6. Zeinaf Muradova, MS, PhD

Metal-based nanoparticles with high atomic numbers enhance radiotherapy by improving multimodal tumor imaging and increasing radiation dosage. AGuIX-Bi is a theranostic nanoparticle made from gadolinium and bismuth chelates attached to a polysiloxane core. We hypothesize that modifying the surface of AGuIX-Bi with targeted peptides will improve radiation therapy responses. The cyclic Arg-Gly-Asp (cRGD) peptide binds strongly to αvβ3 integrins, which are overexpressed on many tumor cells, including those in lung cancer. In this study, we attached cRGD peptides to the surface of AGuIX-Bi nanoparticles using a PEG spacer to form an amide bond with the nanoparticles’ surface amino groups. In vitro, AGuIX-Bi-cRGD nanoparticles showed increased internalization via integrin binding and enhanced radio sensitization in LLC and A549 radioresistant lung cancer cells. In murine Lewis lung carcinoma (LLC) tumors, AGuIX-Bi-cRGD accumulated and was retained in tumors without causing systemic toxicity. When combined with fractionated radiation, AGuIX-Bi-cRGD transformed a “cold” tumor microenvironment (TME) into a “hot” one by increasing the immunogenic cell death marker HMGB1 and the density of tumor-infiltrating CD3+ CD8+ cytotoxic T cells, which delayed tumor growth and improved survival. These findings suggest that targeted AGuIX-Bi-cRGD nanoparticles could be an effective strategy for enhancing the sensitivity of lung cancers to radiation and immunotherapies.