99mTc glucarate high-resolution imaging of drug sensitive and drug resistant human breast cancer xenografts in SCID mice

Abstract

Background and aim: Previous studies have showed that 99mTc labelled glucarate (GLA) might be an agent for non-invasive detection of breast tumours. In xenografted BT20 breast tumours, GLA was found to have higher uptake than 99mTc sestamibi (MIBI). It is unclear whether GLA can localize in all cell line breast cancer xenografts, as well as breast tumours with multidrug resistance (MDR). The present study aimed to investigate the properties of GLA in detecting drug sensitive and drug resistant MCF7 breast cancer xenografts in mice by using dynamic single photon emission computed tomography (SPECT) imaging.

Methods: MCF7/S cells are drug sensitive breast carcinoma cells. MCF7/D40 cells are 40-fold more resistant to doxorubicin compared to MCF7/S. Subcutaneous tumours were grown in SCID mice for 10-14 days after injection of 1 x 10(6) cells into the right thigh. Anaesthetized mice with MCF7/S (MIBI, n=9; GLA, n=8) and MCF7/D40 (MIBI, n=6; GLA, n=5) tumours were imaged using a high-resolution SPECT system called FASTSPECT. Dynamic images were acquired for 2 h after intravenous injection of GLA or MIBI. Expression of MDR P-glycoprotein (Pgp) in the tumours was demonstrated in the MCF7/D40 tumours by western blotting, not in the MCF7/S tumours.

Results: The xenografted tumours were visualized unequivocally within 10-30 min in GLA images and remained detectable for at least 2 h after injection. Drug resistant tumours, from which MIBI was rapidly expelled, retained GLA as readily as did drug sensitive tumours. The biodistribution data of GLA demonstrated significantly higher accumulation (%ID/g) compared to MIBI.

Conclusion: MCF7 tumour xenografts can be detected by 99mTc glucarate imaging. More importantly, 99mTc glucarate can potentially localize drug resistant breast tumours.

Fig. 1

^99mTc glucarate FASTSPECT coronal images (right panel) in a mouse with MCF7/S tumour xenograft on right thigh (left panel) 20 min after injection. Tumour (arrow) was localized clearly with low radioactive background on ^99mTc glucarate images.

Fig. 2

(A and B) ^99mTc glucarate dynamic FASTSPECT images (serial transaxial slices) from a mouse with MCF7/S breast tumour (arrow). The tumour (arrow) was visualized within 5 min and stayed well-defined for at least 120 min after ^99mTc glucarate injection. The time after injection is shown in the lower right corner of each image. (C and D) ^99mTc glucarate dynamic FASTSPECT images (serial transaxial slices) from a mouse with MCF7/D40 breast tumour (arrow). The tumour (arrow) was visualized during the period for dynamic acquisition as well as in the MCF7/S tumour above.

Fig. 3

^99mTc glucarate FASTSPECT images 120 min after injection in a mouse with MCF7/D40 tumour xenograft on right thigh (A). Tumour (arrow) was well localized in all directions of tomographic images (B: coronal; C: sagittal; D: transaxial slices).

Fig. 4

(A and B) Dynamic FASTSPECT images from a mouse with MCF7/S breast tumour on right thigh (arrow) using ^99mTc sestamibi (serial sagittal slices). The tumour was unequivocally visualized after about 10 min and remained detectable until 120 min after injection. (C and D) ^99mTc sestamibi dynamic FASTSPECT images from a mouse with MCF7/D40 tumour xenograft on right thigh (serial sagittal slices). The tumour was visualized only 2–4 min after injection. The tumour radioactivity dropped quickly to the background level.

Fig. 5

Time–activity curves of ^99mTc sestamibi and ^99mTc glucarate in the MCF7/S and MCF7/D40 tumours. The radioactivity in both tumour models with ^99mTc glucarate was significantly higher at all points than with ^99mTc sestamibi. In contrast to ^99mTc sestamibi, the radioactivity from ^99mTc glucarate was not considerably lower in MCF7/D40 than in MCF7/S tumours. MIBI, ^99mTc sestamibi; GLA, ^99mTc glucarate; S, MCF7/S; D40, MCF7/D40; *P<0.05 compared to MIBI/S. Error bar=SEM.

Fig. 6

The peak uptake and end radioactivity detected by FASTSPECT imaging using ^99mTc glucarate were significantly higher than that using ^99mTc sestamibi in both of the MCF7/S and MCF7/D40 tumours. The end activity of ^99mTc sestamibi in the MCF7/D40 tumours was significantly lower than that in the MCF7/S tumours. Abbreviations as in Fig. 5. *P<0.05 compared to MIBI/S.

Fig. 7

^99mTc glucarate and ^99mTc sestamibi washout curves from the MCF7/S and MCF7/D40 breast tumours. The radioactivity is plotted as a percentage of the peak activity in the tumour and extended to 2 h using the TableCurve curve-fitting calculation. Abbreviations as in Fig. 5. *P<0.05 compared to MIBI/S.