In non-phagocytic cells such as endothelial cells, processing of liposomes and subsequent release of drug content is often inefficient due to the absence of professional processing machinery, which limits pharmacological efficacy. We therefore developed a liposome based drug delivery system with superior intracellular release characteristics. The design was based on long circulating conventional liposomes that were formulated with a cationic amphiphile, 1-methyl-4-(cis-9-dioleyl)methyl-pyridinium-chlorid (SAINT-C18). These so-called SAINT-O-Somes had a diameter of 100 nm, were as stable as conventionally formulated liposomes, and showed superior release of their content at pH conditions that liposomes encounter when they are endocytosed by cells. Attachment of anti-E-selectin specific antibodies to the distal end of surface grafted poly(ethylene glycol) resulted in immuno-SAINT-O-Somes that were as efficiently taken up by inflammation activated endothelial cells as conventional anti-E-selectin specific immunoliposomes. More importantly, intracellular release of calcein encapsulated in these targeted SAINT-O-Somes was 10 fold higher as compared to the release of calcein from conventional liposomes. For intracellular delivery siRNA into activated endothelial cells, formulation with SAINT-C18 was a necessity to induce a specific down-regulation of gene expression of VE-cadherin. Additionally, targeted doxorubicin loaded SAINT-O-Somes decreased endothelial cell viability significantly more than targeted conventional doxorubicin liposomes. SAINT-O-Somes therefore represent a new class of lipid based particles with superior drug release characteristics that can be applied for the efficacious intracellular delivery of hydrophilic drugs including siRNA.
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