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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 in this research, 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 opsonizationmore » 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. In conclusion, overall we have established the effectiveness of the protocell platform for individual cell targeting and delivery needed for leukemia and other disseminated disease.« less

Authors:
 [1];  [2];  [3];  [4];  [3];  [5];  [4];  [3];  [6];  [7];  [8];  [2];  [8];  [9]
  1. Univ. of New Mexico, Albuquerque, NM (United States). Dept. of Chemical and Biological Engineering; Univ. of New Mexico, Albuquerque, NM (United States). Center for Micro-Engineered Materials, Advanced Materials Lab.
  2. Univ. of New Mexico, Albuquerque, NM (United States). Internal Medicine; Oncothyreon, Inc., Seattle, WA (United States)
  3. Univ. of New Mexico, Albuquerque, NM (United States). Center for Micro-Engineered Materials, Advanced Materials Lab.
  4. Univ. of New Mexico, Albuquerque, NM (United States). Health Sciences Center, Biochemistry and Molecular Biology
  5. Vanderbilt Univ., Nashville, TN (United States). Dept. of Biomolecular Engineering
  6. Sandia National Lab. (SNL-CA), Livermore, CA (United States). Advanced Materials Lab.
  7. Univ. of New Mexico, Albuquerque, NM (United States). Dept. of Pathology; Univ. of New Mexico, Albuquerque, NM (United States). Comprehensive Cancer Center
  8. Univ. of New Mexico, Albuquerque, NM (United States). Dept. of Pathology; Univ. of New Mexico, Albuquerque, NM (United States). Comprehensive Cancer Center
  9. Univ. of New Mexico, Albuquerque, NM (United States). Dept. of Chemical and Biological Engineering; Univ. of New Mexico, Albuquerque, NM (United States). Center for Micro-Engineered Materials, Advanced Materials Lab.; Sandia National Lab. (SNL-NM), Albuquerque, NM (United States). Advanced Materials Lab.; Univ. of New Mexico, Albuquerque, NM (United States). Comprehensive Cancer Center
Publication Date:
Research Org.:
Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)
Sponsoring Org.:
USDOE National Nuclear Security Administration (NNSA); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Institutes of Health (NIH); National Science Foundation (NSF); US Air Force Office of Scientific Research (AFOSR)
OSTI Identifier:
1340264
Report Number(s):
SAND-2016-12522J
Journal ID: ISSN 1936-0851; 649845
Grant/Contract Number:
AC04-94AL85000; FA 9550-1-14-066; 1344298; DBI-1266377; UO1 CA151792-01
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
ACS Nano
Additional Journal Information:
Journal Volume: 10; Journal Issue: 9; Journal ID: ISSN 1936-0851
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; chorioallantoic membrane; colloidal stability; leukemia cell targeting; mesoporous silica nanoparticle; supported lipid bilayer

