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Background : Photochemical internalisation (PCI) is a light-triggered and site-specific technique that enhances the delivery of therapeutic agents to their intracellular targets using amphiphilic, photosensitizing agents. Methods : This study investigated the effect that the intracellular redox environment of 4T1 breast cancer cells exerts on PCI-facilitated delivery of the type I ribosome inactivating protein, saporin, and the topoisomerase inhibitor, mitoxantrone, either individually or in combination. Buthionine sulfoximime (BSO), a clinically used inhibitor of glutathione synthesis, and the singlet oxygen scavenger, l-histidine, were used to enhance the oxidative and reductive state of the cells respectively. Results : PCI of saporin at 30 nM was effective in reducing cellular viability, which decreased to 16% compared to "dark" controls ( P &lt; 0.01). Addition of BSO enhanced PCI efficacy by a further factor of three ( P &lt; 0.01), but addition of l-histidine completely inhibited cytotoxicity induced by PCI. The combination of the two cytotoxic agents, saporin and mitoxantrone, with PCI, elicited 14% and 17% reduction in cell viability ( P &lt; 0.01) compared to PCI with saporin alone and mitoxantrone alone respectively. Combination treatment with BSO resulted in a further significant reduction in cell viability by 18% ( P &lt; 0.01). Conclusions : Our findings show the efficacy of PCI can be manipulated and potentiated by modifying the intracellular redox environment.

rsc advances

The intracellular redox environment modulates the cytotoxic efficacy of single and combination chemotherapy in breast cancer cells using photochemical internalisation