Development and Applications of Porphyrin-Phospholipid Liposomes
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Small-molecule cancer therapeutics have traditionally had limited selectivity between targeted tumor cells and tissue, and healthy non-target tissues, often leading to significant side effects limiting the efficacy of the such therapies. Nanoparticle based have demonstrated the ability to improve the efficacy of these compounds by favorably enhancing their pharmacokinetics and biodistribution. However, nanoparticle based systems are often limited in efficacy by poor tumor drug uptake and bioavailability of the drugs. Stimuli based drug delivery systems have the ability to overcome such limitations and improve the therapeutic efficacy of nanoparticle drug delivery systems. This thesis focuses on the development and applications of Porphyrin-Phospholipid (PoP) Liposomes. Chapter 1 introduces the concept of triggered drug release and the various approaches used with liposome based drug delivery systems. Chapter 2 describes the initial development of PoP liposomes and the first instance of using PoP liposomes to stably entrap and release cargo using light as a stimuli as well as preliminary in vivo anti-tumor and biodistribution data. Chapter 3 describes the optimization of doxorubicin loaded PoP liposomes with particular focus on improving serum stability and blood circulation time. Chapter 4 describes the use of metal chelation to alter the light release properties and efficacy of mitoxantrone loaded PoP liposomes. Chapter 5 compares differences in the drug loading and stability of doxorubicin and irinotecan in PoP liposomes. Chapter 6 describes in vitro blood interactions, pharmacokinetics, the dependence of drug delivery on light Propagation, and phototoxicity and dose toxicity of the doxorubicin loaded PoP liposomes described in chapter 3. Chapter 7 describes a brief discussion of PoP liposomes and provides some future directions of the technology.