Modification with
polyethylene glycol (PEGylation) and the use of rigid
phospholipids drastically improve the pharmacokinetics of chemotherapeutics and result in more manageable or reduced side-effects. A major drawback is retarded cellular delivery of content, which, along with
tumor heterogeneity, are the two main obstacles against
tumor targeting. To enhance cellular delivery and reach a bigger area of a
tumor, we designed
liposomes decorated with two
ligands: one for targeting
tumor vasculature via a cyclic-pentapeptide containing
arginine-glycine-aspartic acid (RGD), which impacts
tumor independent of passive accumulation inside
tumors, and one for extravascular targeting of
tumor cells via a
cell-penetrating peptide derived from human immunodeficiency virus type 1
transactivator of transcription (TAT).
Liposomes with different
ligand combinations were prepared and compared with respect to performance in targeting. Intravital imaging illustrates the heterogeneous behavior of RGD-
liposomes in both intravascular and extravascular distribution, whereas TAT-
liposomes exhibit a predictable extravascular localization but no intravascular targeting. Dual-
ligand modification results in enhanced vascular targeting and a predictable extravascular behavior that improves the therapeutic efficacy of
doxorubicin-loaded
liposomes but also an augmented clearance rate of
liposomes. However, the dual-modified
liposome could be a great candidate for targeted delivery of non-toxic payloads or
contrast agents for therapeutic or diagnostic purposes. Here we show that the combination of vascular-specific and
tumor cell-specific
ligands in a liposomal system is beneficial in bypassing the heterogeneous expression of
tumor-specific markers.