Evaluation of pharmacokinetic properties, biodistribution and efficacy of modified 227Thorium conjugate
I. The purpose of the experiment/project:
This study is a continuation study performed under FOTS 8438. In that study, we evaluated pharmacokinetic profile of targeting conjugates labelled with 227-Thorium. The study showed higher organ uptake than expected. Therefore, we performed a modified to avoid organ uptake. The aim of the study is to evaluate the pharmacokinetic profile, biodistributuion and efficacy of modified conjugated.
In previous experiments conjugates showed good safety profile, however, the efficacy could be improved. In this study we aim to demonstrate a better tumor-killing potency, as suggested by the in vitro studies.
II. The expected adverse effects on the animals:
Three main adverse effects for the mice in this experiment are ulcerations of the tumors, weight reduction and reduction in white blood cell count. To eliminate the adverse effects, we will daily follow the mice well-being, sacrificing the animals with the first signs of ulcer or 15% weight reduction. White blood cell count didn't lead to any noticeable change in animal well-being. Else, animals will be immediately sacrificed with first signs of distress.
III. The expected scientific benefits or benefits for society:
The selected target is differentially expressed on the surface of cancer cells, where, generally, choices of targets and treatment regimes are limited. Both external radiation treatment, surgery and chemotherapy have huge impact on quality of life for the patients. Thus, there is a need for more specific targeting of cancer cells and more mild treatment protocols. Specific targeting allows delivery of Th227, an alpha emitting isotope. This allows targeted killing of cancer cells. Compared to existing conjugates, new proposed conuugates can allow more beneficial biodistribution profile with less adverse effect.
IV. The number of animals and species:
In this study we aim to utilize a known model with proved efficacy of 227 Thorium labeled conjugates. Both the PK/biodistribution and efficacy studies have to be performed. We will use 370 athymic nude mice in this study
V. How will the requirements for 3R be accomplished by the experiment/project:
Multiple in vitro studies were conducted to prove the efficacy and specific killing of selected tumor models, as well as extensive characterization of the models was performed. We have already acquired promising data in the same model, thus we have good knowledge of this model with regards to group size, timing of treatment etc. Technicians conduction the study have long experience with similar studies using well refined techniques.
This study is a continuation study performed under FOTS 8438. In that study, we evaluated pharmacokinetic profile of targeting conjugates labelled with 227-Thorium. The study showed higher organ uptake than expected. Therefore, we performed a modified to avoid organ uptake. The aim of the study is to evaluate the pharmacokinetic profile, biodistributuion and efficacy of modified conjugated.
In previous experiments conjugates showed good safety profile, however, the efficacy could be improved. In this study we aim to demonstrate a better tumor-killing potency, as suggested by the in vitro studies.
II. The expected adverse effects on the animals:
Three main adverse effects for the mice in this experiment are ulcerations of the tumors, weight reduction and reduction in white blood cell count. To eliminate the adverse effects, we will daily follow the mice well-being, sacrificing the animals with the first signs of ulcer or 15% weight reduction. White blood cell count didn't lead to any noticeable change in animal well-being. Else, animals will be immediately sacrificed with first signs of distress.
III. The expected scientific benefits or benefits for society:
The selected target is differentially expressed on the surface of cancer cells, where, generally, choices of targets and treatment regimes are limited. Both external radiation treatment, surgery and chemotherapy have huge impact on quality of life for the patients. Thus, there is a need for more specific targeting of cancer cells and more mild treatment protocols. Specific targeting allows delivery of Th227, an alpha emitting isotope. This allows targeted killing of cancer cells. Compared to existing conjugates, new proposed conuugates can allow more beneficial biodistribution profile with less adverse effect.
IV. The number of animals and species:
In this study we aim to utilize a known model with proved efficacy of 227 Thorium labeled conjugates. Both the PK/biodistribution and efficacy studies have to be performed. We will use 370 athymic nude mice in this study
V. How will the requirements for 3R be accomplished by the experiment/project:
Multiple in vitro studies were conducted to prove the efficacy and specific killing of selected tumor models, as well as extensive characterization of the models was performed. We have already acquired promising data in the same model, thus we have good knowledge of this model with regards to group size, timing of treatment etc. Technicians conduction the study have long experience with similar studies using well refined techniques.