Quantification of doxorubicin in mouse serum and tumor tissue by liquid chromatography tandem mass spectrometry: An application in an in vivo study with murine prostate cancer xenograft tumor and ultrasound-sensitive liposomal doxorubicin
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Non-specificity and systemic toxicity are major challenges with cancer chemotherapy. This situation is further complicated by abnormality of tumor microenvironment that presents potential barriers to drug delivery. These problems can be solved by localized drug delivery of cytotoxic drugs entrapped within ultrasound-sensitive liposomes. With focused ultrasound exposure, liposomal drug is selectively accumulated in targeted tumor site only. Doxorubicin was chosen a model drug due to its established clinical efficacy with different liposomal formulations. The aims of this study were to establish liquid chromatography tandem mass spectrometry (LC-MS/MS) based method for quantitative measurement of doxorubicin in tumor tissue and serum, and to apply the established method for assessment of ultrasound mediated extravasation of liposomal doxorubicin in tumor tissue. Two sample processing methods i.e. protein precipitation extraction for plasma/serum, and Precellys beads-based homogenization and extraction procedure for tumor tissue were developed. Performance of the established methods was successfully documented with a standard validation procedure. Finally, an in vivo proof-of-principle study was carried out with murine prostate cancer xenograft tumor, and ultrasoundsensitive liposomal doxorubicin. 1MHz ultrasound was focused on the tumor tissue 5 minutes post-liposomal injection with total exposure duration of 10 minutes. Experimental findings of this study could not confirm any improvement in tumor tissue uptake of liposomal doxorubicin under the ultrasound exposure. It was probably due to small sample size and resulting large inter-individual variability in tissue doxorubicin concentration, and also, lack of optimization of ultrasound exposure parameters.