Microtubules dual chemo- and thermo-responsive depolymerization & optimization of noncovalent loading of vinblastine on single-walled carbon nanotube

Li, Zixian (2016) Microtubules dual chemo- and thermo-responsive depolymerization & optimization of noncovalent loading of vinblastine on single-walled carbon nanotube. Masters thesis, Memorial University of Newfoundland.

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Abstract

The effects of the chemotherapeutic agent vinblastine versus the low temperature of 277 K on the structure of αβ-tubulin heterodimer were investigated by means of molecular dynamics simulations. Individual experiments have shown that vinblastine-bound heterodimer, and its apo structure under low temperature of 277 K, both undergo conformational changes toward destabilization of the dimer as compared to the apo tubulin at 300 K. Both factors exhibit weakening the longitudinal interactions of tubulin heterodimer through displacing dimer interfacial segments, resulting in the dominant electrostatic repulsion at the interface of the subunits. The two independent factors of temperature and anti-mitotic agent facilitate folding alterations in the functional segments of H1-S2 loop, H3, H10 helices and T7 loop, which are known to be important in either longitudinal or lateral contacts among αβ-heterodimers in microtubule protofilaments and the depolymerization mechanism of microtubules. Carbon nanotubes have become one of the candidates for transporting drugs to target sites, because of their size scale, huge surface area and high cellular uptake. Many experimental studies of carbon nanotube drug delivery have been performed in the past decade. The delivery studies of vinblastine and its target microtubule are important, because of the significant role of vinblastine in cancer therapy. However, the interactions between vinblastine and carbon nanotubes have yet to be investigated. The computational studies of the interactions between vinblastine and carbon nanotubes under different conditions are presented in this thesis. The vinblastine-carbon nanotube interactions have been studied from the following perspectives: loading capacity (one to three vinblastine molecules loaded); tube structure (armchair, chiral and zigzag tubes); tube functionalization; and temperature variations (277 K and 300 K). The functionalization of carbon nanotubes strengthened the drug-carrier interactions of all systems at 300 K. The functionalized carbon nanotubes of armchair type were identified suitable for drug delivery at both 277 K and 300 K, due to the relatively strong drug-carrier interactions. The functionalized chiral nanotubes were found especially useful for delivery at 277 K due to the enhanced drug-carrier interactions at this temperature.

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