title: Mesoporous Silica Nanoparticle-Supported Lipid Bilayers (Protocells) for Active Targeting and Delivery to Individual Leukemia Cells.
abstract: Many nanocarrier cancer therapeutics currently under development, as well as those used in the clinical setting, rely upon the enhanced permeability and retention (EPR) effect to passively accumulate in the tumor microenvironment and kill cancer cells. In leukemia, where leukemogenic stem cells and their progeny circulate within the peripheral blood or bone marrow, the EPR effect may not be operative. Thus, for leukemia therapeutics, it is essential to target and bind individual circulating cells. Here, we investigate mesoporous silica nanoparticle (MSN)-supported lipid bilayers (protocells), an emerging class of nanocarriers, and establish the synthesis conditions and lipid bilayer composition needed to achieve highly monodisperse protocells that remain stable in complex media as assessed in vitro by dynamic light scattering and cryo-electron microscopy and ex ovo by direct imaging within a chick chorioallantoic membrane (CAM) model. We show that for vesicle fusion conditions where the lipid surface area exceeds the external surface area of the MSN and the ionic strength exceeds 20 mM, we form monosized protocells (polydispersity index <0.1) on MSN cores with varying size, shape, and pore size, whose conformal zwitterionic supported lipid bilayer confers excellent stability as judged by circulation in the CAM and minimal opsonization in vivo in a mouse model. Having established protocell formulations that are stable colloids, we further modified them with anti-EGFR antibodies as targeting agents and reverified their monodispersity and stability. Then, using intravital imaging in the CAM, we directly observed in real time the progression of selective targeting of individual leukemia cells (using the established REH leukemia cell line transduced with EGFR) and delivery of a model cargo. Overall, we have established the effectiveness of the protocell platform for individual cell targeting and delivery needed for leukemia and other disseminated disease.
authors.affiliation: Chemical and Biological Engineering, University of New Mexico , 210 University Blvd NE, Albuquerque, New Mexico 87131-0001, United States.|Center for Micro-Engineered Materials, Advanced Materials Laboratory, University of New Mexico , MSC04 2790, 1001 University Blvd SE, Suite 103, Albuquerque, New Mexico 87106, United States.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Durfee
authors.affiliation: Internal Medicine, University of New Mexico , MSC10 5550, 1 University of New Mexico, Albuquerque, New Mexico 87131, United States.|Oncothyreon, Inc. , 2601 Fourth Avenue, Seattle, Washington 98121-3222, United States.
authors.forename: Yu-Shen
authors.initials: YS
authors.lastname: Lin
authors.affiliation: Center for Micro-Engineered Materials, Advanced Materials Laboratory, University of New Mexico , MSC04 2790, 1001 University Blvd SE, Suite 103, Albuquerque, New Mexico 87106, United States.
authors.forename: Darren R
authors.initials: DR
authors.lastname: Dunphy
authors.affiliation: Health Sciences Center, Biochemistry and Molecular Biology, University of New Mexico , MSC08 4670, 1 University of New Mexico, Albuquerque, New Mexico 87131-5001, United States.
authors.forename: Ayşe J
authors.initials: AJ
authors.lastname: Muñiz
authors.affiliation: Center for Micro-Engineered Materials, Advanced Materials Laboratory, University of New Mexico , MSC04 2790, 1001 University Blvd SE, Suite 103, Albuquerque, New Mexico 87106, United States.
authors.forename: Kimberly S
authors.initials: KS
authors.lastname: Butler
authors.affiliation: Biomedical Engineering, Vanderbilt University , 2301 Vanderbilt Place, Nashville, Tennessee 37235-1826, United States.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Humphrey
authors.affiliation: Health Sciences Center, Biochemistry and Molecular Biology, University of New Mexico , MSC08 4670, 1 University of New Mexico, Albuquerque, New Mexico 87131-5001, United States.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Lokke
authors.affiliation: Center for Micro-Engineered Materials, Advanced Materials Laboratory, University of New Mexico , MSC04 2790, 1001 University Blvd SE, Suite 103, Albuquerque, New Mexico 87106, United States.
authors.forename: Jacob O
authors.initials: JO
authors.lastname: Agola
authors.affiliation: Advanced Materials Laboratory, Sandia National Laboratories , 1001 University Blvd. SE, Suite 100, Albuquerque, New Mexico 87106, United States.
authors.forename: Stanley S
authors.initials: SS
authors.lastname: Chou
authors.affiliation: Department of Pathology, University of New Mexico , MSC08 4640, 1 University of New Mexico, Albuquerque, New Mexico 87131-0001, United States.|Comprehensive Cancer Center, The University of New Mexico , MSC07 4025, 1 University of New Mexico, 1201 Camino de Salud NE, Albuquerque, New Mexico 87131-0001, United States.
authors.forename: I-Ming
authors.initials: IM
authors.lastname: Chen
authors.affiliation: Department of Pathology, University of New Mexico , MSC08 4640, 1 University of New Mexico, Albuquerque, New Mexico 87131-0001, United States.|Comprehensive Cancer Center, The University of New Mexico , MSC07 4025, 1 University of New Mexico, 1201 Camino de Salud NE, Albuquerque, New Mexico 87131-0001, United States.
authors.forename: Walker
authors.initials: W
authors.lastname: Wharton
authors.affiliation: Internal Medicine, University of New Mexico , MSC10 5550, 1 University of New Mexico, Albuquerque, New Mexico 87131, United States.|Oncothyreon, Inc. , 2601 Fourth Avenue, Seattle, Washington 98121-3222, United States.
authors.forename: Jason L
authors.initials: JL
authors.lastname: Townson
authors.affiliation: Department of Pathology, University of New Mexico , MSC08 4640, 1 University of New Mexico, Albuquerque, New Mexico 87131-0001, United States.|Comprehensive Cancer Center, The University of New Mexico , MSC07 4025, 1 University of New Mexico, 1201 Camino de Salud NE, Albuquerque, New Mexico 87131-0001, United States.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Willman
authors.affiliation: Chemical and Biological Engineering, University of New Mexico , 210 University Blvd NE, Albuquerque, New Mexico 87131-0001, United States.|Center for Micro-Engineered Materials, Advanced Materials Laboratory, University of New Mexico , MSC04 2790, 1001 University Blvd SE, Suite 103, Albuquerque, New Mexico 87106, United States.|Advanced Materials Laboratory, Sandia National Laboratories , 1001 University Blvd. SE, Suite 100, Albuquerque, New Mexico 87106, United States.|Comprehensive Cancer Center, The University of New Mexico , MSC07 4025, 1 University of New Mexico, 1201 Camino de Salud NE, Albuquerque, New Mexico 87131-0001, United States.
authors.forename: C Jeffrey
authors.initials: CJ
authors.lastname: Brinker
mesh_terms: D000818:Animals; D058045:Artificial Cells; D016503:Drug Delivery Systems; D007938:Leukemia / Q000188:drug therapy*; D008051:Lipid Bilayers; D053768:Metal Nanoparticles; D051379:Mice; D053758:Nanoparticles; D012822:Silicon Dioxide
chemical_list: D008051:Lipid Bilayers; D012822:Silicon Dioxide
keywords: chorioallantoic membrane; colloidal stability; leukemia cell targeting; mesoporous silica nanoparticle; supported lipid bilayer