Grant: Discovery Grants Program - Individual

We are developing amphiphilic organic molecules that respond to light by changing their structure and properties. These light-driven molecular switches (i.e., photoswitches) will be integrated with lipid vesicles to form photoresponsive self-assembled structures. These biocompatible self-assemblies will have potential application in `on-demand' drug delivery and theranostics (i.e., therapy and diagnostics). Nanoparticle delivery vehicles offer many advantages over conventional drug formulations. They increase drug solubility, minimize drug degradation, reduce clearance from the body, and enhance therapeutic efficacy. In addition, a delivery vehicle with light-triggered release provides a high level of spatial and temporal control. As a result, a higher local concentration of therapeutics can be dispensed, reducing the overall injected dose and systemic toxicity. Further, photoresponsive delivery vehicles with reversible photoswitches allow for repeated `on-demand' dosing from a single administration. Currently, the main challenge facing photoresponsive lipid vesicles as drug delivery systems is the lack of control over the release of hydrophobic therapeutic molecules from the lipid bilayer or hydrophilic molecules from the aqueous core. In addition, most photoswitches rely on high-energy UV light for activity. This dependence hinders the use of photoswitches in biomedical applications because UV light can be damaging to endogenous molecules and has relatively poor tissue penetration, which limits its use to organs that can be directly reached by endoscopic techniques. Consequently, the proposed research program will address these issues. First, we will prepare reversible, amphiphilic photoswitches that undergo a large change in hydrophobicity (i.e., a change in solubility) when irradiated with visible or near infrared (NIR) light. Second, we will examine the effect of photoswitch inclusion and isomerization (i.e., activity) on lipid bilayer mechanics. Namely, we will identify lipid vesicle formulations that undergo large changes in membrane fluidity and thickness upon irradiation with visible or NIR light. Significant photoinduced changes in lipid bilayer mechanics should trigger the formation of pores and enhance membrane permeability. Third, we will perform permeation assays to evaluate the effect of photoswitch activity on the delivery of therapeutics from these vesicle formulations. Overall, we will produce photoresponsive, biocompatible self-assemblies with application in drug delivery and theranostics. These objectives represent a systematic approach for achieving photocontrol in lipid-based self-assembled structures. This approach will lead to patentable technologies and benefit public health.