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\section{Introduction}
The goal of radiotherapy is that of delivering the highest damage (i.e., the highest dose) to the tumor volume while simultaneously sparing the surrounding healthy tissues. In recent years there has been considerable interest on the use of nanoparticles as novel agents for cancer therapy, with many studies in diverse fields including preclinical and clinical trials [Zha07, Jai12, Cao14]. In particular, the use of gold nanoparticles showed promising results for cancerous cells radiosensitization both in vitro and in vivo at kilo- and mega-voltage energies.
The high radiosensitization induced at kilovoltage energies by gold nanoparticles is well documented by both in vitro and in vivo studies (mice with implanted tumors) [Hai04, Kon08, Rah09, Jai12]. As an example, irradiation of cells loaded with gold foils reported dose enhancement factors higher than 100 [Reg98, Reg02]. As the concentration of nanoparticles increases the radiosensitization increases [Rah09, Lec13, Ran10], probably due to the higher number of photoelectric interactions and consequently higher dose deposition as well as an additional oxidative stress induced by the presence of nanoparticles [Pan09, Kan10]. Experimental studies have revealed that gold nanoparticles radiosensitization are also highly sensitive to photon source energy [Chi10, Asg10], cancer cell type [Pat07, Jai11], nanoparticle size [But12] and their localization relative to cellular DNA [Bru09].
The radiosensitization observed at kilovoltage energies by increased photoabsorption cannot help predict the effects occurring at clinically relevant megavoltage energies, where Compton interactions are dominant and photon energy absorption weakly depends on the atomic number. Ionization rates at megavoltage energies seem to be extremely low, meaning that, for doses typically used in radiotherapy, a fair amount of nanoparticles present in the system (i.e., more than 99%) does not contribute to the dose deposition processes. However, despite this minimal dose increase, it is worth noticing that the presence of gold nanoparticles do lead to significant levels of radiosensitization. This must therefore be dependent on factors other than strong photoelectric absorption, such as different distributions of energy deposition compared to those in soft tissues and/or additional oxidative stress induced by the presence of nanoparticles [Pan09, Kan10]. In particular, as it will be later discussed, it was found that only one ionization from the nanoparticles is necessary to lead the cell to its demise.
Additional studies are essential in order to understand the underlying processes of radiosensitization so as to use gold nanoparticles as a clinical therapeutic tool. In particular, the full mechanisms underlying radiosensitization in radiotherapy still need to be investigated in a patient-like geometry. When metallic nanoparticles are injected in the tumor a greater fraction of the incident photon energy can be imparted to it without escalating the damage to the surrounding healthy tissues. Of note, the efficacy of a treatment depends on the nanoparticles concentration and spatial distribution in the tumor cells, as well as on incident beam energy and delivered dose.
Uptake by tumoral cells is a key point to the radiosensitization investigation. Since gold nanoparticles are easily synthesized and can be designed to interact with various biomolecules, improved diagnosis and treatments efficacy can be obtained by using labeled nanoparticles that target specific cell receptors. That is, it is expected that nanoparticles bound to targeting agents should accumulate in higher concentrations in the tumor than in other organs (gold nanoparticles uptake has been found to be highest when bound to sugars [Kon08] and peptides [Kim11]), therefore amplifying the dose release in the cancerous cells while keeping constrained the cellular damage in the surrounding healthy tissues. Thus, it can be seen how the presence of labeled gold nanoparticles significantly enhances the biological effectiveness of a treatment.
Knowledge of the nanoparticles uptake selectivity is fundamental to develop a model predicting radiobiological outcomes. In this paper, radiobiological models are introduced to investigate the mechanisms underlying radiosensitization. In addition, the potential applications of these concepts are applied to a radiotherapy treatment planning.
