Lanterna Rally

Author: Erick Yu

Publisher:

Published: 2016

Total Pages:

ISBN-13: 9781369615951

Drug delivery by nanoparticles has been an important, emergent field in the past decade with mesoporous silica at the forefront. With a high surface area and wide variety of modifications possible, mesoporous silica nanoparticles (MSNs) are a robust platform to load, transport and deliver molecular species, including tracer compounds, macromolecules, and anti-cancer agents. A wide variety of MSN crystalline structures were first synthesized in the 1990s and early 2000s. In the following years, advances in silane, inorganic, and organic chemistry led to “smart” drug delivery, a revolutionary method wherein contained species could be released at a desired rate. In combination with stimuli or target responsive functional groups, MSNs in recent years have shown particular promise for the therapeutic delivery of peptides, proteins, and small genetic material. To fully realize the potential for these applications, the porous structure of MSNs needs to be enlarged to accommodate larger species without compromising the overall nanoparticle structure. Additionally, due to the sensitive nature of these proteins and genetic matter, stability and prevention of structural deformation is important for their delivery into biological environments. Combining expanded pore MSNs with stimuli-responsive functional groups is currently a major focus for drug delivery. In this dissertation I report on modification of MSNs through inorganic and polymeric constituents. Using a pore-expansion process to synthesize MSNs capable of delivering proteins, specifically lysozyme (ca. 3.9 nm diameter) and bovine hemoglobin (c.a. 5.5 nm diameter), I further modified the MSNs using triblock polyethylene oxide-polypropylene-polyethylene oxide (PEO-PPO-PEO), poly(n-isopropylacrylamide) (PNIPAM), and polyethylene glycol (PEG). I show a well-controlled release of drugs and proteins with these nanoparticles. Triblock PEO-PPO-PEO copolymers function as weak surfactants, which allow them to potentially increase drug permeability through lipid bilayers that coat MSNs. The release behavior of lipid-MSNs can then be linearly fine-tuned with both the composition of the triblock copolymer and its concentration. Among the stimuli-sensitive functional groups used to modify MSNs, PNIPAM in particular has been developed significantly in the past decade as a gating molecule for both nanoparticles and porous membranes. As a thermoresponsive polymer, which changes both its surface hydrophilic/hydrophobic nature in addition to its morphology at 32 °C, PNIPAM can be applied to the MSN surface to provide a triggered release when temperatures are elevated to physiological temperatures. PNIPAM was investigated under in situ liquid atomic force microscopy at sub 80 nm grafting lengths in order to better understand and characterize its collapse behavior around nanostructured surfaces, comparable to the surface of mesoporous silica nanoparticles. Here I demonstrate that the collapse behavior occurs even at grafted lengths of 10-20 nm. However, under these conditions, the gating effect is minimal around nanostructured edges, as of those of nanopores. I further show that when PNIPAM is combined with the step-wise, template functionality of MSNs and further modified with PEG (notable for its ability to minimize non-specific binding and interactions between proteins and glass substrates), improved release delivery of loaded proteins is realized. With therapeutic peptide delivery in mind, these MSNs were tested with lysozyme and bovine hemoglobin to show their potential for delivery of both proteins and genetic material.