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Published on: October 5, 2018
Selective Organ-Targeting Hafnium Oxide Nanoparticles with Multienzyme-Mimetic Activities Attenuate Radiation-Induced
Dingxin Liu1,2, Fei Cao1,3, Zhifeng Xu4
1State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
Abstract:
Radioprotective agents hold clinical promises to counteract off-target adverse effects of radiation and benefit radiotherapeutic outcomes, yet the inability to control drug transport in human organs poses a leading limitation. Based upon a validated rank-based multigene signature model, radiosensitivity indices are evaluated of diverse normal organs as a genomic predictor of radiation susceptibility. Selective ORgan-Targeting (SORT) hafnium oxide nanoparticles (HfO2 NPs) are rationally designed via modulated synthesis by α-lactalbumin, homing to top vulnerable organs. HfO2 NPs like Hensify are commonly radioenhancers, but SORT HfO2 NPs exhibit surprising radioprotective effects dictated by unfolded ligands and Hf(0)/Hf(IV) redox couples. Still, the X-ray attenuation patterns allow radiological confirmation in target organs by dual-beam spectral computed tomography. SORT HfO2 NPs present potent antioxidant activities, catalytically scavenge reactive oxygen species, and mimic multienzyme catalytic activities. Consequently, SORT NPs rescue radiation-induced DNA damage in mouse and rabbit models and provide survival benefits upon lethal exposures. In addition to inhibiting radiation-induced mitochondrial apoptosis, SORT NPs impede DNA damage and inflammation by attenuating activated FoxO, Hippo, TNF, and MAPK interactive cascades. A universal methodology is proposed to reverse radioenhancers into radioprotectors. SORT radioprotective agents with image guidance are envisioned as compelling in personalized shielding from radiation deposition.
Insights
Selective Organ-Targeting (SORT) nanoparticles protect against radiation damage by scavenging reactive oxygen species and rescuing DNA damage. This novel approach offers personalized shielding from radiation deposition with image guidance.
Area of Science:
- Nanomedicine
- Radiation Biology
- Biomaterials
Background:
- Radioprotective agents are crucial for mitigating radiation side effects in therapy and exposure.
- Current limitations include the inability to control drug transport to specific human organs.
- Organ radiosensitivity can be predicted using genomic signatures.
Purpose of the Study:
- To design and evaluate Selective ORgan-Targeting (SORT) hafnium oxide nanoparticles (HfO2 NPs) as radioprotectors.
- To investigate the mechanism of radioprotection by SORT HfO2 NPs.
- To demonstrate the efficacy of SORT HfO2 NPs in preclinical models.
Main Methods:
- Rational design of HfO2 NPs using α-lactalbumin for organ homing.
- Evaluation of radiosensitivity indices based on a multigene signature model.
- Assessment of antioxidant activities and ROS scavenging by SORT HfO2 NPs.
- Preclinical testing in mouse and rabbit models for DNA damage rescue and survival benefits.
- Radiological confirmation using dual-beam spectral computed tomography.
Main Results:
- SORT HfO2 NPs demonstrated potent antioxidant and multienzyme-mimicking activities.
- These nanoparticles effectively rescued radiation-induced DNA damage and provided survival benefits.
- SORT HfO2 NPs inhibited radiation-induced mitochondrial apoptosis and attenuated key signaling cascades (FoxO, Hippo, TNF, MAPK).
- X-ray attenuation patterns allowed for radiological confirmation in target organs.
Conclusions:
- A universal methodology was proposed to convert radioenhancers into radioprotectors.
- SORT HfO2 NPs exhibit significant radioprotective effects, reversing their typical radioenhancing properties.
- Image-guided SORT radioprotective agents hold promise for personalized radiation shielding.
