Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Development of a HPLC-MS/MS Method to Assess the Pharmacokinetics and Tumour Distribution of the Dimethylarginine Dimethylaminohydrolase 1 Inhibitors ZST316 and L-257 in a Xenograft Model of Triple Negative Breast Cancer

Tommaso Ceruti
ORCID logo ,
Roberta Frapolli
,
Carmen Ghilardi
,
Alessandra Decio
,
Giulia Dellavedova
,
Sara Tommasi
,
Massimo Zucchetti
ORCID logo ,
Arduino A Mangoni
* ORCID logo
Version 1 : Received: 11 October 2023 / Approved: 11 October 2023 / Online: 12 October 2023 (12:01:21 CEST)

A peer-reviewed article of this Preprint also exists.

Ceruti, T.; Frapolli, R.; Ghilardi, C.; Decio, A.; Dellavedova, G.; Tommasi, S.; Zucchetti, M.; Mangoni, A.A. Development of a HPLC-MS/MS Method to Assess the Pharmacokinetics and Tumour Distribution of the Dimethylarginine Dimethylaminohydrolase 1 Inhibitors ZST316 and L-257 in a Xenograft Model of Triple-Negative Breast Cancer in Mice. Molecules 2023, 28, 8056. Ceruti, T.; Frapolli, R.; Ghilardi, C.; Decio, A.; Dellavedova, G.; Tommasi, S.; Zucchetti, M.; Mangoni, A.A. Development of a HPLC-MS/MS Method to Assess the Pharmacokinetics and Tumour Distribution of the Dimethylarginine Dimethylaminohydrolase 1 Inhibitors ZST316 and L-257 in a Xenograft Model of Triple-Negative Breast Cancer in Mice. Molecules 2023, 28, 8056.

Abstract

We describe the development and validation of a HPLC-MS/MS method to assess the pharmacokinetics and tumour distribution of ZST316, an arginine analogue with inhibitory activity towards dimethylarginine dimethylaminohydrolase 1 (DDAH1) and vasculogenic mimicry, and its active metabolite L-257 in a xenograft model of triple negative breast cancer (TNBC). The method proved to be reproducible, precise, and highly accurate for the measurement of both compounds in plasma and tumour tissue following acute and chronic (five days) intraperitoneal administration of ZST316 (30mg/Kg daily) in six-week-old SCID mice inoculated with MDA-MB-231 TNBC cells. ZST316 was detected in tumour tissue and plasma after 1 hour (6.47 and 9.01M, respectively) and 24 hours (0.13 and 0.16M, respectively) following acute administration, without accumulation during chronic treatment. Similarly, the metabolite L-257 was found in tumour tissue and plasma after 1 hour (15.06 and 8.72M, respectively) and 24 hours (0.17 and 0.17M, respectively) following acute administration of ZST316, without accumulation during chronic treatment. The half-live after acute and chronic treatment ranged between 4.4-7.1hrs (plasma) and 4.5-5.0hrs (tumour) for ZST316, and 4.2-5.3hrs (plasma) and 3.6-4.9hrs (tumour) for L-257. The results of our study demonstrate the a) capacity to accurately measure ZST316 and L-257 concentrations in plasma and tumour tissue in mice using the newly developed HPLC-MS/MS method, b) rapid conversion of ZST316 into L-257, c) good intra-tumour penetration of both compounds, and d) lack of accumulation of both ZST316 and L-257 in plasma and tumour tissue during chronic administration. The new HPLC-MS/MS method is useful to investigate the in vivo effects of ZST316 and L-257 on vasculogenic mimicry, tumour mass, and metastatic burden in xenograft models of TNBC.

Keywords

ZST316; L-257; dimethylarginine dimethylaminohydrolase 1; DDAH1 inhibitors; triple negative breast cancer; pharmacokinetics; xenograft models; analytical chemistry

Subject

Medicine and Pharmacology, Pharmacology and Toxicology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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