Engineering Radiocatalytic Nanoliposomes with Hydrophobic Gold Nanoclusters for Radiotherapy Enhancement

Abstract Chemoradiation therapy is on the forefront of pancreatic cancer care, and there is a continued effort to improve its safety and efficacy. Liposomes are widely used to improve chemotherapy safety, and may accurately deliver high‐Z element‐ radiocatalytic nanomaterials to cancer tissues. In this study, the interaction between X‐rays and long‐circulating nanoliposome formulations loaded with gold nanoclusters is explored in the context of oxaliplatin chemotherapy for desmoplastic pancreatic cancer. Hydrophobic gold nanoclusters stabilized with dodecanethiol (AuDDT) are efficiently incorporated in nanoliposomal bilayers. AuDDT‐nanoliposomes significantly augmented radiation‐induced ^• OH production, which is most effective with monochromatic X‐rays at energies that exceed the K‐shell electron binding energy of Au (81.7 keV). Cargo release assays reveal that AuDDT‐nanoliposomes can permeabilize lipid bilayers in an X‐ray dose‐ and formulation‐dependent manner. The radiocatalytic effect of AuDDT‐nanoliposomes significantly augments radiotherapy and oxaliplatin‐chemoradiotherapy outcomes in 3D pancreatic microtumors. The PEGylated AuDDT‐nanoliposomes display high tumor accumulation in an orthotopic mouse model of pancreatic cancer, showing promise for nanoliposomes as carriers for radiocatalytic nanomaterials. Altogether, compelling proof for chemo‐radiation dose‐enhancement using AuDDT‐nanoliposomes is presented. Further improving the nanoliposomal loading of high‐Z elements will advance the safety, efficacy, and translatability of such chemoradiation dose‐enhancement approaches.