α‐Emitting cancer therapy using <sup>211</sup>At‐AAMT targeting LAT1

Kaneda-Nakashima, Kazuko; Zhang, Zijian; Manabe, Yoshiyuki; Shimoyama, Atsushi; Kabayama, Kazuya; Watabe, Tadashi; Kanai, Yoshikatsu; Ooe, Kazuhiro; Toyoshima, Atsushi; Shirakami, Yoshifumi; Yoshimura, Takashi; Fukuda, Mitsuhiro; Hatazawa, Jun; Nakano, Takashi; Fukase, Koichi; Shinohara, Atsushi

doi:10.1111/cas.14761

Cited by 36 publications

(31 citation statements)

References 29 publications

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“…However, the therapeutic effect of 2- 211 At-AAMP was found to be insufficient, probably due to its low tumor retention. Other 211 At-labeled amino acids, including 211 At-labeled L-phenylalanine ( 211 At-Phe; Figure 1 c) and 211 At-labeled α-methyl-L-tyrosine ( 211 At-AAMT; Figure 1 a), have been successfully developed and have suppressed tumor growth in vivo [ 20 , 21 , 22 , 23 ]. However, there is concern about toxicity by irradiation following treatment with 211 At-Phe or 211 At-AAMT since they have shown a certain level of accumulation in normal organs.…”

Section: Discussionmentioning

confidence: 99%

“…211 At-Phe was found to be taken up via not only LAT1 but also LAT2, which is expressed in normal organs [ 22 ]. 211 At-AAMT is a LAT1-specific radiopharmaceutical, but it showed high renal accumulation in the excretion process [ 23 ]. In addition, dehalogenation to release free 211 At was observed after the injection of 211 At-Phe and 211 At-AAMT, which can cause radiation exposure in the thyroid and stomach.…”

Section: Discussionmentioning

confidence: 99%

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Enhancing the Therapeutic Effect of 2-211At-astato-α-methyl-L-phenylalanine with Probenecid Loading

Hanaoka

Ohshima

Suzuki

et al. 2021

Cancers

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L-type amino acid transporter 1 (LAT1) might be a useful target for tumor therapy since it is highly expressed in various types of cancers. We previously developed an astatine-211 (211At)-labeled amino acid derivative, 2-211At-astato-α-methyl-L-phenylalanine (2-211At-AAMP), and demonstrated its therapeutic potential for LAT1-positive cancers. However, the therapeutic effect of 2-211At-AAMP was insufficient, probably due to its low tumor retention. The preloading of probenecid, an organic anion transporter inhibitor, can delay the clearance of some amino acid tracers from the blood and consequently increase their accumulation in tumors. In this study, we evaluated the effect of probenecid preloading on the biodistribution and therapeutic effect of 2-211At-AAMP in mice. In biodistribution studies, the blood radioactivity of 2-211At-AAMP significantly increased with probenecid preloading. Consequently, the accumulation of 2-211At-AAMP in tumors was significantly higher with probenecid than without probenecid loading. In a therapeutic study, tumor growth was suppressed by 2-211At-AAMP with probenecid, and the tumor volume was significantly lower in the treatment group than in the untreated control group from day 2 to day 30 (end of the follow-up period) after treatment. These results indicate that probenecid loading could improve the therapeutic effect of 2-211At-AAMP by increasing its accumulation in tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Enhancing the Therapeutic Effect of 2-211At-astato-α-methyl-L-phenylalanine with Probenecid Loading

Hanaoka

Ohshima

Suzuki

et al. 2021

Cancers

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“…In the present study, we found that 211 At caused more DSBs in a dose-dependent manner. Previously, we reported the dose-related induction of DSBs by 211 At-AAMT in PANC1 cells [15]. Alpha particles emitted from 211 At have higher LET than beta particles emitted from 131 I, and the severity and complexity of DNA damage signi cantly increase with alpha irradiation [16].…”

Section: Discussionmentioning

confidence: 99%

Comparison of the Therapeutic Effects of [211At]NaAt and [131I]NaI in an NIS-expressing Thyroid Cancer Mouse Model

