UC San Diego

Drugs work best when dosed right. For maximum therapeutic efficacy, one needs to deliver the drug to the right place at the right time. This dissertation exploits the recent advances in nanotechnology and chemistry for the design smart nanoscale constructs that can be triggered to disassemble and deliver encapsulated drugs. We design and evaluate light- and inflammation-sensitive systems for treatment of inflammatory diseases in animals. In Chapter 1, we demonstrate safety and efficacy of a UV light-triggered particles for controlled delivery of anti-angiogenics to treat age-related macular degeneration. The drugs are physically entrapped in a polymeric particle comprised of a series of self-immolative quinone-methide-based monomers protected with a light-sensitive moeity. The cleavage of these moeities results in a scission in the polymeric backbone, leading to the release of the encapsulated drugs. In Chapter 2, we explore chemical signal amplification as a strategy to improve sensitivity of the light-triggered drug delivery systems. We altered the polymer so that photocleavage unmasks acidic groups that then provide intramolecular assistance to ketal hydrolysis in the polymer backbone, resulting in significant polymer degradation upon a brief, low power trigger. Chapter 3 focuses designing a system with a longer wavelength light as the trigger for degradation. Red-shifting the actuating wavelength increases its tissue penetration and allows control over drug delivery at greater depth. In Chapter 4, we investigate if a polymer that reacts and degrades upon an increase in concentration of reactive oxygen species can be used as a drug delivery vehicle for the eye. As pathophysiology of macular degeneration involves oxidative stress, we examine the feasibility of delivering drugs using an inflammation-sensitive depot. This approach tailors release of drugs to the progression of disease, and thus will be useful in its long-term management.