Evaluation of pharmacokinetic properties, biodistribution and efficacy of Thorium-227-conjugates
I. The purpose of the experiment/project:
The aim of this study is to evaluate the pharmacokinetic profile, biodistributuion and efficacy of Thorium-227-conjugates. The suggested molecules can specificially bind to targets important during phases of rapid cell division.
The targets have been investigated as potential targets for cancer therapy, and have clinical proof of concept.
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, distress or 15% weight reduction.
III. The expected scientific benefits or benefits for society:
The first target is expressed in cancers of epithelial origin, including cancers of the ovary, breast, pleura, lung, cervix, endometrium, kidney, bladder and brain, with limited expression in normal tissues. The seconds target is expressed in a variety of cancers, including prostate, breast, brain and pancreatic cancer. Specific targeting of cancer cells expressing these targets could be an new and improved therapy for several cancer types and for patient groups that do not benefit from conventional therapies. Compounds conjugated with Thorium-227, an alpha emitting isotope, can allow specific delivery and targeted killing of cancer cells. Compared to existing molecules, new suggested molecules can allow more beneficial biodistribution profile with less adverse effect.
IV. The number of animals and species:
In this study we aim to utilize patient-derived breast cancer model, a known tumor model with proved expression of both targets. Both the PK/biodistribution and efficacy studies will be performed. We will use 455 athymic nude mice in this study.
V. How will the requirements for 3R be accomplished by the experiment/project:
Multiple in vitro studies will be conducted to prove the efficacy, characterization and specific killing in the in vitro culture if breast cancer cells before the conduction of the in vivo experiments. We have already utilized this breast cancer model in vivo, and have good knowledge of this model with regards to group size, timing of treatment etc. The technicians conducting the study have long experience with similar studies using well refined techniques.
 
The aim of this study is to evaluate the pharmacokinetic profile, biodistributuion and efficacy of Thorium-227-conjugates. The suggested molecules can specificially bind to targets important during phases of rapid cell division.
The targets have been investigated as potential targets for cancer therapy, and have clinical proof of concept.
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, distress or 15% weight reduction.
III. The expected scientific benefits or benefits for society:
The first target is expressed in cancers of epithelial origin, including cancers of the ovary, breast, pleura, lung, cervix, endometrium, kidney, bladder and brain, with limited expression in normal tissues. The seconds target is expressed in a variety of cancers, including prostate, breast, brain and pancreatic cancer. Specific targeting of cancer cells expressing these targets could be an new and improved therapy for several cancer types and for patient groups that do not benefit from conventional therapies. Compounds conjugated with Thorium-227, an alpha emitting isotope, can allow specific delivery and targeted killing of cancer cells. Compared to existing molecules, new suggested molecules can allow more beneficial biodistribution profile with less adverse effect.
IV. The number of animals and species:
In this study we aim to utilize patient-derived breast cancer model, a known tumor model with proved expression of both targets. Both the PK/biodistribution and efficacy studies will be performed. We will use 455 athymic nude mice in this study.
V. How will the requirements for 3R be accomplished by the experiment/project:
Multiple in vitro studies will be conducted to prove the efficacy, characterization and specific killing in the in vitro culture if breast cancer cells before the conduction of the in vivo experiments. We have already utilized this breast cancer model in vivo, and have good knowledge of this model with regards to group size, timing of treatment etc. The technicians conducting the study have long experience with similar studies using well refined techniques.