Development and optimization of shape-specific, stimuli-responsive drug delivery nanocarriers using Step and Flash Imprint Lithography
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The advent of highly sophisticated drugs designed to interfere with specific cellular functions has created the demand for “intelligent” carriers that can efficiently deliver therapeutic agents in response to a pathophysiogical condition. Nanoscale intelligent systems can maximize the efficacy of therapeutic treatments in numerous ways because they have the ability to rapidly detect and response to disease states directly at the site and sparing physiologically healthy cells and tissues, thereby improving a patient’s quality of life. Nanoparticle fabrication has primarily relied on emulsions, self-assembly and micelles based methods which inherently generate polydisperse spherical particles with little control over particle geometry. Despite significant progress in such drug delivery systems, critical limitations remain in synthesizing nanocarriers with highly controllable architecture (size, shape or aspect ratio) that can, at the same time, impart response-sensitive release mechanisms. These parameters are essential for controlling the in-vivo transport, bio-distribution, and drug release mechanisms. The objective of my dissertation is to employ the nanofabrication technique Step and Flash Imprint Lithography (S-FIL) to synthesize stimuli-responsive nanocarriers of precise architectures and composition. Applying S-FIL technology, fabrication of nanocarriers of a variety of shapes and sizes (down to 36nm length scale) that are also environmentally responsive by incorporating enzymatically-degradable peptides into the nanocarrier hydrogel matrix, to provide triggered release of encapsulated therapeutic agents in response to specific pathophysiological conditions, has been accomplished. Besides disease-responsive release, the two key properties of an effective nanocarrier are (a) efficient targeting to specific tissues and cells and (b) avoiding rapid clearance and remaining in circulation in the blood stream for a significant amount of time to increase particle uptake in target tissues. These two properties are expected to be dependent on the shape and size of the carriers. Using various shape and size S-FIL fabricated nanoparticles, the effects of particle geometry on intracellular uptake has also been evaluated. In this dissertation, I will present the extensive work that has been done in the fabrication and optimization of the S-FIL nanocarriers, evaluation of the nanocarrier’s in vitro properties, and evaluation of the effects of nanocarrier geometry on intracellular uptake.