Even though ionizing irradiation has been extensively used for diagnosis and therapeutic purposes, risks from radiation damage are always problematic in the human body. Especially, it is known that the ROS level is significantly increased in the field of irradiation and then these induce oxidative stress against cells and tissues ^[6][41]. The increased ROS and/or reactive nitrogen species (RNS) level induce metabolic stress and affect the nuclear function of DNA repair mechanism ^[41]. Due to these reasons, clinicians use a radioprotectant such as amifostine to prevent radiation-induced cell/tissue damage ^[11][12]. However, many scientists have tried to develop novel and non-toxic antioxidants since adverse side effects of amifostine are always problematic in clinical use ^{[13][14][15][16]}. Many kinds of antioxidants have been investigated to prevent radiation-damage and to substitute amifostine ^{[7][8][9][10][14][15][42][43]}. For example, Bai et al. reported that CAPE effectively prevents cellular oxidative stress from radiation by elimination of free radicals and then improves cell viability ^[42]. They argued that CAPE properly reduced the intracellular ROS level after radiation of L929 cells. Song et al. also reported that intracellular ROS accumulation induced by H₂O₂ stimulation was effectively inhibited by the pretreatment of CAPE ^[44]. They argued that H₂O₂-induced upregulation of TNF-α and COX-2 expression can be suppressed by the treatment of CAPE with a dose/time dependent manner. Moreover, we showed that CAPE-incorporated nanoparticles as well as CAPE effectively suppressed intracellular ROS accumulation induced by the irradiation of cells. These behaviors must be correlated with higher viability of cells as shown in Figure 1b,c. Furthermore, CAPE and CAPE-incorporated nanoparticles efficiently prevented H₂O₂-induced cell death, i.e., the viability of cells treated with CAPE or CAPE-incorporated nanoparticles was almost two times higher than the control (Figure 1a). CAPE or CAPE-incorporated nanoparticles against H₂O₂-induced cell death were dose-dependently protected cells. Furthermore, they also showed positive effects against survivability of mice from irradiation. Especially, CAPE-incorporated nanoparticles showed extended survivability of mice after irradiation at 7 Gy compared to CAPE itself (Figure 2). These results indicated that CAPE-incorporated nanoparticles have a superior activity against radiation-induced injury. Actually, CAPE-incorporated nanoparticles appropriately reduced apoptotic cell death and improved tissue morphologies as shown in Figure 5. CAPE and CAPE-incorporated nanoparticles are a great potential for preventing radiation-induced injury. Yoncheva et al. reported that CAPE-incorporated polymeric micelles exhibited a superior protective effect against H₂O₂-induced oxidative stress compared to the free CAPE treatment ^[39]. Furthermore, CAPE-loaded poly(DL-lactide-co-glycolide) nanoparticles are more effective in the reduction of mutagenicity than the free CAPE itself ^[40]. We also prepared CAPE-incorporated nanoparticles using HAsPBPE conjugates since HA is a biocompatible and water-soluble biopolymer, and TbEA-PBPE moiety acts as a hydrophobic moiety in polymer backbone ^[45]. Then, HAsPBPE conjugates may form core-shell type nanoparticles, i.e., HA acts as an outershell of the nanoparticles while TbEA-PBPE is composed of the hydrophobic inner-core of the nanoparticles. Nanoparticles showed spherical morphologies with small particle sizes less than 100 nm in the average diameter as shown in Figure 3. In the drug release experiment, nanoparticles showed a burst release behavior until 12 h and then was released continuously until 96 h, indicating that the CAPE existing near the surface of the nanoparticles was released rapidly and, after that, the CAPE in the core of the nanoparticles was released more slowly. In our previous reports, the burst release of CAPE from nanoparticles was also observed in the initial phase of drug release study followed by a sustained release pattern ^[46].

Nanoparticulate-based delivery systems for bioactive agents are suitable for eliminating disease cells such as cancer stem cells and ROS ^[47][48]. For example, polymeric nanoparticles decorated with specific ligands or antibodies have the potential to target and reject cancer stem cells ^[47]. Furthermore, nanocarriers incorporating the dual or multi drug delivery strategy have a great potential to diminish ROS production in disease cells and then reduce oxidative damage in mitochondria ^[48]. Then, these dual/multi drug deliveries using nanocarriers may provide a synergistic effect in the improvement of therapeutic index of neuroregenerative strategy ^[48]. Our concept for radioprotection is to develop radio-sensitive nanomedicine for the sustained and/or radio-responsive release of CAPE. Since CAPE itself is a lipophilic agent and is hardly dissolved in an aqueous solution, nanoparticles can solve these problems, i.e., nanoparticles enable us to dissolve CAPE in an aqueous solution ^[28]. Furthermore, nanoparticles can be modified to be sensitive to physicochemical stimulus such as radiation, pH, ROS, magnetic field, and light ^{[32][33][34][35][36][37]}. HAsPBPE nanoparticles can respond to ROS since the PBPE moiety and thiol group in TbEA in the polymer backbone are known to have ROS-sensitivity and these moieties are able to be decomposed in the oxidative stress ^[45].

Actually, CAPE-incorporated nanoparticles of HAsPBPE were disintegrated in the presence of H₂O₂ as shown in Figure 3a,b. HAsPBPE nanoparticles showed an accelerated CAPE release through irradiation (Figure 4). Then, HAsPBPE nanoparticles specifically decomposed and released CAPE when they were exposed to irradiation, i.e., drug release can be suppressed in the absence of irradiation and then irradiation of nanoparticles accelerated drug release. Even though nanoparticles in the in vitro cell culture showed a similar protective activity compared to CAPE, they were improved by the biological activity in the in vivo animal irradiation study, as shown in Figure 2 and Figure 5.