Lipid modification of polymeric nanocarriers for drug and siRNA delivery

  • Author / Creator
    Falamarzian, Arash
  • The use of nanotechnology in pharmaceutical development has progressed significantly in recent decades. This rapid advancement is driven by crucial need for improving the performance of present diagnostic and therapeutic modalities, as well as development of a new class of delivery systems for complex entities such as genes and proteins. Nanocarriers currently in use for the delivery of drugs and genetic materials can be generally divided to two categories: those made from lipids and those made from synthetic or natural polymers. Although lipid-based carriers are generally regarded to be safe and efficient, they do not possess sufficient chemical flexibility to fit individual requirements in delivery. In this thesis, we have explored lipid-substitution of three different polymer-based nanocarriers as means to develop optimum structures for drug as well as siRNA delivery. For the delivery of a potent amphiphilic antifungal drug, amphotericin B (AmB), lipid modification (particularly cholesteryl modification) of the core structure in poly(ethylene oxide)-poly(caprolactone) micelles was proved to be efficient in enhancing the solubility while reducing the hemolytic activity of encapsulated AmB. On the other hand, lipid modification of low molecular weight (2 kDa) polyethyleneimine (PEI2) has enhanced the properties of the nanocarriers in the delivery of STAT3-siRNA in wild type and resistant breast cancer cell models leading to an improved anti-cancer efficacy in combination with chemotherapeutic drugs, i.e. DOX and PTX. Finally, cholesteryl modification of poly(ethylene oxide)-poly(caprolactone-g-spermine) enhanced the properties of these nanocarriers for in vivo delivery of siRNA. This modification enhanced the stability, safety and cellular uptake of complexed siRNA leading to better silencing activity at the mRNA level. Overall, our results pointed to the positive impact of lipid modification in enhancing the properties of polymeric nanocarriers leading to viable formulations for effective delivery of AmB and siRNA therapeutics.

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  • Degree
    Doctor of Philosophy
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    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.