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.
Highlights
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
Photochemical internalisation (PCI) is a novel drug delivery platform derived from photodynamic therapy (PDT) that can enhance the delivery of molecules that become sequestered within endolysosomes into the cytosol.[2]
Since enhanced cytotoxicity using PCI of saporin is triggered by sub-lethal PDT, we studied the effect of buthionine sulfoximine (BSO) on the PDT response
Summary
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. Many mechanisms contribute to drug resistance, poor accessibility to intracellular targets is a signi cant factor.[1] Entrapment and degradation of drugs within endolysosomes is one of the key challenges to overcome for efficient delivery to intracellular targets. This problem applies to macromolecular therapeutics taken up via endocytosis as well as smaller agents that are weak bases and susceptible to ion-trapping following protonation within the acidic lysosomes. Light activation of the photosensitiser results in the formation of reactive oxygen
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