Cu-64 radiopharmaceuticals as theranostic agents: a mouse xenograft model
Purpose
Tumor hypoxia (oxygen deficiency) is a common feature of tumor microenvironment in solid tumors. It is a key indicator for cancer progression and poor prognosis, and a key contributor for chemo- and radiotherapy resistance. Currently diagnostic methods of tumor hypoxia are imprecise and immature. Recent studies demonstrated that Positron Emission Tomography (PET) may be used to image tumor hypoxia, when a hypoxia-specific tracer is used, such as [64Cu][Cu-diacetyl-bis(N(4)-methylthiosemicarbazone)] (64Cu-ATSM). In addition, when an appropriate radionuclide is used it can also act as a therapeutic agent which lead to significant reduction or disappearance of tumors, effectively as a "theranostic" agent for simultaneous detection and treatment in solid tumors. This is because Cu-64 has a complex decay scheme, in which electron capture leads to emission of low energy, high linear energy transfer (LET) Auger electron. We have summarized recent findings of Cu-64 radiopharmaceuticals as theranostic agents in our review article [1]. We have obtained promising results from our previous pilot in vivo experiment using with 64Cu-ATSM and a novel Cu-64 radiopharmaceutical. In this study we will investigate the therapeutic aspects of the novel Cu-64 radiopharmaceuticals in two human cancer mouse xenograft models.
The general aim for this experiment is as following:
- To evaluate the therapeutic effects of the novel Cu-64 radiopharmaceuticals in two human cancer models;
- To compare the therapeutic effects administrated in single dose or multiple doses;
- To visualize the tumor uptake and biodistribution using PET/MR.
Distress
This study has minimum distress to the animals.
Expected benefit
Development of PET tracers as theranostic agents for tumor hypoxia is clinically relevant for both doctors and patients.
Development of Cu-64 radiopharmaceuticals to target hypoxic solid tumors provides an attractive option to provide individualized cancer treatments to optimize efficiency and reduce adverse effects. Successful development of a theranostic pharmaceutical may improve overall treatment efficiency and survival among cancer patients.
Number and types of animals
In this study we planned to use 100 mice in total. Based on prior studies in literature male BALB/c nude mice will be used.
5 How to adhere to 3R
This experiment was designed in compliance with the 3R principle.
Replacement
The tracer candidates have been extensively studied during in vitro experiments and in vivo/in vitro studies in literatures. They both have been involved in clinical studies previously for difference purposes. The in vitro characteristic and toxicity have been extensively characterized in our prior studies. However, the therapeutic aspects have not been thoroughly characterized in vivo, thus in vivo experiments are needed.
Reduction
The tracer has been tested in vitro and have demonstrated promising results. Only the most necessary experiments will be performed in vivo and only the minimum number of animal to achieve scientific significance will be used.
Refinement
All animals will be treated with care during the experiment. Upon injection of tracers and during experiment, the animals will be under general anesthesia and kept on a heated blanket to maintain their body temperature.
Tumor hypoxia (oxygen deficiency) is a common feature of tumor microenvironment in solid tumors. It is a key indicator for cancer progression and poor prognosis, and a key contributor for chemo- and radiotherapy resistance. Currently diagnostic methods of tumor hypoxia are imprecise and immature. Recent studies demonstrated that Positron Emission Tomography (PET) may be used to image tumor hypoxia, when a hypoxia-specific tracer is used, such as [64Cu][Cu-diacetyl-bis(N(4)-methylthiosemicarbazone)] (64Cu-ATSM). In addition, when an appropriate radionuclide is used it can also act as a therapeutic agent which lead to significant reduction or disappearance of tumors, effectively as a "theranostic" agent for simultaneous detection and treatment in solid tumors. This is because Cu-64 has a complex decay scheme, in which electron capture leads to emission of low energy, high linear energy transfer (LET) Auger electron. We have summarized recent findings of Cu-64 radiopharmaceuticals as theranostic agents in our review article [1]. We have obtained promising results from our previous pilot in vivo experiment using with 64Cu-ATSM and a novel Cu-64 radiopharmaceutical. In this study we will investigate the therapeutic aspects of the novel Cu-64 radiopharmaceuticals in two human cancer mouse xenograft models.
The general aim for this experiment is as following:
- To evaluate the therapeutic effects of the novel Cu-64 radiopharmaceuticals in two human cancer models;
- To compare the therapeutic effects administrated in single dose or multiple doses;
- To visualize the tumor uptake and biodistribution using PET/MR.
Distress
This study has minimum distress to the animals.
Expected benefit
Development of PET tracers as theranostic agents for tumor hypoxia is clinically relevant for both doctors and patients.
Development of Cu-64 radiopharmaceuticals to target hypoxic solid tumors provides an attractive option to provide individualized cancer treatments to optimize efficiency and reduce adverse effects. Successful development of a theranostic pharmaceutical may improve overall treatment efficiency and survival among cancer patients.
Number and types of animals
In this study we planned to use 100 mice in total. Based on prior studies in literature male BALB/c nude mice will be used.
5 How to adhere to 3R
This experiment was designed in compliance with the 3R principle.
Replacement
The tracer candidates have been extensively studied during in vitro experiments and in vivo/in vitro studies in literatures. They both have been involved in clinical studies previously for difference purposes. The in vitro characteristic and toxicity have been extensively characterized in our prior studies. However, the therapeutic aspects have not been thoroughly characterized in vivo, thus in vivo experiments are needed.
Reduction
The tracer has been tested in vitro and have demonstrated promising results. Only the most necessary experiments will be performed in vivo and only the minimum number of animal to achieve scientific significance will be used.
Refinement
All animals will be treated with care during the experiment. Upon injection of tracers and during experiment, the animals will be under general anesthesia and kept on a heated blanket to maintain their body temperature.