作者: Frosini, Maria ; Diana, Sara ; Grossi, Giancarlo ; Dreassi, Elena ; Schenone, Silvia ; Brai, Annalaura ; Carbone, Anna ; Musumeci, Francesca ; Vagaggini, Chiara ; Botta, Maurizio ; Poggialini, Federica ; Rango, Enrico

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer and a cause of cancer-related death, characterized by poor survival outcomes. Significant progress has been made in developing new targeted therapies, including the use of tyrosine kinase inhibitors, which have shown promise in improving patient prognosis. This study focuses on SI306, a small competitive inhibitor of the c-Src tyrosine kinase and a promising anticancer agent, along with its liposomal formulation (Lipo-SI306), in the treatment of NSCLC. Firstly, the antiproliferative profile of both SI306 and Lipo-SI306 was investigated in three NSCLC cell lines (A549, PC-9, and Calu-3), along with their effects toward healthy keratinocytes (HaCaT). SI306 demonstrated a superior antiproliferative efficacy across all NSCLC cells (IC₅₀s between 1.76 and 6.37 µM after 72 h) compared to Lipo-SI306 (IC₅₀s between 3.63 and 14.01 µM after 72 h). Furthermore, both SI306 and Lipo-SI306 exhibited lower cytotoxicity towards HaCaT cells than dasatinib and gefitinib, with CC₅₀s approximately one order of magnitude higher. Mechanistic studies revealed that SI306 induces irreversible damage, promotes DNA fragmentation and cell cycle deregulation, and reduces cell migration. Hemolytic activity (ranging from 1.85 % as liposomal formulation, to 3.81 % in DMSO and to 14.83 % in Tween80 MIX, respectively) and the median lethal dose (LD₅₀) of 200 mg/kg on Tenebrio molitor coleoptera confirmed the favorable safety profile of SI306. Finally, pharmacokinetic and biodistribution studies in healthy mice showed prolonged circulation time and increased lung accumulation of SI306 when administered as liposomal formulation, highlighting the potential therapeutic advantages of this drug delivery system for NSCLC treatment.

2024-04-01·Journal of Instrumentation

A novel boron-conjugated SRC inhibitor for Proton Boron Capture Therapy in glioblastoma treatment

作者: Torrisi, F. ; Parenti, R. ; Charalampopoulou, A. ; Botta, L. ; Pullia, M. ; Cammarata, F. P. ; Pavone, A. M. ; Rotili, D. ; Denaro, S. ; Russo, G. ; Facoetti, A. ; D'Aprile, S.

Abstract:

The ability of protons to deliver the maximum dose at the tumor region can work synergistically with boron atoms to emit alpha particles, enhancing therapy effects with less damage to healthy tissue. Protons and boron nuclear fusion reaction is the principle for the so-called Proton Boron Capture Therapy, that can contribute to high therapy efficiency by using smaller flux than conventional proton therapy, especially for radioresistant brain tumors such as glioblastoma. Glioblastoma is the most infiltrating and aggressive tumor of the brain with a very low life expectancy, ranging from 6 to 24 months. In this study we evaluated the protons combined effectwithanovelboron-conjugated compound, which is a pyrazolo[3,4-d]pyrimidine derivative, acting as SRC tyrosine kinase inhibitor. Indeed, this drug includes a boron cluster, that can be directed in tumor cells using the ATP-competitive mechanism of the pyrazolo[3,4 d]pyrimidine ring in activated SRC form of glioblastoma cells, achieving tumor uptake of boron for Proton Boron Capture Therapy reaction. This preliminary study showed interesting results that could offer important contributions for further experiments.

2024-02-01·Drug development research

Early investigation of a novel SI306 theranostic prodrug for glioblastoma treatment

Article

作者: D'Antona, Lucia ; Francesconi, Valeria ; Cavallini, Chiara ; D'Agostino, Ilaria ; Schenone, Silvia ; Cianciusi, Annarita ; Damonte, Gianluca ; Petroni, Debora ; Dreassi, Elena ; Vagaggini, Chiara ; Salis, Annalisa ; Menichetti, Luca ; Musumeci, Francesca ; Poggialini, Federica ; Manetti, Fabrizio ; Carbone, Anna

Abstract:

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(68Ga) 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(68Ga) 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.

100 项与 Si-306 相关的药物交易

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