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Synthetic Hollow Enzyme Loaded Nanospheres for Diagnostic and Therapeutic Applications

Abstract

Although enzymes of non-human origin have been studied for a variety of therapeutic and diagnostic applications, including cancer, gout, diabetes, and various enzyme- deficiency disorders, their use in the clinic has been limited by the immune response generated against them and the challenges involved with their delivery and effective operation in vivo. We describe here a novel nanoparticle, the Synthetic Hollow Enzyme Loaded nanoSpheres (SHELS), that protects the encapsulated enzymes within its hollow interior, obviating an immune attack while allowing constant access to their substrates through its nanopores. The fabrication process of SHELS relies on is a template- based, versatile, scalable, and robust "nanomasking" patterning method that permits the realization of a dual- scale-porosity nanoparticle class well suited for the efficient loading and trapping of larger payloads while also enabling their interactions with smaller molecules through its nanoscale pores. In this dissertation, the unique capabilities and functionalities made possible by the nanomasking method and the SHELS platform are discussed and illustrated for various therapeutic and diagnostic applications. Specifically we provide : 1. a comprehensive evaluation and a detailed characterization of dual-scale porosity hollow nanoparticles fabricated using the novel nano-masking technique, 2. the evaluation of the relevant parameters of the SHELS platform for its successful implementation in the clinic, including : a. exquisite control in synthesis (nanoparticles with 100-500 nm diameters and 3-40 nm pore sizes), b. high enzyme entrapment capacity (\textgreater 1.5 mg/g), c. efficient protection from antibody access and neutralization and shielding from proteolysis, d. unperturbed in vivo enzyme activity, and 3. results of preclinical studies demonstrating the potential usefulness of the SHELS platform to facilitate therapeutic formulations for various cancer types, and 4. results of ex vivo experiments conducted to demonstrate usefulness in diagnostic applications

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