"Our theoretical results predict that a major localized dose enhancement to the highly radiosensitive nuclei of the neovascular endothelial cells targeted by the AuNPs is achievable," Wilfred Ngwa from Harvard's Department of Radiation Oncology told nanotechweb.org's sister website medicalphysicsweb. "If these results can be mirrored in vivo, this method could become a more effective treatment option for neovascular AMD patients treated with SRS, significantly improving visual outcomes with minimal side effects and inconvenience to patients."

Nanoparticle boost

AMD is a common condition that typically affects individuals aged 50 years or over and is caused by the deterioration of the central portion of the retina known as the macula. In neovascular AMD, the rapid creation of new leaky blood vessels in the choroid layer of the macula gradually destroys the patient's central vision – a process called choroidal neovascularization.

SRS is being pioneered as a treatment option because evidence suggests that the rapidly proliferating neovascular endothelial cells that drive AMD development are relatively more radiosensitive than quiescent or less actively dividing normal cells. As AuNPs can be specifically targeted to neovascular endothelial cells, the Harvard team envisaged that the particles could potentially enhance the effects of the kilovoltage X-rays used during SRS treatment of neovascular AMD.

Microdosimetry calculations

During nanoparticle-enhanced SRS treatment, incident kilovoltage X-rays will interact with the AuNPs causing the emission of many photoelectrons and Auger electrons. Of these electrons, those that pass through the nucleus of any endothelial cell will enhance the radiation damage to its DNA promoting cell death. In turn, this inhibits the proliferation of the leaky blood vessels that cause neovascular AMD.

The task for Ngwa and his colleagues Mike Makrigiorgos and Ross Berbeco was to use an in-house developed Mathlab-based program to model these interactions and, ultimately, to calculate the dose enhancement to the nucleus of the neovascular AMD endothelial cells due to photon-induced photoelectrons and Auger electrons.

The group modelled the endothelial cells as a 2 µm thick slab with a centrally located nucleus and AuNP concentrations ranging from 1 to 7 mg/g. They then duplicated the specifications of the only commercially available SRS treatment system for AMD, the IRay from Oraya Therapeutics (Newark, CA), which uses three 100 kVp X-ray beams to deliver a prescribed dose to the choroidal neovasculature. For comparison, they also modelled X-ray energies of 80, 90, 110 and 120 kVp.

Significant dose enhancement

For 100 kVp X-rays, the results predicted nucleus dose enhancement factors (nDEF) ranging from 1.30 to 3.26, for a AuNP concentration range of 1 to 7 mg/g respectively. "An nDEF of 1.30 essentially means that a directly delivered Oraya therapy dose of 18.5 Gy would result in 24 Gy, due to the presence of neovasculature-targeted AuNPs," explained Ngwa. "Similarly, an nDEF of 3.26 means an Oraya therapy dose of 7.4 Gy would be equivalent to 24 Gy for the neovascular endothelial cells targeted with AuNPs."

In comparison, for the same AuNP concentration range, nDEF values of 1.32–3.4, 1.31–3.33, 1.29–3.19 and 1.28–3.12 were calculated for 80, 90, 110 and 120 kVp X-rays respectively. Subsequent calculations as a function of distance revealed that the dose enhancement is markedly confined to the neovascular endothelial cells containing the nanoparticles.

"We are now in the process of conducting experimental studies in vitro and in vivo in small animals," commented Ngwa. "If successful this would lead to clinical trials."

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