Developing photoresponsive lipid nanoparticles for the triggered release of small molecules

Abstract

This thesis will examine numerous photo responsive drug delivery nanoparticles containing two different first-generation (1G) donor-acceptor Stenhouse adduct (DASA) molecules, DOPC, DLPC, cholesterol and lauric acid. The DASA isomerizes upon visible light irradiation, thereby increasing membrane permeability through disruption of the bilayer and releasing cargo. A 1G dioctyl DASA and a new 1G cholesterol-DASA conjugate were synthesized, and their photophysical properties were studied and compared. The dioctyl DASA was studied in DLPC with and without lauric acid, as it was observed that the lauric acid promotes thermal isomerization of the photochrome, eliminating photocontrol of the system. Thus, the incorporation of acid was removed for the remaining studies. DLPC was found to be a “leaky” system, so DOPC was studied afterwards. The dioctyl DASA in DOPC was found to be a highly stable system capable of responding to a visible light trigger, but additional disruption is required for therapeutical applications. Cholesterol was incorporated into this system and found to further stabilize the nanoparticle, releasing even less cargo. Again, this system responded to a visible light trigger but released insufficient cargo. The cholesterol-DASA conjugate was hypothesized to create further disruption within the DOPC liposome, triggering a greater amount of release upon its photoswitch, but unfortunately the opposite was observed. However, useful insights were gained regarding the effects of the donor group on the switching capacity of 1G DASAs, the impact of the incorporation of cholesterol on a DOPC liposome, as well as important aspects of the calcein release assay were discovered, providing valuable information to researchers continuing with these methods. Finally, it was discovered that the highly lipophilic cholesterol-DASA conjugate was able to incorporate into the lipid bilayer to a higher extent than was seen with the dioctyl DASA. This has potential in creating a photo responsive nanoparticle system, as photochrome incorporation tends to be a challenge in developing such systems. Overall, advancements were made in tailoring the design of the components within these nanoparticles as well as the methods used to study release. Keywords: DASA, Photoswitching, Liposome Nanoparticle, Cholesterol-DASA conjugate, Triggered release