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    Efficient Drug and Nucleic Acid Delivery Systems based on Synthetic Amphiphiles with Tuned Oil/Water Interfaces

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    Genre
    Thesis/Dissertation
    Date
    2018
    Author
    Satyal, Uttam
    Advisor
    Ilies, Marc A.
    Committee member
    Canney, Daniel J.
    Fassihi, Reza
    Lebo, David
    Brailoiu, Eugen
    Department
    Pharmaceutical Sciences
    Subject
    Pharmaceutical Sciences
    Nanoscience
    Nanotechnology
    Block Copolymers
    Drug Delivery
    Gene Delivery
    Peg-pcl
    Pyridinium Amphiphiles
    Self-assembly
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/2315
    
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    DOI
    http://dx.doi.org/10.34944/dspace/2297
    Abstract
    Today, drugs are an integral part of healthy human life, with new drug entities being introduced every year in clinic. The advancement of drug development brings complexity and variation, in terms of both physical and chemical properties. Some of these physicochemical characteristics are many times suboptimal, eventually requiring robust delivery systems that can precisely deliver the drugs to the desired tissues. Although many materials have been studied for the generation of drug delivery systems, there is always a need for biomaterials with better properties that can translate into superior delivery systems. In this context, new drug delivery systems that are interface-engineered at materials level for better stability and delivery efficiency in vitro and in vivo are introduced in this dissertation. In the first part of the dissertation, novel oil/water interface-engineered amphiphilic block copolymer micelles that were previously introduced by our lab were assessed for their stability in the presence of various esterase enzymes present in serum and on blood vessel walls, normally encountered by drug delivery systems on route to the targeted tissues. I also assessed the vulnerability of the polymeric micelles in presence of enzymes typically present either inside the tumor cells or secreted in the tumor microenvironment. I revealed the selective stability of empty- and docetaxel-loaded polymeric micelles to enzymatic degradation en route/in tumors and I have correlated this selective stability with polymer structure and interfacial engineering mentioned above. The unique delivery capabilities of interfacial-engineered polymeric micelles were tested in vivo using a mouse model of triple negative breast cancer. We proved that our novel engineered triblock copolymer-based drug delivery systems are superior to similar delivery systems made out of standard diblock copolymer micelles and also to the clinically used Taxotere® formulation towards cancer cell killing and tumor treatment, without displaying any significant toxicity in experimental animals. The second part of the dissertation focuses on the development and assessment of a pyridinium-based pseudo-gemini surfactant that combined the high nucleic acid packaging capacity of pyridinium lipids with the high transfection efficiency of gemini surfactants while displaying a reduced associated cytotoxic effect. I have analyzed the temperature treatment on compaction of nucleic acids into lipoplexes and I have established a high temperature annealing method for this purpose. This novel formulation technique allowed a substantial reduction of the amount of amphiphiles required to compact a specific amount of nucleic acids. This in turn also reduced the cytotoxic effect associated with the use of pyridinium amphiphiles. The effect of inclusion of colipids to lipoplex compaction, the robustness and the transfection efficiency of the lipid/nucleic acid lipoplex systems were assessed in detail, and correlations between formulation composition and biological activity were established. I was also able to show for the first time that pyridinium pseudo-gemini surfactants were able to compact different types of nucleic acids, including pDNA, mRNA and siRNA at lower charge ratios than standard, state-of-the art formulations used for this purposes. I also showed that irrespective to the nucleic acid compacted within the lipoplexes, the novel amphiphiles can efficiently deliver the cargo into the targeted cells even in the presence of very high concentration of serum, a premise for future use of these amphiphiles and formulations in vivo.
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