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Tuning ultrasmall theranostic nanoparticles for MRI contrast and radiation dose amplification.

ABSTRACT: 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 evidence of toxicity. Conclusions: We confirmed the safety and enhanced efficacy of AGuIX-Bi with radiation therapy at the selected ratio of 30Gd/70Bi. These results provide crucial evidence towards patient translation.

SUBMITTER: Brown N

PROVIDER: S-EPMC10526655 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Tuning ultrasmall theranostic nanoparticles for MRI contrast and radiation dose amplification.

Brown Needa N Rocchi Paul P Carmès Léna L Guthier Romy R Iyer Meghna M Seban Léa L Morris Toby T Bennett Stephanie S Lavelle Michael M Penailillo Johany J Carrasco Ruben R Williams Chris C Huynh Elizabeth E Han Zhaohui Z Kaza Evangelia E Doussineau Tristan T Toprani Sneh M SM Qin Xingping X Nagel Zachary D ZD Sarosiek Kristopher A KA Hagège Agnès A Dufort Sandrine S Bort Guillaume G Lux François F Tillement Olivier O Berbeco Ross R

Theranostics 20230821 14

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 ne ...[more]

PMID: 37771768

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Project description:Rationale: As a cancer, Glioblastoma (GBM) is a highly lethal and difficult-to-treat. With the aim of improving therapies to GBM, we developed novel and target-specific theranostic nanoparticles (TNPs) that can be selectively cleaved by cathepsin B (Cat B) to release the potent toxin monomethyl auristatin E (MMAE). Methods: We synthesized TNPs composed of a ferumoxytol-based nanoparticle carrier and a peptide prodrug with a Cat-B-responsive linker and the tubulin inhibitor MMAE. We hypothesized that intratumoral Cat B can cleave our TNPs and release MMAE to kill GBM cells. The ferumoxytol core enables in vivo drug tracking with magnetic resonance imaging (MRI). We incubated U87-MG GBM cells with TNPs or ferumoxytol and evaluated the TNP content in the cells with transmission electron microscopy and Prussian blue staining. In addition, we stereotaxically implanted 6- to 8-week-old nude mice with U87-MG with U87-MG GBM cells that express a fusion protein of Green Fluorescence Protein and firefly Luciferase (U87-MG/GFP-fLuc). We then treated the animals with an intravenous dose of TNPs (25 mg/kg of ferumoxytol, 0.3 mg/kg of MMAE) or control. We also evaluated the combination of TNP treatment with radiation therapy. We performed MRI before and after TNP injection. We compared the results for tumor and normal brain tissue between the TNP and control groups. We also monitored tumor growth for a period of 21 days. Results: We successfully synthesized TNPs with a hydrodynamic size of 41 ± 5 nm and a zeta potential of 6 ± 3 mV. TNP-treated cells demonstrated a significantly higher iron content than ferumoxytol-treated cells (98 ± 1% vs. 3 ± 1% of cells were iron-positive, respectively). We also found significantly fewer live attached cells in the TNP-treated group (3.8 ± 2.0 px2) than in the ferumoxytol-treated group (80.0 ± 14.5 px2, p < 0001). In vivo MRI studies demonstrated a decline in the tumor signal after TNP (T2= 28 ms) but not control (T2= 32 ms) injections. When TNP injection was combined with radiation therapy, the tumor signals dropped further (T2 = 24 ms). The combination therapy of radiation therapy and TNPs extended the median survival from 14.5 days for the control group to 45 days for the combination therapy group. Conclusion: The new cleavable TNPs reported in this work accumulate in GBM, cause tumor cell death, and have synergistic effects with radiation therapy.

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Tuning ultrasmall theranostic nanoparticles for MRI contrast and radiation dose amplification.

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Tuning ultrasmall theranostic nanoparticles for MRI contrast and radiation dose amplification.

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