Lerchbammer-Kreith Yvonne, Hejl Michaela, Sommerfeld Nadine S, Weng-Jiang Xian, Odunze Uchechukwu, Mellor Ryan D, Workman David G, Jakupec Michael A, Schätzlein Andreas G, Uchegbu Ijeoma F, Galanski Mathea S, Keppler Bernhard K
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria.
School of Pharmacy, University College London, Brunswick Square 29-39, London WC1N 1AX, UK.
Pharmaceuticals (Basel). 2023 Jul 19;16(7):1027. doi: 10.3390/ph16071027.
Quaternary ammonium palmitoyl glycol chitosan (GCPQ) has already shown beneficial drug delivery properties and has been studied as a carrier for anticancer agents. Consequently, we synthesised cytotoxic platinum(IV) conjugates of cisplatin, carboplatin and oxaliplatin by coupling via amide bonds to five GCPQ polymers differing in their degree of palmitoylation and quaternisation. The conjugates were characterised by H and Pt NMR spectroscopy as well as inductively coupled plasma mass spectrometry (ICP-MS), the latter to determine the amount of platinum(IV) units per GCPQ polymer. Cytotoxicity was evaluated by the MTT assay in three human cancer cell lines (A549, non-small-cell lung carcinoma; CH1/PA-1, ovarian teratocarcinoma; SW480, colon adenocarcinoma). All conjugates displayed a high increase in their cytotoxic activity by factors of up to 286 times compared to their corresponding platinum(IV) complexes and mostly outperformed the respective platinum(II) counterparts by factors of up to 20 times, also taking into account the respective loading of platinum(IV) units per GCPQ polymer. Finally, a biodistribution experiment was performed with an oxaliplatin-based GCPQ conjugate in non-tumour-bearing BALB/c mice revealing an increased accumulation in lung tissue. These findings open promising opportunities for further tumouricidal activity studies especially focusing on lung tissue.
棕榈酰化乙二醇壳聚糖季铵盐（GCPQ）已显示出良好的药物递送特性，并已作为抗癌剂的载体进行研究。因此，我们通过酰胺键将顺铂、卡铂和奥沙利铂的细胞毒性铂（IV）共轭物与五种棕榈酰化和季铵化程度不同的GCPQ聚合物偶联合成。通过氢核磁共振光谱和铂核磁共振光谱以及电感耦合等离子体质谱（ICP-MS）对共轭物进行表征，后者用于确定每个GCPQ聚合物中铂（IV）单元的含量。通过MTT法在三种人类癌细胞系（A549，非小细胞肺癌；CH1/PA-1，卵巢畸胎瘤；SW480，结肠腺癌）中评估细胞毒性。与相应的铂（IV）配合物相比，所有共轭物的细胞毒性活性均显著提高，提高倍数高达286倍，并且在考虑每个GCPQ聚合物中铂（IV）单元的各自负载量的情况下，大多比各自的铂（II）对应物表现出高达20倍的优势。最后，用基于奥沙利铂的GCPQ共轭物在无肿瘤的BALB/c小鼠中进行了生物分布实验，结果显示肺组织中的积累增加。这些发现为进一步的杀肿瘤活性研究，尤其是针对肺组织的研究，开辟了有希望的机会。
