《Tyrosine kinase inhibitor prodrug-loaded liposomes for controlled release at tumor microenvironment》 was written by Salmaso, Stefano; Mastrotto, Francesca; Roverso, Marco; Gandin, Valentina; De Martin, Sara; Gabbia, Daniela; De Franco, Michele; Vaccarin, Christian; Verona, Marco; Chilin, Adriana; Caliceti, Paolo; Bogialli, Sara; Marzaro, Giovanni. HPLC of Formula: 1193-21-1This research focused ontyrosine kinase inhibitor prodrug liposomes controlled release tumor microenvironment; Drug release; Kinase inhibitors; Liposomes; Microsomes; pH-dependent hydrolysis. The article conveys some information:
Tyrosine kinase inhibitors (TKIs) represent one of the most advanced class of therapeutics for cancer treatment. Most of them are also cytochrome P 450 (CYP) inhibitors and/or substrates thereof. Accordingly, their efficacy and/or toxicity can be affected by CYP-mediated metabolism and by metabolism-derived drug-drug interactions. In order to enhance the therapeutic performance of these drugs, we developed a prodrug (Pro962) of our TKI TK962 specifically designed for liposome loading and pH-controlled release in the tumor. A cholesterol moiety was linked to TK962 through pH-sensitive hydrazone bond for anchoring to the liposome phospholipid bilayer to prevent leakage of the prodrug from the nanocarrier. Bioactivity studies performed on isolated target kinases showed that the prodrug maintains only partial activity against them and the release of TK962 is required. Biopharmaceutical studies carried out with prodrug loaded liposomes showed that the prodrug was firmly associated with the vesicles and the drug release was prevented under blood-mimicking conditions. Conversely, conventional liposome loaded with TK962 readily released the drug. Flow cytometric studies showed that liposomes efficiently provided for intracellular prodrug delivery. The use of the hydrazone linker yielded a pH-controlled drug release, which resulted in about 50% drug release at pH 4 and 5 in 2 h. Prodrug, prodrug loaded liposomes and active lead compound have been tested against cancer cell lines in either 2D or 3D models. The liposome formulation showed higher cytotoxicity than the unformulated lead TK962 in both 2D and 3D models. The stability of prodrug, prodrug loaded liposomes and active lead compound in human serum and against human, mouse, and rat microsomes was also assessed, demonstrating that liposome formulations impair the metabolic reactions and protect the loaded compounds from catabolism. The results suggest that the liposomal formulation of pH releasable TKI prodrugs is a promising strategy to improve the metabolic stability, intracellular cancer cell delivery and release, and in turn the efficacy of this class of anticancer drugs. In the experiment, the researchers used 4,6-Dichloropyrimidine(cas: 1193-21-1HPLC of Formula: 1193-21-1)
4,6-Dichloropyrimidine(cas: 1193-21-1) is a member of organic chlorides. Organic chlorides are compounds containing a carbon-chlorine bond, which are widely used in the oil field as a wax dissolver. They are generally not present in crude oils and are typically the result of additives, cleaning solutions or chemicals used for oil recovery.HPLC of Formula: 1193-21-1
Referemce:
Pyrimidine | C4H4N2 – PubChem,
Pyrimidine – Wikipedia