Development of Physiologically Based Pharmacokinetic Model (PBPK) of Cancer Treatment in Mice

In hormone-dependent cancers, tumor growth is driven by the binding of the hormone to its receptor. Vitamin D3 can have both preventive and therapeutic effects by regulating cell growth, cell cycle, apoptosis, and differentiation - a role much greater than earlier views that focused primarily on bone health and maintenance of calcium homeostasis. Epidemiological studies have found a significant association between low serum levels and low dietary intake of Vitamin D3 and the incidence, degree of malignancy, metastases, and mortality of cancers of the breast, prostate, colon, and ovaries. We used Semiconductor Nanoparticles (Quantum Dots, (QDs)) in conjunction with a binding procedure to develop a Calcitriol-QD conjugate. Based on this research a Physiologically-Based Pharmacokinetic (PBPK) model has been developed to determine steady-state distribution of Calcitriol-QD in mice. The multi-compartmental PBPK model represents relevant organ/tissues with physiological accuracy. Four processes characterized the change in the concentration of the protein in every compartment: blood flow in, blood flow out, protein turnover and receptor binding in the organ. The unique aspects of the model are the determination of elimination using receptor kinetics and generation using protein turnover. The model also predicts steady state concentrations of Calcitriol-QD in tissues in mice and may be used for possible scale-up of dosage regimens in humans. Due to the QDs fluorescent characteristics, our Calcitriol conjugates can be applied successfully to image the distribution and uptake of Calcitriol into cells. Our data show that we successfully generated a Calcitriol-QD conjugate that is biologically active and stable for at least 48h at RT. Additionally we were able to image the uptake and the distribution of Calcitriol in real time and determine its interaction with the cell membrane and accumulation in the cell nucleus.