Platinum(IV)-Loaded Degraded Glycol Chitosan as Efficient Platinum(IV) Drug Delivery Platform

Author(s): Yvonne Lerchbammer-Kreith, Nadine S. Sommerfeld, Klaudia Cseh, Xian Weng-Jiang, Uchechukwu Odunze, Andreas G. Schätzlein, Ijeoma F. Uchegbu, Mathea S. Galanski, Michael A. Jakupec, Bernhard K. Keppler
Abstract: 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 ¹H and ¹⁹⁵Pt 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). IC₅₀ 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 (IC₅₀ 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.
Organisation(s): Department of Inorganic Chemistry, NMR Centre
External organisation(s): University College London, Research Cluster Translational Cancer Therapy Research
Journal: Pharmaceutics
Volume: 15
DOI: https://doi.org/10.3390/pharmaceutics15041050
Publication date: 04-2023
Peer reviewed: Yes
Austrian Fields of Science 2012: 301209 Pharmacy, 301206 Pharmacology, 104003 Inorganic chemistry, 301904 Cancer research
Keywords
ASJC Scopus subject areas: Pharmaceutical Science
Sustainable Development Goals: SDG 3 - Good Health and Well-being
Portal url: https://ucrisportal.univie.ac.at/en/publications/f466fa16-a3f4-435f-ae28-0e97a77db09a