| Majority of clinically approved imaging and therapeutic agents have a short blood half-life and diffuse quickly into healthy tissue. Efficient imaging or efficacious drug therapy is often hindered because a low concentration is present at the target tissue. Although repeated and higher dosing regimens are an option, it may not be safe, convenient or economical. Macromolecular carriers improve delivery of low molecular weight compounds because they accommodate a large payload, prevent degradation, minimize toxicity, passively accumulate within diseased tissue and facilitate cellular uptake. The work that is discussed in this thesis will describe the design and synthesis of two new macromolecular platforms. First, biodegradable polydisulfide copolymers were prepared as carriers for MRI contrast agents. These polymeric Gd(III) complexes were designed to provide high contrast enhancement within the vasculature, but eventually degrade over time to prevent long-term retention. The polymer backbone was modified with a variety of alkyl amide side groups to investigate its effect on in vitro and in vivo properties. In addition, poly(L-lysine) dendrimers up to generation 4 were prepared from an octa(3-aminopropyl)silsesquioxane (OAS) core. These poly(L-lysine) OAS dendrimers, or nanoglobules, exhibit a rigid, globular morphology that improves conjugation of surface moieties during agent preparation and modification. The preliminary studies show that nanoglobules are effective and diverse carriers for MRI contrast agents, nucleic acids and chemotherapeutics. Nanoglobular MRI contrast agents up to generation 3 were prepared by conjugating Gd(III) complexes onto the surface. These agents exhibit a size-dependent contrast enhancement within the vasculature and passively accumulate within tumor tissue at 1/10 th clinical dose. The nanoglobules can also condense nucleic acids, facilitate cellular entry, and exhibit higher transfection efficiency as compared to commercial agents. Lastly, nanoglobules are highly modifiable, as is evident by the preparation of targeted, nanoglobule doxorubicin conjugates for co-delivery with siRNA. In vitro silencing studies show that the dual-loaded nanoglobule conjugates can simultaneously silence gene expression and mediate cell death by effectively transporting siRNA and doxorubicin, respectively, into cells. |
