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  • Methods Very briefly PLA polymeric

    2021-11-24

    Methods Very briefly: PLA polymeric nanoparticles as well as liposomes were synthesized and loaded with three different FGFR inhibitors. The encapsulation efficiency, average size, PDI, zeta potential, stability and release kinetics were investigated. The most promising formulations were biologically investigated by MTT cytotoxicity assays, Western blot, ERK/AKT phosphorylation levels, cellular uptake via flow cytometry and in vivo studies.
    Results
    Discussion Liposomal drug formulations are an established and very important tool to improve the efficacy and tolerability of anticancer drugs. This is illustrated by the approval of liposomal formulations of doxorubicin (Doxil®, Myocet® and Lipodox®), daunorubicin (DaunoXome®), vincristine (Marqibo®) and mifamurtide (Mepact®).35, 36 Additionally, many other liposomal formulations for classical chemotherapeutics, like e.g. of cisplatin and paclitaxel, are currently under clinical evaluation.35, 36 However, in case of the large class of targeted anticancer agents, clinical approvals of liposomal preparations are so far missing and only a number of preclinical studies have been reported. These include for instance the clinically used tyrosine kinase inhibitors (TKIs) sunitinib, imatinib, gefitinib and cabozantinib,38, 39, 40, 41, 42 but also experimental compounds such as the pan-kinase inhibitor staurosporine or the VEGFR2 inhibitor apatinib.43, 44 In addition, some studies have addressed nanoparticle-based co-delivery of cytotoxic drugs with a TKI like paclitaxel with lapatinib and doxorubicin with erlotinib. With respect to cancer nanomedicine, FGFRs have been frequently used as targets for tumor-selective delivery strategies of chemotherapeutics-loaded nanoparticles.46, 47, 48, 49 In contrast, regarding FGFRs as therapeutic target per se, solely one very recent publication for ponatinib encapsulated into polymeric Nepafenac with and without a Janus kinase 2 (JAK2) inhibitor is available. Concerning the liposomal stability, relatively similar values were reported in these studies for the different encapsulated drugs. In case of the liposomal sunitinib formulation, 18% of sunitinib were released after 48 h. Comparably, for the liposomal imatinib, gefitinib and cabozantinib formulations between ~20 and 40% release after 48 h was reported, respectively.40, 41, 42 For the drug combination studies of classical chemotherapeutic agents and TKIs, slightly faster release kinetics (~ 70% after 48 h) compared to the nanoformulations of only a single TKI were observed.30, 45 In comparison, our liposomal formulations of ponatinib, PD173074 and nintedanib showed very high stability with respect to size, PDI and zeta potential and the release kinetics with <10% in 48 h (only in case of nintedanib using the Float-A-Lyzer tubes 16% release after 48 h were measured). The EE of the liposomal formulations of sunitinib, imatinib and cabozantinib was reported to be between 80 and 90%.39, 40, 42 In contrast, for gefitinib a broad range from 20 to 90% EE, depending on the lipids used for preparation, was observed. The EE of our nintedanib and PD173074 liposomes was moderate with 34 ± 10 and Nepafenac 23 ± 1%, respectively, and only for ponatinib a very high EE of 92 ± 7% could be achieved. This indicates that the EE strongly depends on the exact chemical nature and physico-chemical properties of the encapsulated inhibitor. Notably, in the recently reported polymeric micelles of ponatinib the EE was extremely low with only around 3%. It is worth mentioning that also in this work encapsulation into polymeric nanoparticles was very ineffective with an EE between 2 and 6% only. The significantly higher EE into liposomes compared to the polymeric nanoparticles might be due to stronger interaction of the lipid bilayer with the very lipophilic drugs compared to polylactic acid of the polymeric micelles/nanoparticles. Hence, encapsulation into liposomes seems to be of great advantage to achieve high-loaded nanoformulations.