Targeted-theranostic nanoparticles induce anti-tumor immune response in lung cancer
Zeinaf Muradova, Léna Carmès, Needa Brown, Fabien Rossetti, Romy Guthier, Sayeda Yasmin‐Karim, Michael Lavelle, Toby Morris, Éder José Guidelli, Mileni Isikawa, Sandrine Dufort, Guillaume Bort, Olivier Tillement, François Lux, Ross Berbeco
Abstract
High atomic number metal-based nanoparticles (NPs) enhance radiotherapy efficacy by improving tumor multimodal imaging and intensifying radiation dosage. AGuIX-Bi represents a theranostic NP comprising gadolinium and bismuth chelates grafted on a polysiloxane core. We hypothesize that modulating the surface of AGuIX-Bi with targeted peptides will enhance the therapeutic responses of radiation therapy. The cyclic Arg-Gly-Asp (cRGD) peptide has a high affinity to RGD-binding integrins overexpressed on various tumor cells, including lung cancer. In the present study, we introduced cRGD peptides onto the surface of AGuIX-Bi NPs using a PEG spacer to form an amide bond with the free amino functions present at the surface of the NPs. In vitro, AGuIX-Bi-cRGD showed enhanced internalization of NPs via integrin binding and increased radiosensitization. In murine Lewis lung carcinoma (LLC) tumors, AGuIX-Bi-cRGD exhibited increased accumulation and retention in tumors without causing systemic toxicity. Combined with fractionated irradiation, AGuIX-Bi-cRGD converted a “cold” LLC tumor microenvironment (TME) into a “hot” one by inducing the overexpression of the immunogenic cell death marker HMGB1 and increasing the density of tumor-infiltrating CD3+ CD8+ cytotoxic T cells and thereby delaying tumor growth and improving mice survival. Therefore, these results suggest a potential strategy for using targeted AGuIX-Bi-cRGD NPs to sensitize lung tumors to radiation and immunotherapies.