Evaluation of Pharmacokinetic properties and efficacy of alpha-labelled targeting peptides
1 Formål
Evaluation of the pharmacokinetic properties, biodistribution and efficacy of new alpha-labelled targeting peptides in relevant subcutaneous tumor models overexpressing the target.
2 Skadevirkninger
Based on previous experience with the tumor models and targeted alpha therapies, the three main adverse effects for the mice in this experiment are ulceration of the tumors, weight reduction and a reduction in white blood cells count. To eliminate the adverse effects, we will monitor the mice daily, and immediately sacrifice the mice with first signs of ulcers or 15% weight reduction. Monitoring of white blood cells count will not be performed in the current study, but reduction in white blood cells have not previously lead to noticeable signs to animal well-being, but the mice will be immediately sacrificed at first signs of distress.
3 Forventet nytteverdi
Based on results from the literature, previous experience, model development and immunohistochemistry it is known that the selected target is selectively expressed on the surface of the cancer cells. Non-targeted therapies like external beam radiation and chemotherapy can significantly reduce the quality of life for the patients, and lead to serious side effects. Thus, there is a need for more specific targeting of the cancer, limiting damage to normal and healthy tissues. Specific targeting of the cancer cells by newly acquired targeting peptides, allows delivery of alpha emitting isotopes e.g. Actinium-225 or Thorium-227, to the cancer cells and efficiently kill them. Due to the limited travelling distance of the alpha emitting particle, the damage to the surrounding tissue will be limited. Compared to other targeting molecules, the peptides can allow for a more favorable biodistribution profile, decreasing the off-target effects and thereby side effects of the treatment.
4 Antall dyr og art
Athymic nude mice will be used in this study, to successfully be able to grow human, subcutaneous tumors overexpressing the desired target. Confirmation of the take rate, growth rate and target expression has been performed in a previous model development study.
We will use 600 mice in this study.
5 Hvordan etterleve 3R
All test items utilized in the study has been extensively tested in in vitro assays prior to start of the in vivo study, limiting the number of test items and thereby the number of mice needed for the study. The number of mice in each group has been reduced to a minimum, while still ensuring the power of statistical analysis. The animal technicians working on this study had long experience with similar studies using well refined techniques.
Evaluation of the pharmacokinetic properties, biodistribution and efficacy of new alpha-labelled targeting peptides in relevant subcutaneous tumor models overexpressing the target.
2 Skadevirkninger
Based on previous experience with the tumor models and targeted alpha therapies, the three main adverse effects for the mice in this experiment are ulceration of the tumors, weight reduction and a reduction in white blood cells count. To eliminate the adverse effects, we will monitor the mice daily, and immediately sacrifice the mice with first signs of ulcers or 15% weight reduction. Monitoring of white blood cells count will not be performed in the current study, but reduction in white blood cells have not previously lead to noticeable signs to animal well-being, but the mice will be immediately sacrificed at first signs of distress.
3 Forventet nytteverdi
Based on results from the literature, previous experience, model development and immunohistochemistry it is known that the selected target is selectively expressed on the surface of the cancer cells. Non-targeted therapies like external beam radiation and chemotherapy can significantly reduce the quality of life for the patients, and lead to serious side effects. Thus, there is a need for more specific targeting of the cancer, limiting damage to normal and healthy tissues. Specific targeting of the cancer cells by newly acquired targeting peptides, allows delivery of alpha emitting isotopes e.g. Actinium-225 or Thorium-227, to the cancer cells and efficiently kill them. Due to the limited travelling distance of the alpha emitting particle, the damage to the surrounding tissue will be limited. Compared to other targeting molecules, the peptides can allow for a more favorable biodistribution profile, decreasing the off-target effects and thereby side effects of the treatment.
4 Antall dyr og art
Athymic nude mice will be used in this study, to successfully be able to grow human, subcutaneous tumors overexpressing the desired target. Confirmation of the take rate, growth rate and target expression has been performed in a previous model development study.
We will use 600 mice in this study.
5 Hvordan etterleve 3R
All test items utilized in the study has been extensively tested in in vitro assays prior to start of the in vivo study, limiting the number of test items and thereby the number of mice needed for the study. The number of mice in each group has been reduced to a minimum, while still ensuring the power of statistical analysis. The animal technicians working on this study had long experience with similar studies using well refined techniques.