Polymeric Nanoparticle and Bioconjugate MRI Contrast Agents for In Vivo Imaging
- Author(s): Le Guyader, Clare Lee Matilda
- Advisor(s): Gianneschi, Nathan C
- et al.
Nanoparticles are the hallmark of nanomedicine, proving clinically relevant for the delivery of therapeutic and diagnostic drugs. Nanomaterials are highly versatile, with the ability for scientists to tailor composition and function to suit the desired application. Herein, two types of nanocarriers are investigated in the context of magnetic resonance imaging contrast agents: polymeric nanoparticles and protein carriers.
A key research focus in applying nanoparticles for drug delivery is in understanding physicochemical properties affecting in vivo fate. Shape or morphology of a particle is a vastly underutilized property in the design of nanoparticles, and is difficult to predictably control in the context of polymeric nanoparticles. Investigations of block copolymer nanoassemblies evaluate effects of the polymer structure and the self-assembly process to form interesting and diverse structures.
In this work, ring-opening metathesis polymerization is employed to prepare and study block copolymer amphiphile self-assembly. First, a small library of amphiphiles are prepared in which the hydrophobic block functionality is varied. In varying the polymer structure and the solvent for assembly, different morphologies are produced, including small and large spheres, cylinders, y-junctions, and rods. In several cases, one polymer can take on different morphologies depending on the organic cosolvent used during micellization, highlighting the importance of assembly conditions and dynamics in forming kinetically trapped structures versus thermodynamically stable structures. These are important considerations when designing, synthesizing, and formulating polymeric nanoparticles for in vivo applications.
Next, direct incorporation of a gadolinium based contrast agent for magnetic resonance imaging is studied. A novel monomer and chain transfer agent of a gadolinium-chelate are used to directly incorporate the contrast agent in to a polynorbornene polymer backbone. The resulting spherical and fibrillar nanoparticles exhibited enhanced relaxivity and are studied as MRI contrast agents using live imaging in murine models.
Finally, a fatty acid ligand is conjugated to a gadolinium-based contrast agent is prepared and formulated with human serum albumin. In formulation with HSA, the agent exhibits high relaxivity and prolonged blood circulation. In addition, therapeutic conjugates formulated with HSA are evaluated for in vitro cytotoxicity and found to be effective in tumor growth suppression in vivo.