Abstract
Endosomal entrapment is a key issue for the intracellular delivery of many nano-sized biotherapeutics to their cytosolic or nuclear targets. Photochemical internalisation (PCI) is a novel light-based solution that can be used to trigger the endosomal escape of a range of bioactive agents into the cytosol leading to improved efficacy in pre-clinical and clinical studies. PCI typically depends upon the endolysosomal colocalisation of the bioactive agent with a suitable photosensitiser that is administered separately. In this study we demonstrate that both these components may be combined for codelivery via a novel multifunctional liposomal nanocarrier, with a corresponding increase in the biological efficacy of the encapsulated agent. As proof of concept, we show here that the cytotoxicity of the 30 kDa protein toxin, saporin, in MC28 fibrosarcoma cells is significantly enhanced when delivered via a cell penetrating peptide (CPP)-modified liposome, with the CPP additionally functionalised with a photosensitiser that is targeted to endolysosomal membranes. This innovation opens the way for the efficient delivery of a range of biotherapeutics by the PCI approach, incorporating a clinically proven liposome delivery platform and using bioorthogonal ligation chemistries to append photosensitisers and peptides of choice.
Highlights
The intracellular delivery of many promising biotherapeutics and nanomedicines is often hampered by endosomal entrapment.[1]
Other researchers have adopted this principle of peptidetargeting with other photoactivatable dyes,[23,24,25,26] and in this context, we recently demonstrated that cell penetrating peptide (CPP)-conjugation can be a very attractive way of repurposing well-known photosensitisers that are clinically approved for photodynamic therapy (PDT) such as chlorin e6, which lack the appropriate physical properties for Photochemical internalisation (PCI).[27]
Building on our previous studies with CPP-conjugated photosensitisers,[21,22] the novel aspect of our nanocarrier approach for PCI is that the photosensitiser moiety that provides an endosomal escape trigger is covalently linked to the carrier in a highly predictable fashion via such a CPP
Summary
The intracellular delivery of many promising biotherapeutics and nanomedicines is often hampered by endosomal entrapment.[1]. An additional issue is that in order for encapsulated agents to exert their effects after internalisation, they must escape the interior of such nanocarriers,[32] which ideally might be effected in a directed fashion by application of an external stimulus such as heat or light.[33,34] Fretz et al have demonstrated that the endosomal entrapment of liposome systems may be overcome by PCI using a conventional coadministered photosensitiser,[35] and such studies have led to considerable recent interest in the development of light-triggered systems where a photosensitiser is loaded into the liposome structure itself to effect the destabilisation of the bilayer membranes of both the endolysosomes where the nanocarrier is entrapped[15] and the liposome nanocarrier itself.[36,37,38,39] this meets the key requirement for PCI of colocalisation of the photosensitiser and entrapped agent, the effectiveness of such systems depends upon the localisation and orientation of a given photosensitiser in the lipid bilayer of the carrier, with incorporation of the photosensitiser itself potentially having a significant effect on the stability of the liposomal formulation.[40]. As a proof of concept for such a modular delivery system, we have incorporated a nano-sized protein toxin within such a tailored liposomal system and examined the light-triggered endosomal release of the entrapped cytotoxin in a fibrosarcoma cell line
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