Liu

Watabe

Kaneda-Nakashima

et al. 2021

Preprint

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Purpose Compared to a conventional beta-emitter 131I, an alpha-emitter 211At can have a stronger treatment effect against differentiated thyroid cancer. However, its therapeutic advantage has not been fully elucidated. Thus, here, we compared the therapeutic effect of [211At]NaAt with that of [131I]NaI. Methods In vitro observation of double-stranded breaks (DSBs) and colony formation assays were performed in K1-NIS cells. The biodistribution of [131I]NaI and [211At]NaAt was measured in K1-NIS xenograft mice at 3 and 24 h (n=12). The treatment effect was compared between [131I]NaI and [211At]NaAt in K1-NIS xenograft mice using different radioactivities for each solution (1 (n=4), 4 (n=4), and 8 MBq (n=4) of [131I]NaI and 0.4 (n=7), 0.8 (n=9), and 1.2 MBq (n=4) of [211At]NaAt).Results 211At caused more DSBs in K1-NIS cells and had a greater inhibitory effect on colony formation than 131I. In K1-NIS xenograft mice, the uptake of [131I]NaI in the thyroid gland was significantly higher than that of [211At]NaAt. In other organs and tumours, the uptake of [211At]NaAt was significantly higher than that of [131I]NaI. While both [211At]NaAt and [131I]NaI showed dose-dependent therapeutic effects, [211At]NaAt showed a stronger tumour-suppressive effect. Tumour regrowth was suppressed until 18, 25, and 46 days after 0.4, 0.8, and 1.2 MBq [211At]NaAt administration, respectively, whereas it was observed within 0–12 days after [131I]NaI administration (1, 4, and 8 MBq).Conclusions The stronger tumour-suppressive effect of [211At]NaAt solution supports the promising clinical application of [211At]NaAt therapy in patients with iodine-avid thyroid cancer refractory to [131I]NaI treatment.

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“…211 At, which can be produced in cyclotrons without the use of nuclear fuel material, emits high-energy α-rays with a relatively short half-life and can be clearly imaged by clinical scanners or autoradiography. 211 At has been recently labeled with various molecules including amino acid transporter substrates, inhibitors of prostate-specific membrane antigens, or antibodies against cancer-specific antigens for targeted alpha therapy of cancer via intravenous administration [ 18 – 20 ]. On the other hand, as far as we know, no treatments for antineoplastic tumors with 211 At-labeled AuNP have been reported so far.…”

Section: Introductionmentioning

confidence: 99%

Intratumoral administration of astatine-211-labeled gold nanoparticle for alpha therapy

et al. 2021

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Background 211At is a high-energy α-ray emitter with a relatively short half-life and a high cytotoxicity for cancer cells. Its dispersion can be imaged using clinical scanners, and it can be produced in cyclotrons without the use of nuclear fuel material. This study investigated the biodistribution and the antitumor effect of 211At-labeled gold nanoparticles (211At-AuNP) administered intratumorally. Results AuNP with a diameter of 5, 13, 30, or 120 nm that had been modified with poly (ethylene glycol) methyl ether (mPEG) thiol and labeled with 211At (211At-AuNP-S-mPEG) were incubated with tumor cells, or intratumorally administered to C6 glioma or PANC-1 pancreatic cancers subcutaneously transplanted into rodent models. Systemic and intratumoral distributions of the particles in the rodents were then evaluated using scintigraphy and autoradiography, and the changes in tumor volumes were followed for about 40 days. 211At-AuNP-S-mPEG was cytotoxic when it was internalized by the tumor cells. After intratumoral administration, 211At-AuNP-S-mPEG became localized in the tumor and did not spread to systemic organs during a time period equivalent to 6 half-lives of 211At. Tumor growth was strongly suppressed for both C6 and PANC-1 by 211At-AuNP-S-mPEG. In the C6 glioma model, the strongest antitumor effect was observed in the group treated with 211At-AuNP-S-mPEG with a diameter of 5 nm. Conclusions The intratumoral single administration of a simple nanoparticle, 211At-AuNP-S-mPEG, was shown to suppress the growth of tumor tissue strongly in a particle size-dependent manner without radiation exposure to other organs caused by systemic spread of the radionuclide. Graphic Abstract

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α‐Emitting cancer therapy using ²¹¹At‐AAMT targeting LAT1

Cited by 36 publications

References 29 publications

Enhancing the Therapeutic Effect of 2-211At-astato-α-methyl-L-phenylalanine with Probenecid Loading

Enhancing the Therapeutic Effect of 2-211At-astato-α-methyl-L-phenylalanine with Probenecid Loading

Comparison of the Therapeutic Effects of [211At]NaAt and [131I]NaI in an NIS-expressing Thyroid Cancer Mouse Model

Intratumoral administration of astatine-211-labeled gold nanoparticle for alpha therapy

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α‐Emitting cancer therapy using 211At‐AAMT targeting LAT1

Cited by 36 publications

References 29 publications

Enhancing the Therapeutic Effect of 2-211At-astato-α-methyl-L-phenylalanine with Probenecid Loading

Enhancing the Therapeutic Effect of 2-211At-astato-α-methyl-L-phenylalanine with Probenecid Loading

Comparison of the Therapeutic Effects of [211At]NaAt and [131I]NaI in an NIS-expressing Thyroid Cancer Mouse Model

Intratumoral administration of astatine-211-labeled gold nanoparticle for alpha therapy

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α‐Emitting cancer therapy using ²¹¹At‐AAMT targeting LAT1