Brachytherapy dose enhancement using gold nano particles (AuNPs) and their effects on cell motility
Creators: name: Shahhoseini, Elham
Publisher: name: RMIT University
Year: 2024
Subjects: classificationCode: 511002
subject: Instruments and techniques

description: Cancer is a major cause of illness in Australia with a notable social and economic impact on the community, as such in 2020 about 150,000 new cases of cancer were diagnosed and about 50,000 related deaths recorded [1]. Currently, cancer treatment mainly consists of either surgery, chemotherapy and radiation therapy or in combination. Amongst these, radiation therapy plays an important role as about half of all cancer patients undertake at least one type of radiation therapy during their treatment course [2, 3].
 
A challenge in clinical radiation therapy is the damage that the ionising radiations (IR) can cause to the normal tissues surrounding tumours [4]. This could be minimised by increasing the sensitivity of cancer cells to the IR or in other words dose enhancement (DE) in the cancer area.

Another challenge in cancer treatment is the formation of metastasis which causes up to 90% of cancer-related deaths [5, 6]. By suppressing the migration abilities of cancer cells, the probability of cancer metastasis could be diminished, and this could potentially decrease the rate of secondary cancers.

Metallic nanomaterials such as gold nanoparticles (AuNPs) enhance the dose [7-9] and inhibit cell migration [10, 11], which implies that they satisfy reduction of the effects of both of the above two radiotherapy challenges.

The energy range of the IR plays an important role in the DE. At high energies `megavoltage' (used in radiotherapy) DE caused by AuNPs is very low while it is significant at kilovoltage energies [8]. Therefore, this thesis investigates the feasibility of clinical applications of AuNPs for DE in kilovoltage brachytherapy as well as using these nanoparticles in combination with IR to inhibit cancer cell migration. Two aspects of the effects of AuNPs in combination with IR are investigated; optimal dose enhancement application stemming from cell kill and their influence on cell biomechanics.

1) Brachytherapy dose enhancement caused by AuNPs
         
As known, high Z elements significantly increase the probability for photoelectric effect in the irradiated targets [12-18]. However, the probability of occurrence for this interaction is only significant in the kilovoltage range. Hence, DE caused by the inclusion of high Z nanoparticles into a target is more important in the kV energy range.
 
Monte Carlo study [19] show amongst four metal nanoparticles, gold was the most effective with the highest dose enhancement factor (DEF) of ~3 in kilovoltage range. Gold is also an inert, nontoxic and biocompatible element [9] which makes it suitable for dose enhancement in radiation therapy.
This in vitro project examines the DE caused by AuNPs in kilovoltage brachytherapy (eBxTM). Two cancer cell lines which are commonly used to study brachytherapy  [20] i.e. human lung (A549) prostate (DU145) were used.

Cells in treated groups were incubated with 1mM AuNP and along with untreated ones were exposed to a range of radiation doses from 0 to 6 Gy, with eBxTM and 192Ir sources separately. This dose range was chosen as ~6 Gy per fraction is common in HDR brachytherapy [21]. High DEF values were achieved in treated groups exposed to eBxTM i.e. 2.90 for DU145 and 2.06 for A549 while the DEFs measured cells exposed to 192Ir brachytherapy were 1.67 and 1.54 for DU145 and A549 respectively. Higher DEF values were obtained in the case of eBxTM compared to 192Ir brachytherapy which can be attributed to the lower energy of the former and being closer to the optimal energy for DE. These findings could potentially be utilised to achieve similar tumour control with a significantly lower dose from the eBxTM compared to the 192Ir brachytherapy treatment.
 
2) The effects of gold nanoparticles on cell migration

This in vitro study determined the effects of AuNPs and/or IR on cell migration and adhesion. This study consisted of two phases: phase I, DU145 and A549 were investigated. Results showed AuNPs and/or IR inhibit cell migration while promoting cell adhesion. Phase II then focused on the differential effects of these stimuli on two common cancers i.e. colon (SW48) and skin (mm418-C1) and their non-cancerous counterparts i.e. (CCD841) and (HEM) respectively.
 
Cell migration was measured by observing the closing of a gap created on cell monolayers. The ratio of the gap areas at 0 h and 24 h were used to calculate relative migration. Relative migration of cancer cells irradiated with 5 Gy was decreased to 89%, 86%, 85% and 89% for DU145, A549, MM418-C1 and SW48 cells respectively. When cells were treated with 1 mM AuNPs this was reduced to ~75% for all cell lines. However, when cells were treated with both AuNPs and IR an additive effect was seen, and relative migration decreased to ~60%. Notably, when the cells were exposed to either 2 or 5 Gy IR, their ability to adhere to the surface of culture plates was significantly enhanced, unlike that seen for AuNPs. Reduced cell migration in cells treated with IR and/or AuNPs can be attributed to cellular changes which also may have altered cell motility. Changes to the cytoskeleton of the cancer cells may have also affected adhesiveness and the motility response to IR. Of interest was that AuNPs and IR, alone and in combination, stimulated relative cell migration of primary cells i.e. HEM and CCD841. The relative migration in HEM and CCD841 cells irradiated with 5 Gy radiation was ~110%. When cells were treated with AuNPs this increased to ~ 120 % for both cell lines. However, when cells were treated with both AuNPs and IR an additive effect was seen, as relative migration increased to ~140%.

The differential effects of AuNPs and/or IR on cell motility can be attributed to changes in IR-induced adhesive proteins and ROS also a different level of AuNPs-induced cell motility between cancer cells and their non-cancerous counterparts. In addition to AuNPs role as a dose enhancing agent, these findings highlight a potential application of these nanoparticles in decreasing the risk of secondary cancers caused by metastasis which could have positive benefits for cancer patients.