Nanoformulations of anticancer FGFR inhibitors with improved therapeutic index

Publication date: Available online 16 August 2018Source: Nanomedicine: Nanotechnology, Biology and MedicineAuthor(s): Sebastian Kallus, Bernhard Englinger, Julia Senkiv, Anna Laemmerer, Petra Heffeter, Walter Berger, Christian R. Kowol, Bernhard K. KepplerAbstractFibroblast growth factor receptor (FGFR) inhibitors like ponatinib and nintedanib are clinically approved for defined cancer patient cohorts but often exert dose-limiting adverse effects. Hence, we encapsulated FGFR inhibitors ponatinib, PD173074, and nintedanib into polylactic acid nanoparticles and liposomes to enable increased tumor accumulation/specificity and reduce side effects. Different methods of drug loading were tested and the resulting formulations compared regarding average size distribution as well as encapsulation efficiency. Appropriate encapsulation levels were achieved for liposomal preparations only. Nanoencapsulation resulted in significantly decelerated uptake kinetics in vitro with clearly decreased short-term (up to 72 hours) cytotoxicity at higher concentrations. However, in long-term clonogenic assays liposomal formations were equally or even more active as compared to the free drugs. Accordingly, in a FGFR inhibitor-sensitive murine osteosarcoma transplantation model (K7 M2), only liposomal but not free ponatinib resulted in significant tumor growth inhibition (by 60.4%) at markedly reduced side effects.Graphical AbstractThe clinically approved FGFR inhibitors ponatinib and ninteda...
Source: Nanomedicine: Nanotechnology, Biology and Medicine - Category: Nanotechnology Source Type: research