Enhanced functionality of monodispersed polymeric nanocarriers in medicine

Singh, Vikramjit
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Polymeric monodispersed nanocarriers with controlled shape and size have been fabricated in the literature primarily using top down processes such as imprint lithography. In this dissertation, the geometric and material property limits of imprint based techniques have been studied. The resulting insight has led to the creation of new processes that significantly extend the limits of imprint processes in several ways: (i) Ability to print nanocarriers with ultra-soft biomaterials (<1MPa modulus); (ii) Sub-50nm diameter cylindrical particles with >3:1 aspect ratio with >5x enhanced wafer yield; (iii) Creation of reentrant barrel shapes that have the potential to be valuable in cellular uptake, such shapes being significant as they lead to fundamental demolding challenges in prior imprint processes; and (iv) Multi-layer nanocarriers which can potentially provide sophisticated functionality such as tailored release kinetics of one or more drugs. By understanding the requirements of bio-functional nanocarriers and related manufacturing constraints, a previously explored Bio Jet and Flash Imprint Lithography (Bio J-FIL) process was refined to perform successful imprints and improve the nanocarrier fabrication scalability. Next, two new fabrication processes have been developed. The first process is called Decoupled Functional Imprint Lithography (D-FIL) which allows fabrication of ultra-soft bio-functional materials (modulus of <1 MPa), challenging sizes (sub-50nm diameter cylinders with aspect ratio > 3:1), and reentrant barrel shapes. The second decoupled process, Dual Removable Layer Lithography (DRLL), has been developed to specifically create multi-layered cylindrical nanocarriers. Nanocarriers fabricated with D-FIL and DRLL process have been shown to chemically bind with an imaging agent, and model anti-cancer drugs. Drug (siRNA) retention (>90% over 9 days) and stimuli triggered release studies were performed on sub-100nm cylindrical PEGDA nanocarriers. It was found that these nanocarriers show accelerated triggered drug release when exposed to a hydrolase, Cathepsin B. While the exact mechanisms causing the triggered release are not fully understood, a few possible explanations are provided based on the experiments reported. Finally, the D-FIL, the DRLL, and the refined Bio J-FIL processes have been successfully demonstrated at the prototype scale as well as at the pilot scale in collaboration with an industrial partner, Molecular Imprints Inc.