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Traditional liposomes degrade into lower-order micelles when PEGylated to even minor degrees (6-7 mol %) and therefore can offer only limited steric exclusion against opsonization during in vivo delivery. In this work, we present for the first time a liposome coated exclusively by PEGylated phospholipids, utilizing lipid-coated calcium phosphate (CaP) cores of diverse sizes (10-15 nm, 30-40 nm) as well as varying polyethylene glycol (PEG) chain lengths (350-5000 Da). Such fully-PEGylated liposome calcium phosphate (LCP) particles exhibit a PEG chain length-dependent circulation longevity and robust immune evasion, while facilitating both strong accumulation within solid tumors upon intravenous injection and a more rapid and extensive lymphatic drainage upon subcutaneous administration. Further, these fully-PEGylated liposomes remain amenable to active targeting strategies which facilitate improved degrees of focused distribution and nanoparticle uptake, represent a lipid packing density commensurate with the formation of a lipid bilayer, and avoid use of scale-limited physical resuspension methods. We expect such improved delivery properties to translate into improved therapeutic safety and efficacy for a variety of systemic and lymphatic diseases.

Maximizing the Supported Bilayer Phenomenon: Liposomes Comprised Exclusively of PEGylated Phospholipids for Enhanced Systemic and Lymphatic Delivery