title: Sticky Patches on Lipid Nanoparticles Enable the Selective Targeting and Killing of Untargetable Cancer Cells.
abstract: Effective targeting by uniformly functionalized nanoparticles is limited to cancer cells expressing at least two copies of targeted receptors per nanoparticle footprint (approximately ≥2 × 10(5) receptor copies per cell); such a receptor density supports the required multivalent interaction between the neighboring receptors and the ligands from a single nanoparticle. To enable selective targeting below this receptor density, ligands on the surface of lipid vesicles were displayed in clusters that were designed to form at the acidic pH of the tumor interstitium. Vesicles with clustered HER2-targeting peptides within such sticky patches (sticky vesicles) were compared to uniformly functionalized vesicles. On HER2-negative breast cancer cells MDA-MB-231 and MCF7 {expressing (8.3 ± 0.8) × 10(4) and (5.4 ± 0.9) × 10(4) HER2 copies per cell, respectively}, only the sticky vesicles exhibited detectable specific targeting (KD ≈ 49-69 nM); dissociation (0.005-0.009 min(-1)) and endocytosis rates (0.024-0.026 min(-1)) were independent of HER2 expression for these cells. MDA-MB-231 and MCF7 were killed only by sticky vesicles encapsulating doxorubicin (32-40% viability) or α-particle emitter (225)Ac (39-58% viability) and were not affected by uniformly functionalized vesicles (>80% viability). Toxicities on cardiomyocytes and normal breast cells (expressing HER2 at considerably lower but not insignificant levels) were not observed, suggesting the potential of tunable clustered ligand display for the selective killing of cancer cells with low receptor densities.
authors.forename: Michelle
authors.initials: M
authors.lastname: Sempkowski
authors.forename: Charles
authors.initials: C
authors.lastname: Zhu
authors.affiliation: Department of Chemistry, New York University , New York, New York 10003, United States.
authors.forename: Monica Zofia
authors.initials: MZ
authors.lastname: Menzenski
authors.affiliation: Department of Chemical and Biological Engineering, Program in Applied and Computational Mathematics, Princeton University , A319 Engineering Quad, Princeton, New Jersey 08544, United States.
authors.forename: Ioannis G
authors.initials: IG
authors.lastname: Kevrekidis
authors.affiliation: European Commission, Joint Research Centre, Institute for Transuranium Elements , P.O. Box 2340, D-76125 Karlsruhe, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Bruchertseifer
authors.affiliation: European Commission, Joint Research Centre, Institute for Transuranium Elements , P.O. Box 2340, D-76125 Karlsruhe, Germany.
authors.forename: Alfred
authors.initials: A
authors.lastname: Morgenstern
authors.forename: Stavroula
authors.initials: S
authors.lastname: Sofou
mesh_terms: D000186:Actinium / Q000008:administration & dosage; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D004705:Endocytosis; D005260:Female; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008055:Lipids / Q000737:chemistry*; D061986:MCF-7 Cells; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D036103:Nanotechnology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism
chemical_list: D000186:Actinium; D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D008024:Ligands; D008055:Lipids; D018719:Erb-b2 Receptor Tyrosine Kinases; C000615155:Actinium-225; C508053:ERBB2 protein, human