Int J Biol Sci 2020; 16(8):1363-1375. doi:10.7150/ijbs.41395 This issue Cite

Research Paper

Quantitative determination of niraparib and olaparib tumor distribution by mass spectrometry imaging

Lavinia Morosi1*✉, Cristina Matteo1*, Tommaso Ceruti1, Silvia Giordano2, Marianna Ponzo1, Roberta Frapolli1, Massimo Zucchetti1, Enrico Davoli2, Maurizio D'Incalci1#, Paolo Ubezio1#

1. Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Department of Oncology
2. Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Laboratory of Mass Spectrometry
*L.M. and C.M. contributed equally
#M.D. and P.U. co-last authors

Citation:
Morosi L, Matteo C, Ceruti T, Giordano S, Ponzo M, Frapolli R, Zucchetti M, Davoli E, D'Incalci M, Ubezio P. Quantitative determination of niraparib and olaparib tumor distribution by mass spectrometry imaging. Int J Biol Sci 2020; 16(8):1363-1375. doi:10.7150/ijbs.41395. https://www.ijbs.com/v16p1363.htm
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Abstract

Graphic abstract

Rationale: Optimal intratumor distribution of an anticancer drug is fundamental to reach an active concentration in neoplastic cells, ensuring the therapeutic effect. Determination of drug concentration in tumor homogenates by LC-MS/MS gives important information about this issue but the spatial information gets lost. Targeted mass spectrometry imaging (MSI) has great potential to visualize drug distribution in the different areas of tumor sections, with good spatial resolution and superior specificity. MSI is rapidly evolving as a quantitative technique to measure the absolute drug concentration in each single pixel.

Methods: Different inorganic nanoparticles were tested as matrices to visualize the PARP inhibitors (PARPi) niraparib and olaparib. Normalization by deuterated internal standard and a custom preprocessing pipeline were applied to achieve a reliable single pixel quantification of the two drugs in human ovarian tumors from treated mice.

Results: A quantitative method to visualize niraparib and olaparib in tumor tissue of treated mice was set up and validated regarding precision, accuracy, linearity, repeatability and limit of detection. The different tumor penetration of the two drugs was visualized by MSI and confirmed by LC-MS/MS, indicating the homogeneous distribution and higher tumor exposure reached by niraparib compared to olaparib. On the other hand, niraparib distribution was heterogeneous in an ovarian tumor model overexpressing the multidrug resistance protein P-gp, a possible cause of resistance to PARPi.

Conclusions: The current work highlights for the first time quantitative distribution of PAPRi in tumor tissue. The different tumor distribution of niraparib and olaparib could have important clinical implications. These data confirm the validity of MSI for spatial quantitative measurement of drug distribution providing fundamental information for pharmacokinetic studies, drug discovery and the study of resistance mechanisms.

Keywords: drug distribution, mass spectrometry imaging, PARPi


Citation styles

APA
Morosi, L., Matteo, C., Ceruti, T., Giordano, S., Ponzo, M., Frapolli, R., Zucchetti, M., Davoli, E., D'Incalci, M., Ubezio, P. (2020). Quantitative determination of niraparib and olaparib tumor distribution by mass spectrometry imaging. International Journal of Biological Sciences, 16(8), 1363-1375. https://doi.org/10.7150/ijbs.41395.

ACS
Morosi, L.; Matteo, C.; Ceruti, T.; Giordano, S.; Ponzo, M.; Frapolli, R.; Zucchetti, M.; Davoli, E.; D'Incalci, M.; Ubezio, P. Quantitative determination of niraparib and olaparib tumor distribution by mass spectrometry imaging. Int. J. Biol. Sci. 2020, 16 (8), 1363-1375. DOI: 10.7150/ijbs.41395.

NLM
Morosi L, Matteo C, Ceruti T, Giordano S, Ponzo M, Frapolli R, Zucchetti M, Davoli E, D'Incalci M, Ubezio P. Quantitative determination of niraparib and olaparib tumor distribution by mass spectrometry imaging. Int J Biol Sci 2020; 16(8):1363-1375. doi:10.7150/ijbs.41395. https://www.ijbs.com/v16p1363.htm

CSE
Morosi L, Matteo C, Ceruti T, Giordano S, Ponzo M, Frapolli R, Zucchetti M, Davoli E, D'Incalci M, Ubezio P. 2020. Quantitative determination of niraparib and olaparib tumor distribution by mass spectrometry imaging. Int J Biol Sci. 16(8):1363-1375.

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