Surface PEGylation of MIL-101(Fe) nanoparticles for co-delivery of radioprotective agents

Abstract

Providing protection from radiation damage is a great medical challenge. Metal-organic frameworks (MOFs) have high drug-loading capacities and excellent biocompatibility and are thus useful as drug-delivery systems. We fabricated a new drug carrier based on nanoscale MIL-101(Fe) to co-deliver two radioprotective agents by encapsulating WR-1065 (the active metabolite of amifostine) and glutathione (GSH). Consequently, the drug loading amounts of our drug carrier were 35.6 wt% and 6.5 wt% for WR-1065 and GSH, respectively. Moreover, radioprotective efficacy improved after PEGylation, which increased permeability and stability of these nanoparticles. In vitro studies showed that the MOF-based radioprotector had lower cytotoxicity compared with free WR-1065, and it increased cell viability by scavenging the accumulated reactive oxygen species and resisting DNA damage after irradiation. The MOF-based radioprotector—administered orally to mice—demonstrated efficacy at mitigating acute radiation syndrome; and its 30-d survival rate after lethal total body irradiation (TBI, 8 Gy) was 80%. The MOF-based radiation countermeasures led to significant improvements in peripheral blood cell count, hematopoietic stem and progenitor cells (HSPCs) frequency, and clonogenic function of hematopoietic progenitor cell. The ameliorated hematopoietic system injury in HSPCs is probably attributable to downregulation of BAX and BAK expression and upregulation of BCL-CL expression through the inhibition hematopoietic cell apoptosis. Therefore, the MOF-based radioprotectant has the potential to be used as a promising therapeutic candidate to attenuate TBI-induced hematopoietic injury.