In recent decades, a variety of nanoparticle drug delivery systems (NP DDS) – nanometer-scaled materials physically or covalently interacting with therapeutics – has been developed to overcome biological barriers, improve the half-life, reduce toxicity, and improve the efficacy of conventional drug delivery. However, many NP DDS fail to translate to the clinic. While this is in part due to immense heterogeneity within many disease types across individuals, the conflicting size and surface chemistries required in the “drug delivery pathway” (i.e. to avoid the clearance mechanisms and unintended tissues in the body, then to reach and specifically enter target tissues) also pose a significant challenge.
Recent advances in the field of drug delivery have created size- and surface-switching nanoparticles that overcome biological barriers. For example, large (100 – 200 nm) NPs are adequate at evading corporeal defense mechanisms, while small (< 50 nm) NPs can actively enter cancerous tissue. Further, release profiles of drug-loaded NP DDS must be tailored to stay within a narrow therapeutic window to prevent toxic effects.
This thesis highlights the synthesis of “nanoassemblies”, an NP DDS that contains small, drug-loaded starch nanoparticles (SNPs) within a larger nanogel matrix. Nanoassemblies are chemically tuned to reach specific targets via different administration routes (notably, cancerous tissues via systemic administration and brain tissue via intranasal administration). Furthermore, therapeutic-loaded SNPs are released under endogenous (pH, redox) or exogenous (ultrasound) stimuli for disease-specific release kinetics, allowing for deeper penetration into tumor cores or through the nose-to-brain pathway as required. Both the physicochemical characterization of these nanoassemblies as well as in vitro and in vivo experiments have been performed to assess the efficacy of nanoassemblies in biological systems and how they may provide performance improvements over non-assembled SNPs. As such, nanoassemblies show great promise in overcoming complex biological barriers to ultimately improve drug delivery in clinical applications. / Thesis / Doctor of Philosophy (PhD) / Using drugs to treat diseases is not always effective: the drug often does not work or comes with many side effects. A combination of factors prevents promising drugs from working. Most often the drug is either (partially or fully) removed from the body before it reaches the disease, or it improperly enters healthy tissue to cause undesirable responses. Previous research has shown that if drugs are put into nanoparticles, the nanoparticles can better deliver the drug to the correct target. However, conflicting sizes are needed to travel through different parts of the body, making nanoparticle-based drug delivery only of limited effectiveness in humans. This thesis aims to address these issues by creating “nanoassemblies” – nanoparticles with smaller, drug-containing nanoparticles inside of them – that overcome the typical issues with drug delivery. Nanoassemblies are able to switch their size to better reach the target tissue, ultimately leading to more effective and safe treatments.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/29438 |
| Date | January 2023 |
| Creators | Campea, Matthew Adrian |
| Contributors | Hoare, Todd, Chemical Engineering |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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