Abstract
We previously developed a triazole modified tetraiodothyroacetic acid (TAT) conjugated to a polyethylene glycol (PEG)-based thyrointegrin αvβ3 antagonist targeted compound, called P-bi-TAT. It exhibited potent anti-angiogenic and anticancer activities in vivo. The objective of the current study is to develop a quantitative bioanalytical method for P-bi-TAT using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and to elucidate pharmacokinetics (PK) and biodistribution of P-bi-TAT in animals. We used in-source collision-induced dissociation (CID) for ionization of P-bi-TAT in the positive mode, followed by multiple reaction monitoring (MRM) for quantification. P-bi-TAT was quantified using P-mono-TAT as an internal standard because of its similarity in structure and physicochemical properties to P-bi-TAT. The LOQ for P-bi-TAT was 30 ng/μL and the recovery efficiency was 76% with the developed method. Cmax and AUC results at different doses (1, 3, 10 mg/kg) in rats suggest that P-bi-TAT is dose-dependent within the range administered. Results for Cmax and AUC in monkeys at a low dose (25 mg/kg) were comparable to those in rats. Biodistribution of subcutaneously administered P-bi-TAT in the brain of rats ranged from 7.90 to 88.7 ng/g brain weight, and levels of P-bi-TAT in the brain were dose-dependent. The results suggest that P-bi-TAT is a potential candidate as a molecular-targeted anticancer therapeutic with blood-brain barrier permeability and acceptable PK parameters. Its accumulation in organs, toxicokinetic, and pharmacodynamics needs to be further investigated.Graphical
Highlights
Cancer was the second leading cause of death in the USA in 2018, after heart disease (Xu et al 2020)
We developed a conjugate of β-cyclodextrin with triazole-modifiedtetraiodothyroacetic acid (TAT), named β-C-TAT (CTAT)
Deprotonated pseudo-molecular ions [M-2H]2− of P-bi-TAT were detected in negative mode (Fig. 2)
Summary
Cancer was the second leading cause of death in the USA in 2018, after heart disease (Xu et al 2020). We developed a conjugate of β-cyclodextrin with triazole-modifiedtetraiodothyroacetic acid (TAT), named β-C-TAT (CTAT) It showed anti-angiogenic in a chicken embryo chorioallantoic membrane (CAM) assay and anticancer activities in human primary GBM cells and in glioblastoma xenografted mice (unpublished data). Encouraged by the results, we synthesized a polyethylene glycol (PEG)-based targeted drug, P-bi-TAT (1, Fig. 1), which is a conjugate of PEG4000 with two TAT moieties (Sudha et al 2017b; Rajabi et al 2019) It showed high affinity with a receptor on integrin αvβ (IC50 0.14 nM), anti-angiogenic activity in a CAM assay, and anticancer activities in human primary GBM cells and in glioblastoma xenografted mice (10 mg/kg) (Rajabi et al 2019). We developed a bioanalytical method for P-bi-TAT to determine its pharmacokinetics (PK) and biodistribution in experimental animals, i.e., rats and monkeys
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