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Title: Porous nanoparticle-supported lipid bilayers (protocells) for targeted delivery and methods of using same

Abstract

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 nucleus 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 cancermore » treatment and drug discovery.« less

Inventors:
; ; ;
Publication Date:
Research Org.:
Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1345394
Patent Number(s):
9,579,283
Application Number:
14/113,371
Assignee:
STC.UNM SNL-A
DOE Contract Number:
AC04-94AL85000
Resource Type:
Patent
Resource Relation:
Patent File Date: 2012 Apr 27
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Brinker, C. Jeffrey, Carnes, Eric C., Ashley, Carlee Erin, and Willman, Cheryl L.. Porous nanoparticle-supported lipid bilayers (protocells) for targeted delivery and methods of using same. United States: N. p., 2017. Web.
Brinker, C. Jeffrey, Carnes, Eric C., Ashley, Carlee Erin, & Willman, Cheryl L.. Porous nanoparticle-supported lipid bilayers (protocells) for targeted delivery and methods of using same. United States.
Brinker, C. Jeffrey, Carnes, Eric C., Ashley, Carlee Erin, and Willman, Cheryl L.. Tue . "Porous nanoparticle-supported lipid bilayers (protocells) for targeted delivery and methods of using same". United States. doi:. https://www.osti.gov/servlets/purl/1345394.
@article{osti_1345394,
title = {Porous nanoparticle-supported lipid bilayers (protocells) for targeted delivery and methods of using same},
author = {Brinker, C. Jeffrey and Carnes, Eric C. and Ashley, Carlee Erin and Willman, Cheryl L.},
abstractNote = {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 nucleus 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.},
doi = {},
journal = {},
number = ,
volume = ,
place = {United States},
year = {Tue Feb 28 00:00:00 EST 2017},
month = {Tue Feb 28 00:00:00 EST 2017}
}

Patent:

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  • Abstract not provided.
  • 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 bilayermore » 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.« less
  • Abstract not provided.
  • Abstract not provided.