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

Abstract

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 < 0.01). Addition of BSO enhanced PCI efficacy by a further factor of three (P < 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 < 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 < 0.01). Conclusions: Our findings show the efficacy of PCI can be manipulated and potentiated by modifying the intracellular redox environment.

Paclitaxel-Potentiated Photodynamic Theranostics for Synergistic Tumor Ablation and Precise Anticancer Efficacy Monitoring

“…However, the generated lipid peroxides could disintegrate the cytomembrane and improve membrane permeability 49 and consequently enhance cellular uptake and cytotoxicity of TPCI/ PTX@Lipo. In addition, because of the PCI effect, the TPCIgenerated ROS accelerated the damage of the endosomal membranes 14,15,50,51 and facilitated the subsequent release of the drugs to cytosol, therefore avoiding the degradation of agents by lysosomal enzymes. 52 In fact, we have observed a significant increase in the amount of internalized PTX in PC3 cells (Figure 3F), which boosted the overall cytotoxicity.…”

Synergy between Photodynamic Therapy and Dactinomycin Chemotherapy in 2D and 3D Ovarian Cancer Cell Cultures

“…Following light illumination, the photosensitisers are activated and generate reactive oxygen species (ROS), resulting in partial rupture of the endolysosomes enabling the sequestered agents to escape and reach their intracellular targets. The light and photosensitiser doses employed for PCI are relatively small corresponding to a low dose sub-lethal PDT treatment [12]. The amphiphilic photosensitiser, meso-tetraphenyl porphine disulfonate (TPPS 2a ), which has been employed in our study, bears two sulfonate groups on adjacent phenyl rings of the porphyrin macrocycle (Figure 1A) that can localise to the aqueous-lipid interface of lipid membranes with the unsubstituted more hydrophobic part of the macrocycle lying within the lipid bilayer [13].…”