UBC Theses and Dissertations

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UBC Theses and Dissertations

Chemical modification of drugs to promote their self-assembly into nanoparticles for improved delivery Nguyen, Anne


Many small molecule drugs face challenges with aqueous solubility during their development, which can lead to issues with drug delivery. A commonly employed method to improve the solubility and delivery of drug-like molecules is to modify the compounds with hydrophilic groups. However, it can be very challenging to incorporate these groups without sacrificing the activity of the molecule. Alternative approaches include encapsulating the hydrophobic drug into a delivery vessel, such as a nanoparticle (NP), or introducing functional groups that help with solubility and delivery of the drug-like molecule but are cleaved in biological settings to release the original drug molecule (for example, a prodrug approach). Combining these approaches, a hydrophilic group such as water-soluble polymer poly(ethylene glycol) (PEG) can be added to a hydrophobic drug molecule to produce an “amphiphile”. These amphiphiles can self-assemble in aqueous media to form NPs where the hydrophobic, poorly water-soluble drug is protected in the core and the water-soluble polymer forms the outer shell. These NPs can have prolonged circulation, reduced clearance, and may therefore enhance efficacy. These PEG groups are appended to the molecule via a functional group that can be cleaved under biological conditions to release the active drug molecule. The physicochemical and pharmacological properties of these NPs can be modulated by altering different aspects of the amphiphilic drug-PEG conjugate. To optimize these conjugates and maximize their therapeutic potential, it is important to take a structure-activity relationship (SAR)-based approach when undertaking such an investigation. To facilitate the rapid and facile generation of drug conjugates, this thesis focused on developing a new platform technology using azide-alkyne click chemistry. Small molecule drugs with poor aqueous solubility were “clicked” to linear short-chain PEG. The resulting PEG conjugates then self-assembled into NPs. Multiple conjugates were generated to demonstrate the robustness and versatility of this technology. This thesis demonstrated that the developed click chemistry platform is a robust synthetic technology that has potential application to improve the delivery of poorly soluble drugs.

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