Nanoparticle-based delivery vehicles have received substantial interest in the field of drug delivery particularly pertaining to chemotherapeutics. By virtue of their size, nanoscale drug delivery vehicles overcome many obstacles encountered by traditional systems. Moreover, nanocarriers can be fabricated to be ‘smart’, meaning they can be responsive to internal stimuli relating to the microenvironment of the tumor and/or external stimuli that can be delivered non-invasively from outside of the body. One such external trigger is ultrasound, well-known for its role in biomedical imaging based on its wide availability, non-invasiveness, and safety but increasingly being applied for drug delivery.
This thesis proposes solutions to two key challenges associated with locally-targeted polymer-based drug delivery: enhanced tumor accumulation and externally-triggered control over release kinetics. In the former case, brush polymer PLA-PEG analogues are synthesized and explored to correlate how the architecture of these brush blocks affects the resulting self-assembled nanoparticle size, zeta potential, cytotoxicity in vitro, circulation time, and accumulation profiles in vivo. Indeed, brush copolymer analogues allow for copolymerization with additional monomers while conserving ‘stealth properties of linear copolymers, as well as exhibit superior circulation times and longer-term tumor accumulation. In the latter case, a new ultrasound-triggered drug delivery platform is designed consisting of a hollow polymeric shell in which silica “corks” are entrapped; the application of ultrasound can exploit the high difference in the compressibility between the polymeric shell and the silica corks to pop out or otherwise perturb the cork particles, allowing for both on-demand drug release as well as a pulsatile release profiles to be achieved. Overall, by manipulating the surface properties and/or morphologies of polymer-based micro/nanoparticles, the results of this thesis show that key challenges in local drug delivery can be addressed and applied specifically to applications in cancer therapy. / Dissertation / Doctor of Philosophy (PhD) / Drug delivery vehicles attempt to address many of the shortcomings of traditional therapeutics, in particular their low solubility and a lack of tissue targeting, which result in poor efficacy and unwanted side-effects. Polymers specifically have been commonly employed in biomedical applications as there are a wide range of biodegradable polymers that do not cause adverse effects during intended application and can be removed from the body through normal biological function. More recently, more advanced, ‘smart’ materials have been developed that can respond to internal or external stimuli to better address treatment needs. This thesis presents novel polymer-based drug delivery vehicles with new structures useful to passively target particular sites in the body and/or alter drug release profiles, enabling improved drug efficacy and reduced side-effects.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/29736 |
| Date | January 2024 |
| Creators | Singh, Andrew |
| Contributors | Hoare, Todd, Chemical Engineering |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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