Evaluation of pharmacokinetic properties, biodistribution and efficacy of PSMA-targeting small molecules labelled with different radioactive isotopes
I. The purpose of the experiment/project:
The aim of this study is to compare the pharmacokinetic profile, biodistributuion and efficacy of small molecules-chelator conjugates labeled with different radioactive isotopes commonly used and that can potentially be used for radioimmunotherapy (RIT). Typically, alpha- and beta-particle emitting isotopes are used for systemic RIT have a particle range around 0.04-3mm allowing specific targeting of tumor cells. Differences in range between alpha and beta particles, half-life time for small molecules-chelator conjugates and radioisotopes contributed to differences in doses to different parts of the tumor and other organs, leading to differences in efficacy and toxicity profiles. In this study, we will generate data for head-to-head comparison of these parameters for two small molecules-chelator conjugates and three different isotopes.
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. All doses used in this study are below the doses causing dose-limiting toxicity.
III. The expected scientific benefits or benefits for society:
PSMA is selectively expressed in prostate cancer, where, generally, choices of targets and treatment regimes are limited. Both external radiation treatment, surgery and hormonal therapy have huge impact on quality of life for the patients. Thus, there is a need for more specific targeting of prostate cancer cells and more mild treatment protocols. Currently, there are several small molecule test items in clinical development labelled with 2 radioisotopes used in the current study. Data generated in the current study will allow us to select isotopes for further development. Moreover, no data comparing these 3 widely used isotopes exists in the literature and will be useful for many research groups working in the field. A paper describing the experiment and the results will be published in a journal allowing a wide public to access this knowledge.
IV. The number of animals and species:
In this study we aim to utilize a known model with proved efficacy of PSMA-targeting conjugates. We will perform comparative biodistribution and pharmacokinetic study and efficacy study comparing PSMA-targeting conjugates at 3 dose levels. We will use 275 Rj:NMRI-Foxn1nu/nu 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 model 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.
The aim of this study is to compare the pharmacokinetic profile, biodistributuion and efficacy of small molecules-chelator conjugates labeled with different radioactive isotopes commonly used and that can potentially be used for radioimmunotherapy (RIT). Typically, alpha- and beta-particle emitting isotopes are used for systemic RIT have a particle range around 0.04-3mm allowing specific targeting of tumor cells. Differences in range between alpha and beta particles, half-life time for small molecules-chelator conjugates and radioisotopes contributed to differences in doses to different parts of the tumor and other organs, leading to differences in efficacy and toxicity profiles. In this study, we will generate data for head-to-head comparison of these parameters for two small molecules-chelator conjugates and three different isotopes.
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. All doses used in this study are below the doses causing dose-limiting toxicity.
III. The expected scientific benefits or benefits for society:
PSMA is selectively expressed in prostate cancer, where, generally, choices of targets and treatment regimes are limited. Both external radiation treatment, surgery and hormonal therapy have huge impact on quality of life for the patients. Thus, there is a need for more specific targeting of prostate cancer cells and more mild treatment protocols. Currently, there are several small molecule test items in clinical development labelled with 2 radioisotopes used in the current study. Data generated in the current study will allow us to select isotopes for further development. Moreover, no data comparing these 3 widely used isotopes exists in the literature and will be useful for many research groups working in the field. A paper describing the experiment and the results will be published in a journal allowing a wide public to access this knowledge.
IV. The number of animals and species:
In this study we aim to utilize a known model with proved efficacy of PSMA-targeting conjugates. We will perform comparative biodistribution and pharmacokinetic study and efficacy study comparing PSMA-targeting conjugates at 3 dose levels. We will use 275 Rj:NMRI-Foxn1nu/nu 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 model 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.