Computational and experimental protein engineering for targeted drug delivery

Current cancer drug delivery methods target both rapidly dividing cancer cells and healthy cells. As a result cancer patients face many harmful side effects. By using a targeted drug delivery method, these harmful side effects may be minimized while still effectively treating cancer. An approach to targeted drug delivery is using protein-polymer conjugates (PPCs) as a drug delivery system. A PPC will allow for targeted drug delivery to the cancer site while overcoming many of the limitations current drug delivery methods present. The goal of this thesis is to computationally model a PPC to assess its structural interactions and behaviors to make informative predictions about the targeted drug delivery system. The PPC consists of an engineered protein that has the ability to bind to a drug loaded polymer as well as bind to an expressed integrin on cancer cell surfaces. First, a model of the engineered protein was obtained using the I-TASSER web-based software. PyMol was then used to determine if the engineered protein had the ability to bind to the αvβ3 integrin receptor at their respective RGD sites. Finally, a complete model of the PPC was obtained once a polymer mimic was attached to a cysteine tag of the engineered protein. With the complete PPC model, a polymer length analysis was done to predict the optimal polymer length for drug loading and limiting binding site blocking. It was concluded that polymer lengths of 50 azlactone repeat units or less was best. For future work, an experimental structural analysis will be done to confirm the computational results obtained as well as binding studies with a cancer cell expressing the αvβ3 integrin