Targeting liposomes loaded with melphalan prodrug to tumour vasculature via the Sialyl Lewis X selectin ligand

Abstract

Earlier we showed that liposome formulation of DL-melphalan lipophilic prodrug bearing tetrasaccharide Sialyl Lewis X (SiaLe^X) caused prolonged therapeutic effect on mammary cancer in mice. Here, we compare antivascular effect of SiaLe^X-liposomes loaded with diglyceride ester of melphalan (Mlph) against SiaLe^X-free formulation in Lewis lung carcinoma model.

Methods: Liposomes of egg phosphatidylcholine/yeast phosphatidylinositol/1,2-dioleoyl glycerol (DOG) conjugate of Mlph/±SiaLe^X-PEG_8–15-DOG, 8:1:1:0.2 by mol, were prepared by standard extrusion. After two intravenous injections with Mlph or liposomes under either standard or delayed treatment protocols, vascular-disrupting effects of the preparations were evaluated basing on tumour section histomorphology, lectin perfusion assay and immunohistochemistry (anti-CD31 staining) data. Also, untreated mice were administered with fluorescently-labelled liposomes to assess their distribution in tumour sections with confocal laser scanning microscopy.

Results: Two injections of SiaLe^X-liposomes reproducibly caused severe injuries of tumour vessels. SiaLe^X-liposomes co-localized with CD31 marker on vascular endothelium while the non-targeted formulation extravasated into tumour.

Discussion: Cytotoxic SiaLe^X-liposomes exhibit superior vascular-disrupting properties compared to non-targeted liposomes, yet the effect starts to transform into gain in tumour growth inhibition only under delayed treatment regimen.

Conclusion: SiaLe^X-ligand provides targeting of cytotoxic liposomes to tumour endothelium and subsequent antivascular effect.

• Antivascular effect
• drug delivery
• Lewis lung carcinoma
• lipophilic prodrugs
• melphalan
• nanomedicine
• tumour endothelium

Acknowledgements

We thank Dr. Elena Svirshchevskaya for her help with confocal laser scanning microscope operation and Dr. Svetlana Sizova for providing access to the dynamic light scattering equipment.

Supplementary material available online

Supplementary Figures S1--S3