Abstract
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.
Highlights
Liposomes are spherical bilayers resulting from the self-assembly of phospholipids in an aqueous environment
Improved stealth and stability trade off intracellular drug delivery due to the steric hindrance effect of Polyethylene glycol (PEG) moieties that minimize liposome–cell interactions and the limited drug release through the rigid liposomal bilayer where drug delivery into cells mainly hinges on accidental uptake or slow drug release from these stable liposomes, which challenges the anti-tumor efficacy of PEGylated liposomes compared to their non-PEGylated counterparts [10,11]
The free functionalized PEG lipids were almost completely consumed by the reaction with free peptides (Figure 1(b3,c3)), and the corresponding mass of free lipids increased proportionally with the molecular weight of free peptides (Figure 1(b4,c3)), indicating the formation of lipopeptides with an efficiency of about 100% with respect to lipid consumption
Summary
Liposomes are spherical bilayers resulting from the self-assembly of phospholipids in an aqueous environment Their application for drug delivery was first proposed by Gregoriadis about half a century ago [1]. High stability due to a rigid and impermeable lipid bilayer, stealth behavior because of a hydrophilic PEG coat, a size around 90 nm, highly efficient encapsulation yield, and a high drug-to-lipid ratio due to remote loading of doxorubicin (DXR) are beneficial features of PLD that guarantee long and stable circulation with restricted distribution volume to the blood pool [4], a reduction in lethal side effects [2,5,6,7] of DXR, and increased DXR delivery to tumors compared to administration of free DXR [8,9]. Improved stealth and stability trade off intracellular drug delivery due to the steric hindrance effect of PEG moieties that minimize liposome–cell interactions and the limited drug release through the rigid liposomal bilayer where drug delivery into cells mainly hinges on accidental uptake or slow drug release from these stable liposomes, which challenges the anti-tumor efficacy of PEGylated liposomes compared to their non-PEGylated counterparts [10,11]
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