Tuning ultrasmall theranostic nanoparticles for MRI contrast and radiation dose amplification

作者：Brown N, Rocchi P, Carmès L, Guthier R, Iyer M, Seban L, Morris T, Bennett S, Lavelle M, Penailillo J, Carrasco R, Williams C, Huynh E, Han Z, Kaza E, Doussineau T, Toprani SM, Qin X, Nagel ZD, Sarosiek KA, Hagège A, Dufort S, Bort G, Lux F, Tillement O, Berbeco R · 发表于：Theranostics · 年份：2023 · DOI：10.7150/thno.85663 · 被引用次数：57 · 研究领域：bismuth、magnetic resonance、nanoparticle、radiation therapy、theranostics

Background: The introduction of magnetic resonance (MR)-guided radiation treatment planning has opened a new space for theranostic nanoparticles to reduce acute toxicity while improving local control. In this work, second-generation AGuIX® nanoparticles (AGuIX-Bi) are synthesized and validated. AGuIX-Bi are shown to maintain MR positive contrast while further amplifying the radiation dose by the replacement of some Gd3+ cations with higher Z Bi3+. These next-generation nanoparticles are based on the AGuIX® platform, which is currently being evaluated in multiple Phase II clinical trials in combination with radiotherapy. Methods: In this clinically scalable methodology, AGuIX® is used as an initial chelation platform to exchange Gd3+ for Bi3+. AGuIX-Bi nanoparticles are synthesized with three ratios of Gd/Bi, each maintaining MR contrast while further amplifying radiation dose relative to Bi3+. Safety, efficacy, and theranostic potential of the nanoparticles were evaluated in vitro and in vivo in a human non-small cell lung cancer model. Results: We demonstrated that increasing Bi3+ in the nanoparticles is associated with more DNA damage and improves in vivo efficacy with a statistically significant delay in tumor growth and 33% complete regression for the largest Bi/Gd ratio tested. The addition of Bi3+ by our synthetic method leads to nanoparticles that present slightly altered pharmacokinetics and lengthening of the period of high tumor accumulation with no observed evidenc...