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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. Fri . "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 = {Fri Jul 15 00:00:00 EDT 2016},
month = {Fri Jul 15 00:00:00 EDT 2016}
}

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