I. HIGHLIGHTS OF THE YEARRIKEN Accel. Prog. Rep. 54 (2021)

RIKEN Accel. Prog. Rep. 54 (2021)

Targeted alpha therapy of cancer: Evaluation of [211 At] AAMTtargeting LAT1†
K. Kaneda-Nakashima,∗1,∗2 Z. Zhang,∗2 Y. Manabe,∗1,∗2 A. Shimoyama,∗1,∗2 K. Kabayama,∗1,∗2 T. Watabe,∗1,∗2Y. Kanai,∗1,∗3 K. Ooe,∗1,∗3 A. Toyoshima,∗1,∗2 Y. Shirakami,∗1,∗2,∗3 T. Yoshimura,∗1 M. Fukuda,∗2,∗4J. Hatazawa,∗1,∗3 T. Nakano,∗2,∗4 K. Fukase,∗1,∗2 and A. Shinohara∗1,∗2Methods
The 209 Bi(α, 2n)211 At reaction using the AVF Cyclotron at the Research Center for Nuclear Physics, Osaka University (Ibaraki, Japan) was used to produce
211At.4) Further 211 At was produced with the same nuclear reaction at the Nishina Center for AcceleratorBased Science, RIKEN, and it was then transported tothe Osaka University.
PANC-1 cells were cultured at 37◦ C in D-MEM containing 10% fetal bovine serum and 1% antibiotics ina humidiﬁed incubator with 5% CO2. Cultured cells
were washed in PBS (-) and harvested with trypsin.
Tumor xenograft models were established by the subcutaneous injection of 1 × 107 cells in 0.2 mL of serumfree medium and Matrigel (1:1) into female BALB/cnu/nu mice. PANC-1 xenograft mice (10 weeks old;body weight = 19.3 ± 1.4 g) were used when the tumor
size reached approximately 50 mm3 on average.
The mice were divided into two groups according tothe injected dose [0.4 MBq (n = 4, 4.0 ± 0.2 MBq/mL);
control (n = 4)]. The control group only received sol†

∗1
∗2
∗3
∗4Condensed from the article Cancer Sci. 112(3), 1132 (2021)
Institute for Radiation Sciences, Osaka University
Graduate School of Science, Osaka University
Graduate School of Medicine, Osaka University
Research Center for Nuclear Physics, Osaka University

3000

Tumor volume (mm3)L-type amino acid transporter 1 (LAT1) is an isoform of the system L, which is Na+ -independent neutralamino acid transport agency. LAT1 is expressed in primary human cancers originating in various organs suchas the brain, lung, thymus, and skin, it is a well-known
speciﬁc cancer marker. Amino acid tracers containing
radioactive halogen have attracted attention for use asprobes in single photon emission computed tomography(SPECT) and positron emission tomography (PET). L3-[18 F]- α-methyl-tyrosine (18 F-FAMT) has higher potential for tumor speciﬁcity than 2-deoxy-2-[18 F] ﬂuoroglucose (18 F-FDG), which is widely employed as a PET
probe for cancer staging. Further FDG has the potential for false-positive accumulation within inﬂammation
related to high glucose metabolism in macrophages orneutrophils, whereas 18 F-FAMT accumulates in tumors
via LAT1, which is expressed only in cancer cells.1) In
contrast, 18 F-FAMT is not transported by other isoforms of the system L (e.g., LAT2, LAT3, and LAT4),
that are expressed in normal tissues.2,3) Therefore, ourL-3-[211 At] - α-methyl-tyrosine (211 At-AAMT) is expected to exhibit LAT1 speciﬁcity and to have the potential to be used as a targeting alpha therapy (TAT)
treatment.

Distributionin mice

■ Control○ 211At-AAMT

2000

1000

00

10203040

Days after injection (Days)

Fig. 1. Eﬃcacy of 211 At-AAMT using the PANC-1
xenograft model. Tumor growth inhibition by 211 AtAAMT (Left). Coronal images of 211 At-AAMT intumor-bearing model (Right).

vents.
Tumor sizes and body weights were measured threetimes per week. Mice were sacriﬁced when the tumor
size reached more than 10% of the total weight. The
mice were observed for 40 days. Uptakes were normalized by the injected dose (MBq) and body weight (g).
Results
In the PANC-1 model, the control mice were injected only with solvents (0.2 w/v% AcOH and 1 w/v%
ascorbic acid solution) and the 211 At-AAMT treatmentgroup received i.v. injections of the 0.4 MBq/mouse
211
At-AAMT solution. No inﬂammation or abnormalities were observed around the injection site. In the211
At-AAMT treatment group, the tumor growth wasclearly inhibited and the body weight was not signiﬁcantly decreased compared to the control group (Fig. 1).
Conclusion
211
At-AAMT may be considered a novel anti-cancer
drug. While 211 At-AAMT could inhibit tumor growthwith a single treatment, the tumor was not completelyabolished, and therefore, a single injection was insuﬃcient to decrease the tumor size continuously. Multiple
doses may be necessary to exploit the high anti-tumor
eﬀect of 211 At-AAMT. In conclusion, 211 At-AAMT may
be an eﬀective anti-cancer drug when administered multiple times or in combination with existing anti-cancerdrugs.
References

1) A. Achmad et al., BMC Med. Imaging 17, 66 (2017).
2) L. Wei et al., J. Pharmacol. Sci. 130, 101 (2016).
3) L. Wei et al., Cancer Sci. 107, 347 (2016).
4) T. Watabe et al., J. Nucl. Med. 60, 1301 (2019).
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