dc.contributor.advisor | Darrell J. Irvine and Patrick S. Doyle. | en_US |
dc.contributor.author | Hu, Yuhua, Ph. D. Massachusetts Institute of Technology | en_US |
dc.contributor.other | Massachusetts Institute of Technology. Dept. of Chemical Engineering. | en_US |
dc.date.accessioned | 2008-11-07T14:12:28Z | |
dc.date.available | 2008-11-07T14:12:28Z | |
dc.date.copyright | 2008 | en_US |
dc.date.issued | 2008 | en_US |
dc.identifier.uri | http://hdl.handle.net/1721.1/42942 | |
dc.description | Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2008. | en_US |
dc.description | This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. | en_US |
dc.description | Vita. | en_US |
dc.description | Includes bibliographical references (p. 193-208). | en_US |
dc.description.abstract | Therapeutics such as proteins, DNA, or siRNA, can only exert their function in the cell cytosol or nucleus. However, most of them are cell membrane impermeable molecules that can only be taken up by cells via endocytosis or phagocytosis. Such drug molecules are thus confined in endolysosomes, where reduced pH and degradative enzymes may destroy them without therapeutic gain. Efficient escape of drug molecules to the cytosol before destruction in endolysosomes is a major challenge for intracellular drug delivery. To address this issue, we designed a pH-sensitive core-shell nanoparticle to segregate the functions of the particle into an endosome-disrupting pH-responsive core that would absorb protons at endolysosomal pH, and a shell whose composition could be tuned to facilitate particle targeting, cell binding, and drug binding. Two-stage surfactant-free emulsion polymerization of 2-diethylamino ethyl methacrylate (DEAEMA) (core) and 2-amino ethyl methacrylate (AEMA) (shell) in the presence of a crosslinker was used for the synthesis of monodisperse core-shell hydrogel nanoparticles of 200 nm in diameter. The protonation of tertiary amine groups on the polyDEAEMA core on moving from extracellular to endolysosomal pH resulted in reversible swelling of the nanoparticles with a 2.8-fold diameter change. With the aid of pH-sensitivity of these nanoparticles, efficient cytosolic delivery of calcein (with ~95% efficiency) was achieved by disrupting endolysosomes via proton sponge effect. The primary amine rich shell was found to facilitate cell and drug binding, and provided negligible cytotoxicity by sequestering the proton sponge component from any direct interactions with cells. These particles demonstrated a useful means to deliver therapeutic molecules to the cytosol of cells of interest efficiently. | en_US |
dc.description.abstract | (cont.) The applications of nanoparticles showed significant improvement in delivering a model antigen vaccine protein ovalbumin (OVA) to primary dendritic cells for T cell activation, and promising knockdown of mRNA by delivering siRNA to epithelial cells for gene silencing. To extend this approach to a fully biodegradable system, nanoparticles with a cleavable crosslinker bis (acryloyl) cystamine (BAC) were synthesized. Preliminary explorations of this approach showed that such particles can degrade in the presence of glutathione in vitro, a reducing peptide present at mM concentrations in the cytosol of mammalian cells. This design could potentially serve as a drug releasing mechanism to further improve delivery efficiency. | en_US |
dc.description.statementofresponsibility | by Yuhua Hu. | en_US |
dc.format.extent | 212 p. | en_US |
dc.language.iso | eng | en_US |
dc.publisher | Massachusetts Institute of Technology | en_US |
dc.rights | M.I.T. theses are protected by
copyright. They may be viewed from this source for any purpose, but
reproduction or distribution in any format is prohibited without written
permission. See provided URL for inquiries about permission. | en_US |
dc.rights.uri | http://dspace.mit.edu/handle/1721.1/7582 | en_US |
dc.subject | Chemical Engineering. | en_US |
dc.title | pH-sensitive core-shell nanoparticles for intracellular drug delivery | en_US |
dc.type | Thesis | en_US |
dc.description.degree | Ph.D. | en_US |
dc.contributor.department | Massachusetts Institute of Technology. Department of Chemical Engineering | |
dc.identifier.oclc | 257731443 | en_US |