Purpose: The recent development of clinical MRI-Linacs has opened up a new space for theranostic nanoparticles for tumor visualization and radiation dose amplification. In this study we have developed a second-generation theranostic nanoparticle for MRI contrast and tumor specific radiation dose enhancement.
Methods: A new synthesis methodology was developed to exchange gadolinium-DOTA complexes in AGuIX with bismuth-DOTA complexes. Second-generation bismuth-gadolinium nanoparticles (AGuIX-Bi) were developed with three ratios of Gd/Bi (70/30, 50/50, and 30/70). Nanoparticles were characterized via ICP-MS, DLS, and T1 relaxometry. In vitro toxicity analysis and clonogenic assays were conducted in a human NSCLC cell line. In vivo biodistribution studies via ICP-MS demonstrated nanoparticle accumulation and retention times which were further confirmed via MRI. Radiation dose enhancement effects were assessed in a tumor growth inhibition study in vivo in a human NSCLC model.
Results: Each AGuIX-Bi nanoparticle formulation was characterized with final ratios of 70/30, 50/50, and 30/70 of Gd/Bi with an approximate size of 4.5-5.1 nm. As the ratio of Gd relative to Bi increased, T1 shortening was observed for all ratios, confirming enhancement of MR contrast, which was confirmed in a 0.35T clinical MR-Linac, 3T clinical MRI, and 7T small animal MR scanner. In vitro clonogenic assays identified a sensitizing enhancement ratio of 1.28 for 30/70 AGuIX-Bi nanoparticles compared to 1.125 for AGuIX in a human NSCLC A549 line. DNA damage assay via γH2AX measured increased dsDNA breaks for higher ratios of Bi. In vivo biodistribution studies confirmed differences in nanoparticle accumulation and retention with longer tumor retention time for the AGuIX-Bi, up to 24h, compared to AGuIX. Ongoing tumor inhibition studies showed tumor growth delay compared to controls and radiation groups.
Conclusion: A new generation of theranostic nanoparticles for MR-guidance and localized tumor dose amplification demonstrated improved therapeutic efficacy while retaining strong MR contrast.
Funding Support, Disclosures, and Conflict of Interest: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Institutes of Health (grant number: NIH R01CA240804). Some authors are employed by NH Theraguix.