Supramolecular self-associating amphiphiles (SSAs) as nanoscale enhancers of cisplatin anticancer activity

Abstract

Many chemotherapeutic drugs have a narrow therapeutic window due to inefficient tumour cell permeation. Supramolecular self-associating amphiphilic salts (SSAs) are a unique class of small molecules that offer potential as next generation cancer drugs and/or therapeutic enhancement agents. Herein, we demonstrate the cytotoxicity of seven SSAs towards both ovarian and glioblastoma cancer cells. We also utilize the intrinsic fluorescent properties of one of these lead SSAs to provide evidence for this class of compound to both bind to the exterior cancer cell surface and permeate the cell membrane, to become internalized. Furthermore, we demonstrate synergistic effects of two lead SSAs on cisplatin-mediated cytotoxicity of ovarian cancer cells and show that this correlates with increased DNA damage and apoptosis versus either agent alone. This work provides the first evidence that SSAs interact with and permeate cancer cell membranes and enhance the cytotoxic activity of a chemotherapeutic drug in human cancer cells.

Fig. 1. Chemical structure of cisplatin and SSAs 1–7. TBA = tetrabutylammonium, TMA = tetramethylammonium, TPA = tetrapropylammonium.

Fig. 2. Cartoon illustrating the hypothesised mode of SSA anticancer activity, where the SSAs arrive at the cancer cell surface as self-associated spherical aggregates (evidence provided in previously published data). The SSAs initially interact with the external cell surface to form a coating and are then internalised (evidence provided in Fig. 3). This process enhances the efficacy of the cancer drug cisplatin, upon addition after prior incubation of the cells with an SSA (evidence provided in Fig. 4 and 5).

Fig. 3. Live cell imaging fluorescence microscopy images of: (a) untreated A2780 cells; (b) A2780 cells after addition of 6 (90 μM); (c) untreated U87MG cells; (d) U87MG cells after addition of 6 (600 μM). Scale bar represents 10 μm.

Fig. 4. CI values obtained for 1 and 6 pre-incubated with A2780 cells for one hour before addition of cisplatin and then 96 hour incubation, followed by SRB assay. Each assay comprised n = 3 technical replicates and is representative of three independent experiments. 0.30–0.70 = synergism; 0.70–0.85 = moderate synergism; 0.85–0.95 = slight synergism; 0.95–1.05 = additive; >1.05 = antagonism.

Fig. 5. Western blot of A2780 cells treated with high (approx. 10 × GI₅₀) and low (GI₅₀) concentrations of 1 and cisplatin, after 24 hours incubation. GAPDH used as loading control. Data representative of n = 3.