Nanoimprint lithography based fabrication of size and shape-specific, enzymatically-triggered nanoparticles for drug delivery applications

Our ability to precisely manipulate size, shape, and composition of nanoscale carriers is essential for controlling their in-vivo transport, biodistribution, and drug release mechanism. Shape-specific, "smart" nanoparticles that deliver drugs or imaging agents to target tissues primarily in response to disease-specific or physiological signals could significantly improve therapeutic care of complex diseases. Current methods in nanoparticle synthesis do not allow such simultaneous control over particle size, shape, and environmentally-triggered drug release, especially at the sub-100 nm range. In this dissertation, we discuss the development of high-throughput nanofabrication techniques using synthetic and biological macromers (peptides) to produce highly monodisperse nanoparticles, as well as enzymatically-triggered nanoparticles, of precise sizes and shapes. We evaluated thermal nanoimprint lithography (ThNIL) and step and flash imprint lithography (SFIL) as two possible fabrication techniques. We successfully employed ThNIL and SFIL for fabricating nanoparticles and have extensively characterized the SFIL fabrication process, as well as the properties of the imprinted biopolymers. Particles as small as 50 nm were fabricated on silicon wafers and harvested directly into aqueous buffer using a biocompatible, one-step release technique. These methods provide a novel way to fabricate biocompatible nanoparticles with precise size and geometry. Furthermore, we developed an enzyme-degradable material system and demonstrated successful encapsulation and enzyme-triggered release of antibodies and nucleic acids from these imprinted nanoparticles; thus providing a potential means for disease-controlled delivery of biomolecules. Finally, we evaluated the bioactivity of the encapsulated therapeutics in-vitro. The development of the SFIL method for fabrication of biocompatible nanocarriers has great potential in the drug delivery field for its ability to create monodisperse particles of pre-designed geometry and size, and to incorporate stimulus-responsive release mechanisms. This research provides the potential to broaden the study of how particle size and shape affect the biodistribution of drugs within the body.