pH-sensitive core-shell nanoparticles for intracellular drug delivery

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.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Chemical Engineering.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2008

Author dc:creator

• Hu, Yuhua, Ph. D. Massachusetts Institute of Technology

Advisor dc:contributor.advisor

• Darrell J. Irvine and Patrick S. Doyle.

• Chemical Engineering.

Statement 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.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/42942

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/42942