(584a) Triggered Binding Activity of Anti-HER2/Neu Lipid Vesicles Encapsulating Doxorubicin Enhances Tumor Control In Vivo While Preserving the Potential for Low Toxicities

Ligand-mediated uptake of nanometer-sized drug carriers by cancer cells is usually necessary, since extravasated non-targeted nanocarriers into the tumor interstitium may not associate extensively and fast with the cancer cells that constitute the tumor.  Typically, though, in cancer cells the extracellular leaflet of their plasma membrane is not characterized by unique molecular targets but by overexpression of antigens that are relatively downregulated in healthy cells. Consequently, during circulation in the blood, conventionally targeted drug delivery carriers with “exposed” targeting ligands would specifically bind to receptors expressed by non-cancerous cells ultimately increasing toxicities. Toxicities may also increase due to uptake of carriers by reticuloendothelial cells identifying the targeting ligands during circulation of carriers.

To enable selective cell-kill, we designed functionalized lipid vesicles with pH-triggered heterogeneous membranes and encapsulated doxorubicin that exhibit tunable surface topography. These vesicles “hide” (mask) the targeting ligands from their surface during circulation in the blood, and only progressively “expose” these ligands as they gradually penetrate deeper into the tumor interstitium, where after endocytosis they burst-release their contents. The stimulus to activate the binding reactivity is the pH gradient between the blood stream (pH 7.4–7.0) and the increasingly acidic pH inside the tumor interstitium (pH 6.7–6.0). Doxorubicin release is activated at the endosomal pH 5.5–5.0. In vitro, these targeted vesicles exhibit superior killing efficacy of cancer cells - with lowering the extracellular pH from 7.4 to 6.0 - compared to established liposome formulations. In vivo, in a murine vascularized breast cancer model, these antiHER2/neu-short-peptide vesicles loaded with doxorubicin exhibit superior tumor control compared to established formulations of liposomal doxorubicin labeled with identical antiHER2/neu peptides. Our findings demonstrate the potential of targeted lipid vesicles with triggered binding reactivity to increase the therapeutic efficacy of targeted immunochemotherapy while keeping toxicities and potential immunoreactivity to a minimum.