Exploring Polymer and Liposomal Carriers for Optimized Drug Delivery

The efficacy of chemotherapy drugs is often hampered by poor molecule properties, such as solubility, rapid excretion, indiscriminate toxicity, and lack of targeting to tumor tissue. Macromolecular carriers have been explored for their potential to modulate drug pharmacokinetics and increase tumor uptake through passive targeting. In this work, I examined the design of delivery systems to optimize the delivery of chemotherapeutics. An introduction to polymer and liposomal drug delivery vehicles is presented in Chapter 1. The benefits and challenges with each delivery scaffold, as opposed to conventional chemotherapies, are discussed. The remainder of the chapter will focus on camptothecin and platinum (II) drug delivery in the context of combination therapies and controlled release./nIn Chapter 2, the design of camptothecin pro-drugs for pH sensitive release through a hydrazone bond is explored. I describe the synthesis of a poly-lysine dendrimer, to which camptothecin is conjugated. The synthesis of a new, more synthetically accessible PEGylated ester amide dendrimer is presented. The dendrimer was appended with both camptothecin and doxorubicin to investigate drug synergy for a dual-drug delivery system./nIn Chapters 3 and 4, polymer Pt (II) drug delivery is explored in collaboration with Dr. Derek van der Poll. A PEGylated ester amide dendrimer is modified with a variety of amino acid inspired chelators to study how platinum release is correlated with cytotoxicity and efficacy. Both a fast and slow releasing chelator were evaluated in vivo. Next, a series of ketone containing bidentate Pt (II) drugs were synthesized. Increasingly cytotoxic complexes could be designed by cross coupling additional aromatic ligands, exploring electronic considerations, and modifying platinum ring sizes. Although Pt content was substantially increased in tumors, this did not translate to increased efficacy in the C26 murine colon carcinoma tumor model./nChapter 5, in collaboration with Aditya Kohli and Darren Chan, presents an introduction to the utility of sterol modified lipids (SML). The bilayer properties of liposomes composed of SMLs were characterized using fluorescence anisotropy measurements and content release assays. The influence of the acyl chain length in the SML on contents release is discussed. A pharmacokinetic study indicated that changes in the SML used to form the liposome controlled the release of the liposome contents but did not influence the circulation time of the liposome. This finding highlights one of the advantages of the SMLs for creating a circulating reservoir of drug which could be advantages for tumor targeting./nIn Chapter 6, liposomes composed of SMLs or traditional lipids are prepared to control the release of cisplatin over a range of release rates. I investigated a variety of procedures for encapsulating cisplatin in the liposome and selected the ethanol loading procedure as the best one to obtain good Pt encapsulation with retention of activity. These were used to test the hypothesis that liposomal cisplatin formulations with an intermediate release rate would have improved anti-tumor properties compared to liposomes with slow release rates; however non-leaky formulations had a better anti-tumor efficacy. In an attempt to understand why this was the case, I measured both the distribution of platinum in the tumor using X-ray fluorescence spectroscopy as well as the formation of Pt-DNA adducts in the tumor for free and liposomal cisplatin. All formulations had substantially more Pt in the tumors and a greater amount of Pt-DNA adducts formed than the free cisplatin. Thus, the reason for why liposomal cisplatin formulations do not provide a substantially better anti-tumor effect than the free compound remains elusive.

Advisor: Fréchet, Jean M.J.