Synthesis and Self-Assembly of Miktoarm Polymers and Design of a Drug-Polymer-Imaging Conjugate.

摘要

Miktoarm polymers, a relatively new and unique class of macromolecules, constitute a topical area of research due to their intriguing properties which can be tailored by varying their polymeric arms. Much emphasis has been placed in the recent past in developing synthetic methodologies to these star polymers, and examining their self-assembly behavior in solution. In this thesis, a simple and highly versatile synthetic methodology to ABC type miktoarm star polymers is developed using a combination of highly efficient CuI catalyzed cycloaddition between an alkyne and azide, and ring opening polymerization. To carry out these reactions in sequence, a molecular building block with three orthogonal functionalities was first designed. The two alkynes on this trifunctional core were deprotected sequentially, and coupled with azide terminated poly(ethylene glycol) (PEG) and polystyrene (PS) respectively, using "click" chemistry. It was then followed by ring-opening polymerization of caprolactone at the third reactive centre of the building block. Using this methodology, a library of miktoarm polymers were prepared and characterized using a variety of techniques including 1H and 13C{1 H} NMR and gel permeation chromatography. Aqueous self-assembly of these star polymers was examined using dynamic light scattering (DLS) and transmission electron microscopy (TEM). These miktoarm polymers form spherical micelles which were found to be stable over time, and an inverse relationship between the size of poly(ethylene glycol) and the hydrodynamic diameter of the micelles was observed. The sizes from DLS correlated well to those obtained from TEM which showed the presence of spherical micelles composed of a mixed PS and PCL core, with a PEG corona. The miktoarm polymer mu(PEG775 -PS2700-PCL6900) showed a mixture of micelles and worm-like structures resembling a pearl necklace. The ability of miktoarm polymers to encapsulate small molecules was evaluated using disperse red 1, and loading of up to 2 wt% was achieved. The versatility of the trifunctional building block used in the synthesis of miktoarm polymers was elaborated by constructing a multifunctional carrier containing conjugated therapeutic agent (nicotinic acid), imaging probe (BODIPY as a fluorescent label), and a solubilizing agent, a short PEG arm. A preliminary investigation of the uptake of this multi-tasking carrier by the macrophages in mice suggested that it is taken up quickly into the cells, and targets lipid droplets, as observed by confocal microscopy.