Biomedical Sciences ETDs

Publication Date

Spring 5-12-2018

Abstract

Advances in the field of nanoparticle biomedical applications have made large strides towards achieving targeted deliver­y of therapeutics and imaging agents. However, less is understood on how the shape of a targeted nanoparticle will alter the level of cellular internalization. The research conducted herein demonstrated that by encasing the bare MSNP with a zwitterionic supported lipid bilayer, referred to as a protocell, the aspect ratio of the MSNP was maintained. However, the non-targeted protocell’s conformal coating drastically diminished the ability of the cell’s active sensory system to recognize the protocell. This finding indicates the cell envokes non-specific macropinocytosis in response to interaction with the silanols present on the bare MSNP surface. Thus, the cell's active shape sensory system is controlled by non-covalent electrostatic and hydrogen bonding interactions with the biomolecular mechanosensitive components of the cell membrane. Additionally, we establish a selective, shape enhanced internalization pathway for the targeted rod shaped protocell AR~1.8-2.3 by conjugation of the SLB with the ligand GE 11, which binds to EGF receptors highly over-expressed on A549 cells. Flow cytometry studies of the effects of chemical inhibitors on nanoparticle cell uptake, along with confocal microscopy colocalization, and TEM studies were performed with A549 cells. The outcomes from these studies showed a shift in the shape-stimulated internalization pathway from non-specific macropinocytosis for anionic bare rod-shaped MSNP to a selective, shape-stimulated, predominantly caveolae-dependent pathway with highly preferential uptake of zwitterionic EGFR-targeted rod shaped protocells in comparison to zwitterionic EGFR-targeted spherical shaped protocells.

Keywords

EGFR (epidermal growth factor receptor), aspect ratio, shape, caveolae-dependent endocytosis, macropinocytosis, mesoporous silica nanoparticles, targeted nanoparticles, cellular mechanism of internalization

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Dr. Larry A. Sklar

Second Committee Member

Dr. C. Jeffrey Brinker

Third Committee Member

Dr. Diane S. Lidke

Fourth Committee Member

Dr. Walker Wharton

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