Citation Formats

Durfee, Paul N., Lin, Yu-Shen, Dunphy, Darren R., Muñiz, Ayşe J., Butler, Kimberly S., Humphrey, Kevin R., Lokke, Amanda J., Agola, Jacob O., Chou, Stanley S., Chen, I-Ming, Wharton, Walker, Townson, Jason L., Willman, Cheryl L., and Brinker, C. Jeffrey. Mesoporous Silica Nanoparticle-Supported Lipid Bilayers (Protocells) for Active Targeting and Delivery to Individual Leukemia Cells. United States: N. p., 2016. Web. doi:10.1021/acsnano.6b02819.
Durfee, Paul N., Lin, Yu-Shen, Dunphy, Darren R., Muñiz, Ayşe J., Butler, Kimberly S., Humphrey, Kevin R., Lokke, Amanda J., Agola, Jacob O., Chou, Stanley S., Chen, I-Ming, Wharton, Walker, Townson, Jason L., Willman, Cheryl L., & Brinker, C. Jeffrey. Mesoporous Silica Nanoparticle-Supported Lipid Bilayers (Protocells) for Active Targeting and Delivery to Individual Leukemia Cells. United States. doi:10.1021/acsnano.6b02819.
Durfee, Paul N., Lin, Yu-Shen, Dunphy, Darren R., Muñiz, Ayşe J., Butler, Kimberly S., Humphrey, Kevin R., Lokke, Amanda J., Agola, Jacob O., Chou, Stanley S., Chen, I-Ming, Wharton, Walker, Townson, Jason L., Willman, Cheryl L., and Brinker, C. Jeffrey. 2016. "Mesoporous Silica Nanoparticle-Supported Lipid Bilayers (Protocells) for Active Targeting and Delivery to Individual Leukemia Cells". United States. doi:10.1021/acsnano.6b02819. https://www.osti.gov/servlets/purl/1340264.
@article{osti_1340264,
title = {Mesoporous Silica Nanoparticle-Supported Lipid Bilayers (Protocells) for Active Targeting and Delivery to Individual Leukemia Cells},
author = {Durfee, Paul N. and Lin, Yu-Shen and Dunphy, Darren R. and Muñiz, Ayşe J. and Butler, Kimberly S. and Humphrey, Kevin R. and Lokke, Amanda J. and Agola, Jacob O. and Chou, Stanley S. and Chen, I-Ming and Wharton, Walker and Townson, Jason L. and Willman, Cheryl L. and Brinker, C. Jeffrey},
abstractNote = {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 in this research, 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. In conclusion, overall we have established the effectiveness of the protocell platform for individual cell targeting and delivery needed for leukemia and other disseminated disease.},
doi = {10.1021/acsnano.6b02819},
journal = {ACS Nano},
number = 9,
volume = 10,
place = {United States},
year = 2016,
month = 7
}

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Cited by: 6works
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  • Abstract not provided.
  • The present invention is directed to protocells for specific targeting of hepatocellular and other cancer cells which comprise a nanoporous silica core with a supported lipid bilayer; at least one agent which facilitates cancer cell death (such as a traditional small molecule, a macromolecular cargo (e.g. siRNA or a protein toxin such as ricin toxin A-chain or diphtheria toxin A-chain) and/or a histone-packaged plasmid DNA disposed within the nanoporous silica core (preferably supercoiled in order to more efficiently package the DNA into protocells) which is optionally modified with a nuclear localization sequence to assist in localizing protocells within the nucleusmore » of the cancer cell and the ability to express peptides involved in therapy (apoptosis/cell death) of the cancer cell or as a reporter, a targeting peptide which targets cancer cells in tissue to be treated such that binding of the protocell to the targeted cells is specific and enhanced and a fusogenic peptide that promotes endosomal escape of protocells and encapsulated DNA. Protocells according to the present invention may be used to treat cancer, especially including hepatocellular (liver) cancer using novel binding peptides (c-MET peptides) which selectively bind to hepatocellular tissue or to function in diagnosis of cancer, including cancer treatment and drug discovery.« less
  • Abstract not provided.
  • Here, proteins are key components in a multitude of biological processes, of which the functions carried out by transmembrane (membrane-spanning) proteins are especially demanding for investigations. This is because this class of protein needs to be incorporated into a lipid bilayer representing its native environment, and in addition, many experimental conditions also require a solid support for stabilization and analytical purposes. The solid support substrate may, however, limit the protein functionality due to protein–material interactions and a lack of physical space. We have in this work tailored the pore size and pore ordering of a mesoporous silica thin film tomore » match the native cell-membrane arrangement of the transmembrane protein human aquaporin 4 (hAQP4). Using neutron reflectivity (NR), we provide evidence of how substrate pores host the bulky water-soluble domain of hAQP4, which is shown to extend 7.2 nm into the pores of the substrate. Complementary surface analytical tools, including quartz crystal microbalance with dissipation monitoring (QCM-D) and fluorescence microscopy, revealed successful protein-containing supported lipid bilayer (pSLB) formation on mesoporous silica substrates, whereas pSLB formation was hampered on nonporous silica. Additionally, electron microscopy (TEM and SEM), light scattering (DLS and stopped-flow), and small-angle X-ray scattering (SAXS) were employed to provide a comprehensive characterization of this novel hybrid organic–inorganic interface, the tailoring of which is likely to be generally applicable to improve the function and stability of a broad range of membrane proteins containing water-soluble domains.« less