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• W2959883341 abstract "Author(s): Mokhtari, Negin | Advisor(s): Esener, Sadik J | Abstract: Foreign enzymes have shown great promise as therapeutic agents, owing to their natural specificity, substrate selectivity, and validated mechanism of action; however, since most of these enzymes have bacterial sources, they are rapidly cleared by the immune system. Their relatively large size and delicate nature complicates their encapsulation in most current delivery technologies, resulting in their poor pharmacokinetics and survival through biological barriers, as well inefficient therapeutic effect. Thus, there is an imminent need for a platform that protects these enzymes from the immune system and efficiently delivers them to the target site. This dissertation examines two different nanoparticle platforms and their applications in enzyme delivery: synthetic hollow enzyme loaded nanospheres (SHELS) and enzyme-loaded silica-coated PLGA nanoparticles (SiLGA). The porous silica coating on the nanoparticles will allow them to operate like nanosharkcages, where an enzyme (the scuba diver) is trapped in the nanoparticles (the sharkcage) and are only accessible to small molecules like their substrate (small fish), but not bigger molecules like antibodies and blood proteins (sharks). The application of SHELS (previously developed) is examined in the depletion of the amino acid, methionine, using the enzyme, methioninase (MethSHELS). MethSHELS are clearly superior to bare methioninase in vitro in terms of protecting the enzyme from proteases and inactivation by albumin, as well as a more widespread and sustained methionine depletion in vivo. In an attemptto develop a simpler synthesis process using FDA approved materials, as well as to address challenges associated with current technologies (e.g. limitation of cargo encapsulation by size and burst release of protein cargo), a new delivery platform, SiLGA, is introduced. SiLGA was successfully synthesized and characterized its encapsulation capabilities were also tested with multiple enzymes in vitro. SiLGA shows superior protection capability compared to bare enzyme. SiLGA retains more than %83 of its cargo’s enzymatic activity in the presence of protease enzymes in vitro and exhibits exceptional tissue residence time in vivo for more than 60 days. While SiLGA has shown minimal toxicity in mice and cells, our preliminary results in enzyme prodrug therapy shows successful and selective prodrug activation by enzyme-loaded SiLGA and cytotoxicty against cancer cells. SiLGA is a new delivery platform and can be employed in several different therapeutic and diagnostic applications. The inert nature of the FDA-approved materials used to fabricate these nanoparticles, as well as their mechanism of action, gives a high edge to the practical use of SiLGA for enzyme delivery for cancer and other diseases." @default.
• W2959883341 created "2019-07-23" @default.
• W2959883341 creator A5045252266 @default.
• W2959883341 date "2017-01-01" @default.
• W2959883341 modified "2023-09-27" @default.
• W2959883341 title "Nanoparticle Enabled Enzyme Delivery for Cancer" @default.
• W2959883341 hasPublicationYear "2017" @default.
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