Proton therapy is usually delivered using a spread-out Bragg peak, which leads to an increased entrance dose. In this work, the authors used a pristine Bragg Peak to irradiate metallic nanoparticles localized within a tumour. Use of a single Bragg peak retains the high peak-to-plateau dose ratio, generating short-ranged secondary radiation while sparing normal tissue.

"A major component of secondary radiation is Auger electrons, which penetrate a few to hundreds of nanometres," explained Jong-Ki Kim from the Catholic University of Daegu. "The characteristic X-rays, at 7 or 13 keV, are also sharply attenuated in tissue, effectively giving rise to the high-LET [linear energy transfer] nature of particle-induced radiation."

In vivo studies

Kim and colleagues studies two approaches to particle-induced radiotherapy (PIRT). In the first (PIRT-Ab), a single Bragg peak is placed at the greatest depth of the tumour, with the resulting therapeutic dose a combination of particle-induced radiation and plateau or Bragg peak dose from the primary proton beam. This scheme is suitable for treating tumours with infiltrating cells.

The second configuration (PIRT-Tr) uses a traversing proton beam that passes through the body with minimal energy deposition. In this arrangement, which can be used to treat the infiltration, the Bragg peak lies behind the tumour and dose is mainly due to induced radiation.

The researchers examined gold and iron nanoparticles (AuNPs and FeNPs) injected at 100 or 300 mg/kg body weight into tumour-bearing mice. As preferential tumour uptake is a prerequisite for this approach, they assessed nanoparticle concentration in blood, muscle and tumour at various post-injection times. At 24 hr after injection, tumour-to-normal tissue uptake ratios were 169.7 and 88, for AuNP and FeNP, respectively, demonstrating the feasibility of this proposed therapy.

Proton therapy was thus delivered 24 h after nanoparticle injection, using a 45 MeV proton beam. For the PIRT-Ab groups, the beam irradiated a tumour in the mouse flank with a single dose of 41 Gy delivered at the Bragg peak. For the PIRT-Tr groups, a tumour in the mouse leg was irradiated by a traversing beam, with a plateau dose of 10, 21 or 31 Gy. Plateau doses of 10, 21, 31, 40 and 45 Gy were also administered to proton-only control groups.

Particle boost

All proton-only treatments retarded tumour growth compared with untreated control mice. The increase in complete tumour regression for mice injected with nanoparticles (compared with the proton-only group) was 37–62% for PIRT-Ab, and 50–100% for PIRT-Tr, dependent on both proton and nanoparticle dose.

In the PIRT-Ab group, mice treated with 100 mg/kg of nanoparticles exhibited a mean tumour volume growth rate (TVGR) of –11.3±32.5 mm3/day (averaged over both nanoparticle types). Increasing the dose to 300 mg/kg, resulted in a mean TVGR of –20.1±25.9 mm3/day, and resulted in complete tumour volume remission at 3–4 weeks post-treatment.

In the PIRT-Tr group, mice treated at 21 Gy, and injected with 300 mg/kg of AuNPs demonstrated negative TVGR and complete tumour remission. When the dose was increased to 31 Gy, mice receiving 100 or 300 mg/kg of either nanoparticle had a negative TVGR and complete tumour remission.

Asides an inflammatory response at the tumour periphery, there was no damage to the surrounding muscles and no oedema or haemorrhage in the normal tissue upon exposure to therapeutic doses of 10–31 Gy.

The team also assessed long-term survival. Animals demonstrating complete tumour remission survived for the one-year follow-up period, while untreated animals died within 2–4 weeks. One-year survival was 58% (PIRT-Ab) or 64–100% (PIRT-Tr), depending on proton dose, compared with 11–13% for the proton-only treatments.

Mice treated with AuNPs exhibited improved response compared with those treated with FeNPs. PIRT-Tr plateau doses producing 100% tumour remission were 21 and 31 Gy, for mice receiving 300 mg/kg of AuNPs and FeNPs, respectively. "In principle, higher-Z elements should produce a larger nanoradiator effect for a given amount of particles," explained Kim. "In this experiment, the better therapeutic effect of AuNPs was due to higher tissue uptake for given injection dose compared with FeNPs. However, iron particles have an advantage over gold in terms of MRI visibility, enabling theranostic applications."

The researchers concluded that single Bragg peak-based PIRT provides a significant increase in complete tumour regression and survival compared with proton irradiation alone. In vitro studies showed that PIRT also increases the generation of reactive oxygen species, suggesting that the secondary radiation provides a potent means of therapeutic enhancement.

"We are going to investigate this rationale for new treatment options of tumour spread into normal tissue, as seen in many infiltrative tumours or disseminated metastases, as well as multidrug-resistant inflammatory diseases," Kim told medicalphysicsweb.