Polyethylene glycol conjugates and vinyl ether constructs for programmed gene and drug delivery

Current cancer therapeutics often suffer from systemic toxicity in vivo due to poor target selectivity, i.e. they tend to accumulate with equal efficiency in both normal and cancerous cells. Furthermore, they tend to have low bioavailability due to their limited solubility and poor structural stability, which leads to reduced blood circulation times and rapid clearance from the body. Consequently, there is still a major unmet need in the design of delivery systems that are capable of selectively delivering biologically effective concentrations of anti-cancer agents to the cytoplasm of target cells. Two approaches to address some of these fundamental problems with chemotherapy were investigated. Improved targeting using folate-modified gold nanoparticles for attachment of chemotherapeutic agents was explored. In addition, approaches to achieve intracellular release of agents from acid-labile carriers were developed. A new synthetic pathway using organobarium intermediates for facile synthesis of plasmalogen type lipids was also developed. These lipids can be used for acid sensitive liposomal gene and drug delivery. Finally, the design, synthesis and application of a family of acid-labile vinyl ether linkers was pursued. As these compounds are both tunable as easily functionalized, they should enable the programmed release of anti-tumor agents from nanostructured carriers