA damage. Obviously, the lower occupancy in Au-S DNA is due to more electron transfer to gold from DNA through sulfur – an established fact.
What does it mean to those improving cancer therapy using gold nanoparticles? Gold is not passive and the effective damage depends on the nature of DNA interaction with gold nanoparticles.
1. Rosenberg, R.A., et al., Phys. Chem. Chem. Phys. 16 (2014) 15319
2. Zheng, Y., et al, Phys. Rev. Lett. 100 (2008) 198101
3. Pan, X. and Sanche, L., Phys. Rev. Lett. 94 (2005) 198104