| Autor: |
Lerchbammer-Kreith Y; Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria., Sommerfeld NS; Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria., Cseh K; Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria., Weng-Jiang X; School of Pharmacy, University College London, Brunswick Square 29-39, London WC1N 1AX, UK., Odunze U; School of Pharmacy, University College London, Brunswick Square 29-39, London WC1N 1AX, UK., Schätzlein AG; School of Pharmacy, University College London, Brunswick Square 29-39, London WC1N 1AX, UK., Uchegbu IF; School of Pharmacy, University College London, Brunswick Square 29-39, London WC1N 1AX, UK., Galanski MS; Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria., Jakupec MA; Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria.; Research Cluster 'Translational Cancer Therapy Research', University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria., Keppler BK; Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria.; Research Cluster 'Translational Cancer Therapy Research', University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria. |
| Abstrakt: |
A new class of anticancer prodrugs was designed by combining the cytotoxicity of platinum(IV) complexes and the drug carrier properties of glycol chitosan polymers: Unsymmetrically carboxylated platinum(IV) analogues of cisplatin, carboplatin and oxaliplatin, namely (OC-6-44)-acetatodiammine(3-carboxypropanoato)dichloridoplatinum(IV), (OC-6-44)-acetaodiammine(3-carboxypropanoato)(cyclobutane-1,1-dicarboxylato)platinum(IV) and (OC-6-44)-acetato(3-carboxypropanoato)(1R,2R-cyclohexane-1,2-diamine)oxalatoplatinum(IV) were synthesised and conjugated via amide bonding to degraded glycol chitosan (dGC) polymers with different chain lengths (5, 10, 18 kDa). The 15 conjugates were investigated with 1 H and 195 Pt NMR spectroscopy, and average amounts of platinum(IV) units per dGC polymer molecule with ICP-MS, revealing a range of 1.3-22.8 platinum(IV) units per dGC molecule. Cytotoxicity was tested with MTT assays in the cancer cell lines A549, CH1/PA-1, SW480 (human) and 4T1 (murine). IC 50 values in the low micromolar to nanomolar range were obtained, and higher antiproliferative activity (up to 72 times) was detected with dGC-platinum(IV) conjugates in comparison to platinum(IV) counterparts. The highest cytotoxicity (IC 50 of 0.036 ± 0.005 µM) was determined in CH1/PA-1 ovarian teratocarcinoma cells with a cisplatin(IV)-dGC conjugate, which is hence 33 times more potent than the corresponding platinum(IV) complex and twice more potent than cisplatin. Biodistribution studies of an oxaliplatin(IV)-dGC conjugate in non-tumour-bearing Balb/C mice showed an increased accumulation in the lung compared to the unloaded oxaliplatin(IV) analogue, arguing for further activity studies. |
