Chemical and Biomolecular Engineering - Theses
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ItemSynthesis and characterizations of anticancer amphiphilic star polypeptides( 2017)The cancer had replaced infectious diseases as the second major leading cause of deaths globally in 2013. Currently, chemotherapy is the main treatment option for inoperable and metastatic cancers. Disappointingly, conventional chemotherapy based on DNA disrupting agents are not successful in more than 50% of cases. The main reason behind most failures in chemotherapies is the development of multidrug resistance (MDR) in cancer cells which nullify the actions of all available chemotherapeutic drugs. Therefore, the development of new anticancer drugs based on the novel mode of actions that can bypass MDR is urgently needed. Previous works from our group have established star-structured amphiphilic polypeptides as a new class of highly biocompatible antimicrobial agents effective against MDR bacteria through membrane disrupting actions. Inspired by many natural-occurring membranolytic host defence peptides (HDPs) that display dual antimicrobial and anticancer activities, this thesis sought to extend the therapeutic scope of amphiphilic polypeptides to anticancer applications. A library of linear and star-structured polypeptides consisting varying compositions of lysine, leucine and valine in a random fashion were synthesized via N-carboxyanhydride ring-opening polymerization (NCA ROP). These polypeptides display similar potency in vitro as some HDPs and their synthetic analogues, with IC50 values in the range of 10 – 30 µg/mL toward CT26 mouse colon cancer cells. Moderate selectivity in the range of 1.0 – 3.0 toward CT26 cells over L929 mouse fibroblast cells was observed for the polypeptides. It was found that the architecture of the amphiphilic polypeptides have a predominant influence on their potency, where polypeptides with a greater number of arms have higher potency against both CT26 and L929 cells. On the other hand, polypeptide composition has no significant influence on potency. Studies on the time-kill kinetics of the polypeptides with xCELLigence real-time cell analysis (RTCA) system revealed that each polypeptide has higher killing rates on CT26 cells over L929 cells at the same concentration. It was also observed that helical propensity of the polypeptides show a strong correlation to the initial killing rate of L929 cells but not CT26 cells. In summary, the findings presented in this thesis provided insights on the structure-activity relationships of amphiphilic polypeptides which will aid in the future development and optimization of membranolytic anticancer polypeptides. It is the hope that this thesis will inspire the research community to pursue innovative solutions in the development of future anticancer agents.