Abstract
BackgroundLiposomes are employed as drug delivery vehicles offering a beneficial pharmacokinetic/distribution mechanism for in vivo therapeutics. Therapeutic liposomes can be designed to target specific cell types through the display of epitope-specific targeting peptides on their surface. The majority of peptides are currently attached by chemical modification of lipid constituents. Here we investigate an alternative and novel method of decorating liposomes with targeting ligand, using remotely and spontaneously inserting chimeric tail-anchored membrane (TA) proteins to drug loaded liposomes.Methods and resultsAn artificial TA protein chimera containing the transmembrane domain from the spontaneously inserting TA protein cytochrome b5 (Cytb5) provided a robust membrane tether for the incorporation of three different targeting moieties into preformed liposomes. The moieties investigated were the transactivator of transcription (TAT) peptide, the EGF-receptor binding sequence GE11 and the placental and tumour homing ligand CCGKRK. In all cases, TA protein insertion neither significantly altered the size of the liposomes nor reduced drug loading. The efficacy of this novel targeted delivery system was investigated using two human cell lines, HeLa M and BeWo. Short term incubation with one ligand-modified TA chimera, incorporating the TAT peptide, significantly enhanced liposomal delivery of the encapsulated carboxyfluorescein reporter.ConclusionThe Cytb5 TA was successfully employed as a membrane anchor for the incorporation of the desired peptide ligands into a liposomal drug delivery system, with minimal loss of cargo during insertion. This approach therefore provides a viable alternative to chemical conjugation and its potential to accommodate a wider range of targeting ligands may provide an opportunity for enhancing drug delivery.
Highlights
Encapsulation of cytotoxic chemotherapeutics in liposomes improves their bioavailability and reduces their toxicity to non-cancerous tissue [1,2]
The cytochrome b5 (Cytb5) TA was successfully employed as a membrane anchor for the incorporation of the desired peptide ligands into a liposomal drug delivery system, with minimal loss of cargo during insertion
We have explored an alternative mechanism for anchoring targeting peptides into liposome surfaces, by using a modifiable TA membrane protein chimera that is capable of spontaneous and remote insertion into the lipid bilayer of preformed, drug-loaded liposomes
Summary
Encapsulation of cytotoxic chemotherapeutics in liposomes improves their bioavailability and reduces their toxicity to non-cancerous tissue [1,2]. The chimeric protein was incorporated into drug-loaded liposomes, and the resultant proteoliposomes exhibited enhanced uptake by cells in culture These liposomes suffered significant cargo leakage during the protein insertion reaction, because of its dependence on the presence of detergent [10,11]. We have explored an alternative mechanism for anchoring targeting peptides into liposome surfaces, by using a modifiable TA membrane protein chimera that is capable of spontaneous and remote insertion into the lipid bilayer of preformed, drug-loaded liposomes. We investigate an alternative and novel method of decorating liposomes with targeting ligand, using remotely and spontaneously inserting chimeric tail-anchored membrane (TA) proteins to drug loaded liposomes
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