title: Tumor Microenvironment-Mediated Construction and Deconstruction of Extracellular Drug-Delivery Depots.
abstract: Protein therapy has been considered the most direct and safe approach to treat cancer. Targeting delivery of extracellularly active protein without internalization barriers, such as membrane permeation and endosome escape, is efficient and holds vast promise for anticancer treatment. Herein, we describe a "transformable" core-shell based nanocarrier (designated CS-NG), which can enzymatically assemble into microsized extracellular depots at the tumor site with assistance of hyaluronidase (HAase), an overexpressed enzyme at the tumor microenvironment. Equipped with an acid-degradable modality, the resulting CS-NG can substantially release combinational anticancer drugs-tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) and antiangiogenic cilengitide toward the membrane of cancer cells and endothelial cells at the acidic tumor microenvironment, respectively. Enhanced cytotoxicity on MDA-MB-231 cells and improved antitumor efficacy were observed using CS-NG, which was attributed to the inhibition of cellular internalization and prolonged retention time in vivo.
authors.affiliation: Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University , Raleigh, North Carolina 27695, United States.|Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Quanyin
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University , Raleigh, North Carolina 27695, United States.|Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Wujin
authors.initials: W
authors.lastname: Sun
authors.affiliation: Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University , Raleigh, North Carolina 27695, United States.|Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Yue
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University , Raleigh, North Carolina 27695, United States.|Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Hunter N
authors.initials: HN
authors.lastname: Bomba
authors.affiliation: Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University , Raleigh, North Carolina 27695, United States.|Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Yanqi
authors.initials: Y
authors.lastname: Ye
authors.affiliation: School of Pharmaceutical Sciences, Nanjing Tech University , Nanjing 210000, Jiangsu China.
authors.forename: Tianyue
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Department of Radiology, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27514, United States.
authors.forename: Ari J
authors.initials: AJ
authors.lastname: Isaacson
authors.affiliation: Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University , Raleigh, North Carolina 27695, United States.|Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.|Department of Medicine, University of North Carolina School of Medicine , Chapel Hill, North Carolina 27599, United States.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Gu
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000737:chemistry; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D016503:Drug Delivery Systems; D011992:Endosomes / Q000187:drug effects; D018014:Gene Transfer Techniques; D006801:Humans; D006821:Hyaluronoglucosaminidase / Q000096:biosynthesis / Q000737:chemistry; D051379:Mice; D012910:Snake Venoms / Q000008:administration & dosage* / Q000737:chemistry; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage*; D059016:Tumor Microenvironment / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D012910:Snake Venoms; D053221:TNF-Related Apoptosis-Inducing Ligand; C422910:Cilengitide; D006821:Hyaluronoglucosaminidase
keywords: Drug delivery; antiangiogenesis; apoptosis; stimuli-responsive; tumor microenvironment