title: Masking and triggered unmasking of targeting ligands on liposomal chemotherapy selectively suppress tumor growth in vivo.
abstract: We investigated the feasibility and efficacy of a drug delivery strategy to vascularized cancer that combines targeting selectivity with high uptake by targeted cells and high bioexposure of cells to delivered chemotherapeutics. Targeted lipid vesicles composed of pH responsive membranes were designed to reversibly form phase-separated lipid domains, which are utilized to tune the vesicle's apparent functionality and permeability. During circulation, vesicles mask functional ligands and stably retain their contents. Upon extravasation in the tumor interstitium, ligand-labeled lipids become unmasked and segregated within lipid domains triggering targeting to cancer cells followed by internalization. In the acidic endosome, vesicles burst release the encapsulated therapeutics through leaky boundaries around the phase-separated lipid domains. The pH tunable vesicles contain doxorubicin and are labeled with an anti-HER2 peptide. In vitro, anti-HER2 pH tunable vesicles release doxorubicin in a pH dependent manner, and exhibit 233% increase in binding to HER2-overexpressing BT474 breast cancer cells with lowering pH from 7.4 to 6.5 followed by significant (50%) internalization. In subcutaneous BT474 xenografts in nude mice, targeted pH tunable vesicles decrease tumor volumes by 159% relative to nontargeted vesicles, and they also exhibit better tumor control by 11% relative to targeted vesicles without an unmasking property. These results suggest the potential of pH tunable vesicles to ultimately control tumor growth at relatively lower administered doses.
authors.affiliation: Department of Biomedical Engineering and Department of Chemical and Biochemical Engineering, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States.
authors.forename: Amey
authors.initials: A
authors.lastname: Bandekar
authors.forename: Charles
authors.initials: C
authors.lastname: Zhu
authors.forename: Ana
authors.initials: A
authors.lastname: Gomez
authors.forename: Monica Zofia
authors.initials: MZ
authors.lastname: Menzenski
authors.forename: Michelle
authors.initials: M
authors.lastname: Sempkowski
authors.forename: Stavroula
authors.initials: S
authors.lastname: Sofou
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D011992:Endosomes / Q000378:metabolism; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008024:Ligands; D008055:Lipids / Q000008:administration & dosage* / Q000737:chemistry; D008081:Liposomes / Q000008:administration & dosage* / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010539:Permeability / Q000187:drug effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D008024:Ligands; D008055:Lipids; D008081:Liposomes; D018719:Erb-b2 Receptor Tyrosine Kinases