Early investigation of a novel SI306 theranostic prodrug for glioblastoma treatment.

Autor: Vagaggini C; Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Siena, Italy., Petroni D; Institute of Clinical Physiology, Italian National Research Council (CNR), Pisa, Italy., D'Agostino I; Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Siena, Italy., Poggialini F; Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Siena, Italy., Cavallini C; Institute of Clinical Physiology, Italian National Research Council (CNR), Pisa, Italy., Cianciusi A; Department of Pharmacy, University of Genoa, Genoa, Italy., Salis A; DIMES, Section of Biochemistry, University of Genova, Genova, Italy., D'Antona L; Medical Genetics Unit, Mater Domini University Hospital, Catanzaro, Italy.; Department of Health Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy., Francesconi V; Department of Pharmacy, University of Genoa, Genoa, Italy., Manetti F; Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Siena, Italy., Damonte G; DIMES, Section of Biochemistry, University of Genova, Genova, Italy., Musumeci F; Department of Pharmacy, University of Genoa, Genoa, Italy., Menichetti L; Institute of Clinical Physiology, Italian National Research Council (CNR), Pisa, Italy., Dreassi E; Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Siena, Italy., Carbone A; Department of Pharmacy, University of Genoa, Genoa, Italy., Schenone S; Department of Pharmacy, University of Genoa, Genoa, Italy.
Jazyk: angličtina
Zdroj: Drug development research [Drug Dev Res] 2024 Feb; Vol. 85 (1), pp. e22158.
DOI: 10.1002/ddr.22158
Abstrakt: Glioblastoma multiforme (GBM) is one of the most aggressive malignancies with a high recurrence rate and poor prognosis. Theranostic, combining therapeutic and diagnostic approaches, arises as a successful strategy to improve patient outcomes through personalized medicine. Src is a non-receptor tyrosine kinase (nRTK) whose involvement in GBM has been extensively demonstrated. Our previous research highlighted the effectiveness of the pyrazolo[3,4-d]pyrimidine SI306 and its more soluble prodrug CMP1 as Src inhibitors both in in vitro and in vivo GBM models. In this scenario, we decided to develop a theranostic prodrug of SI306, ProSI-DOTA( 68 Ga) 1, which was designed to target GBM cells after hydrolysis and follow-up on the disease's progression and improve the therapy's outcome. First, the corresponding nonradioactive prodrug 2 was tested to evaluate its ADME profile and biological activity. It showed good metabolic stability, no inhibition of CYP3A4, suboptimal aqueous solubility, and slight gastrointestinal and blood-brain barrier passive permeability. Compound 2 exhibited a drastic reduction of cell vitality after 72 h on two different GBM cell lines (GL261 and U87MG). Then, 2 was subjected to complexation with the radionuclide Gallium-68 to give ProSI-DOTA( 68 Ga) 1. The cellular uptake of 1 was evaluated on GBM cells, highlighting a slight but significant time-dependent uptake. The data obtained from our preliminary studies reflect the physiochemical properties of 1. The use of an alternative route of administration, such as the intranasal route, could overcome the physiochemical limitations and enhance the pharmacokinetic properties of 1, paving the way for its future development.
(© 2024 Wiley Periodicals LLC.)
Databáze: MEDLINE
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