Ceritinib 150mg tablets

Abstract Metal‐based anticancer agents offer unique opportunities to integrate multiple therapeutic modalities within a single molecular framework. Herein, we present the first Osmium(II)‐Platinum(IV)‐Ceritinib conjugate ( Os‐Pt‐Cer ) that synergistically combines photodynamic therapy (PDT), chemotherapy, and immunotherapy via immunogenic cell death (ICD) induction. This heterobimetallic complex features a photoactive osmium(II) polypyridyl core, a platinum(IV) prodrug derived from oxaliplatin, and the kinase inhibitor ceritinib as an axial ligand. Upon deep‐red irradiation ( λ = 740 nm), the conjugate exhibits potent antiproliferative activity in ovarian 2D cancer cells and 3D tumour spheroids, with IC 50 values in the low nanomolar range. In addition, Os‐Pt‐Cer effectively inhibits cancer cell migration. Mechanistic studies reveal that the conjugate induces hallmarks of ICD, including calreticulin exposure, ATP release, HMGB1 secretion and phagocytosis. This multifunctional approach highlights the potential of osmium(II)‐platinum(IV) conjugates as promising candidates for overcoming resistance and immune evasion in high‐grade ovarian carcinoma.

Abstract licence: CC BY

Because of the specific thermodynamic properties of active pharmaceutical ingredients, the process of crystallization often meets implementation challenges in the pharmaceutical industry. Therefore, it is essential to select the appropriate method and system for the crystallization of a drug. Ceritinib, an active ingredient in the treatment of lung cancer, was formed as a result of pH modification during the cooling crystallization of ceritinib dihydrochloride solution. By carrying out processes in various solvent systems, several polymorphs were produced. A combination of forms B and C was generated in the ethanol–water system, resulting in smaller crystals. The acetone–water system produced pure form A, which has larger crystals and is more applicable for forthcoming studies. To additionally enhance granulometric properties, ceritinib form A was recrystallized in tetrahydrofuran at different temperatures using antisolvent crystallization. Crystallization at a higher saturation temperature results in larger and more compact crystals, which enhances filtration and drying.

Abstract licence: CC BY

Cholangiocarcinoma (CCA) is a difficult-to-treat cancer, with limited therapeutic options and surgery being the only curative treatment. Standard chemotherapy involves gemcitabine-based therapies combined with cisplatin, oxaliplatin, capecitabine, or 5-FU with a dismal prognosis for most patients. Receptor tyrosine kinases (RTKs) are aberrantly expressed in CCAs encompassing potential therapeutic opportunity. Hence, 112 RTK inhibitors were screened in KKU-M213 cells, and ceritinib, an approved targeted therapy for ALK-fusion gene driven cancers, was the most potent candidate. Ceritinib's cytotoxicity in CCA was assessed using MTT and clonogenic assays, along with immunofluorescence, western blot, and qRT-PCR techniques to analyze gene expression and signaling changes. Furthermore, the drug interaction relationship between ceritinib and cisplatin was determined using a ZIP synergy score. Additionally, spheroid and xenograft models were employed to investigate the efficacy of ceritinib in vivo. Our study revealed that ceritinib effectively killed CCA cells at clinically relevant plasma concentrations, irrespective of ALK expression or mutation status. Ceritinib modulated multiple signaling pathways leading to the inhibition of the PI3K/Akt/mTOR pathway and activated both apoptosis and autophagy. Additionally, ceritinib and cisplatin synergistically reduced CCA cell viability. Our data show ceritinib as an effective treatment of CCA, which could be potentially explored in the other cancer types without ALK mutations.

Abstract licence: CC BY