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. 2023 Jul 19;16(7):1027.
doi: 10.3390/ph16071027.

Quaternary Ammonium Palmitoyl Glycol Chitosan (GCPQ) Loaded with Platinum-Based Anticancer Agents-A Novel Polymer Formulation for Anticancer Therapy

Yvonne Lerchbammer-Kreith  1 , Michaela Hejl  1 , Nadine S Sommerfeld  1 , Xian Weng-Jiang  2 , Uchechukwu Odunze  2 , Ryan D Mellor  2 , David G Workman  2 , Michael A Jakupec  1   3 , Andreas G Schätzlein  2 , Ijeoma F Uchegbu  2 , Mathea S Galanski  1 , Bernhard K Keppler  1   3
Affiliations

Quaternary Ammonium Palmitoyl Glycol Chitosan (GCPQ) Loaded with Platinum-Based Anticancer Agents-A Novel Polymer Formulation for Anticancer Therapy

Yvonne Lerchbammer-Kreith et al. Pharmaceuticals (Basel). .

Abstract

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 1H and 195Pt 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.

Keywords: anticancer; drug delivery; platinum(IV) complexes; quaternary ammonium glycol chitosan (GCPQ).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Synthetic steps for preparation of GCPQ polymers starting from degraded glycol chitosan (dGC), containing approximately 5% of acetylated monomers. (i) Palmitic acid N-hydroxysuccinimide (PNS), DMSO/triethylamine (TEA), (ii) sodium hydroxide, sodium iodide, methyl iodide, N-methyl-2-pyrrolidon (NMP), nitrogen atmosphere. Following monomers are shown: (a) acetylated GC, (b) palmitoylated GC, (c) quaternised GC, (d) dimethylamine GC, (e) methylamine GC, (f) GC.
Scheme 2
Scheme 2
Illustration of the coupling reaction of platinum(IV) complexes 1–3 to five different GCPQ polymers resulting in conjugates C1–C11, V1.
Figure 1
Figure 1
Comparison of the biodistribution investigation of platinum(IV) complex 3 and conjugate V1 showing the accumulation of platinum in different organs 1 h after administration (complex 3: n = 5, conjugate V1: n = 4). The values are presented as mean ± SD. The data of complex 3 were published previously [19].
Figure 2
Figure 2
For the biodistribution, unpaired t-test with Welch’s correction was conducted for the determination of significances using following abbreviations: ns = not significant, * p < 0.05, ** p < 0.01. The values are presented as mean ± SEM.
See this image and copyright information in PMC

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