Background: Significant progress has been achieved within the past decade to support novel, personalized disease-targeted drug development in oncology. The development of radiopharmaceutical-based molecular imaging biomarkers and therapeutics requires significant infrastructure to support the necessary basic science investigations for both in vitro and in vivo preclinical investigative new drug supportive studies, including USP compliant radiopharmaceutical formulation. The Harry S. Truman Memorial Veterans’ Hospital is engaged in conducting bench to bedside translation of novel theranostic (therapeutic and diagnostic) radiopharmaceuticals with the goal of supporting a wide range of physician-sponsored phase 1 clinical oncology trials.
Methods: As examples, we have used a combination of commercial chemical synthesis and in-house automated solid phase peptide synthesis to generate peptide vectors targeting the somatostatin and bombesin receptor systems. Automated radiochemical synthesis of Ga-68 products for diagnostic positron emission tomography (PET) imaging and Lu-177 products for targeted radiotherapeutic applications has been accomplished. The resulting radiolabeled products were validated in vitro, using a combination of cell-based assays assessing receptor-binding affinity, cell proliferation, and flow cytometry. Preclinical animal-based screening assays included validating tumor targeting capability by evaluating in vivo drug pharmacokinetics, assessing therapeutic efficacy in human tumor xenografted rodent models, and preclinical molecular imaging of radiopharmaceutical localization employing PET, single-photon emission computed tomography, computed tomography, and MRI. The FDA IND supportive studies to demonstrate routine drug production capability and product reproducibility are accomplished by using commercial automated radiochemical synthesis technology.
Results: Multiple Ga-68- and Lu-177-labeled radiopharmaceuticals have now been produced and tested in vitro and in vivo, using appropriate preclinical models of prostate and breast cancer. Routine data collection for validation of radiopharmaceutical reproducibility is ongoing.
Conclusion: This presentation outlines the resources necessary and validates the steps required to establish a translational radiopharmaceutical research and production facility for the in-house preparation of novel oncology-directed biomarkers and targeted therapeutics.
