Proof-of-concept study of monitoring cancer drug therapy with cerenkov luminescence imaging

Abstract

Cerenkov luminescence imaging (CLI) has emerged as a less expensive, easier-to-use, and higher-throughput alternative to other nuclear imaging modalities such as PET. It is expected that CLI will find many applications in biomedical research such as cancer detection, probe development, drug screening, and therapy monitoring. In this study, we explored the possibility of using CLI to monitor drug efficacy by comparisons against PET. To assess the performance of both modalities in therapy monitoring, 2 murine tumor models (large cell lung cancer cell line H460 and prostate cancer cell line PC3) were given bevacizumab versus vehicle treatments. Two common radiotracers, 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) and (18)F-FDG, were used to monitor bevacizumab treatment efficacy.

Methods: One group of mice (n = 6) was implanted with H460 xenografts bilaterally in the shoulder region, divided into treatment and control groups (n = 3 each), injected with (18)F-FLT, and imaged with PET immediately followed by CLI. The other group of mice (n = 6) was implanted with PC3 xenografts in the same locations, divided into treatment and control groups (n = 3 each), injected with (18)F-FDG, and imaged by the same modalities. Bevacizumab treatment was performed by 2 injections of 20 mg/kg at days 0 and 2.

Results: On (18)F-FLT scans, both CLI and PET revealed significantly decreased signals from H460 xenografts in treated mice from pretreatment to day 3. Moderately increased to unchanged signals were observed in untreated mice. On (18)F-FDG scans, both CLI and PET showed relatively unchanged signals from PC3 tumors in both treated and control groups. Quantifications of tumor signals of Cerenkov luminescence and PET images showed that the 2 modalities had excellent correlations (R(2) > 0.88 across all study groups).

Conclusion: CLI and PET exhibit excellent correlations across different tumor xenografts and radiotracers. This is the first study, to our knowledge, demonstrating the use of CLI for monitoring cancer treatment. The findings warrant further exploration and optimization of CLI as an alternative to PET in preclinical therapeutic monitoring and drug screening.

FIGURE 1

Schematic of experimental design. Tumors were implanted bilaterally in shoulder region and allowed to grow to 150–200 mm³, and tumor-bearing mice were subjected to in vivo imaging via PET and CLI at day −1, 1, and 3. Bevacizumab treatment was performed by 2 injections of 20 mg/kg at days 0 and 2. For ¹⁸F-FDG imaging study, mice were kept fasting overnight before experiment.

FIGURE 2

(A) Tumor growth kinetics for H460 xenografts. Measurements were made at days −5, −3, −1, 1, 2, 3, 4, and 5. (B) Tumor growth kinetics for PC3 xenografts. Measurements were made at days −8, −4, −2, 0, 1, 2, 3, 4, and 5. For both figures, day 0 indicates first dose of bevacizumab.

FIGURE 3

Comparison between Cerenkov luminescence and PET images. White arrows point to tumors in all panels. (Top left) ¹⁸F-FLT scans of representative H460 tumor–bearing mouse during bevacizumab treatment. (Top right) ¹⁸F-FLT scans of representative H460 tumor–bearing mouse of control group. (Bottom left) ¹⁸F-FDG scans of representative PC3 tumor–bearing mouse during bevacizumab treatment. (Bottom right) ¹⁸F-FDG scans of representative PC3 tumor–bearing mouse of control group. In each panel, upper row contains Cerenkov luminescence images, and bottom row contains PET images; for each row, left half contains prescans at day −3, and right half contains scans at day 3.

FIGURE 4

Quantitative analysis of Cerenkov luminescence and PET images and their correlation calculated through fitting by linear regression. P < 0.0001 for all 4 linear regressions. (A) H460 xenografts with bevacizumab treatment. (B) H460 xenografts of control group. (C) PC3 xenografts with bevacizumab treatment. (D) PC3 xenografts of control group.