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Chander, Nisha

University of British Columbia

Lipid-based nanoparticle (LNP) drug delivery vehicles can be used for in vivo delivery of a variety of bioactive molecules including nucleic acid polymers and small molecule drugs for applications ranging from improving the efficacy of anticancer drugs to enabling gene therapies. While liposomal systems containing small molecule drugs can be designed to be relatively nontoxic and long circulating, the ability to trigger rapid release of drug cargo at the target site remains elusive, severely limiting their therapeutic index. The first objective of this thesis is to develop lipid nanoparticles that can release a larger payload at the target site to improve their overall efficacy. Despite more than 30 years of experimentation, triggered release systems for liposomes containing anticancer drugs that leak contents in response to local heating or irradiation have failed to result in clinically approved applications. Chapters 3 and 4 of this thesis focus on incorporating photoswitchable lipids or metal nanoparticles into previously well-established liposomes, making them responsive to externally applied radiation such as laser light to trigger drug release. These novel liposomal systems have similar size and drug encapsulation properties as parent systems, while also exhibiting triggered release properties. Additionally, systems currently being used for delivery of genetic drugs such as RNAbased drugs only result in effective gene silencing or gene expression in the liver. The second objective of this thesis is to develop transfection competent long circulating systems that can transfect extra-hepatic tissues following intravenous administration. Chapter 5 of this dissertation describes an attempt to increase the proportion of so-called “helper” lipids in LNP formulations containing mRNA. It is shown that high (40 mol%) levels of helper lipids such as egg sphingomyelin (ESM) can result in improved gene expression both in vitro and in vivo, particularly in extrahepatic tissues such as bone marrow. This ability is attributed to the unique morphology of these LNP systems which exhibit a “solid” hydrophobic core surrounded by a lipid bilayer. Such systems allow improved distribution to extrahepatic tissues due to an enhanced circulation lifetime.

Text

2023-02-28

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/79276

Biochemistry and Molecular Biology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/