Development of thermoresponsive substituted poly(caprolactone)s: Synthesis, self-assembly, and drug encapsulation

In recent years, extensive research has focused on the development of drug delivery systems that can solubilize, deliver, and release drug molecules at designated targets in vivo. Improving the delivery of currently available drugs can enhance their efficacy, minimize side effects, and potentially discover new targets for already FDA-approved molecules. Drug carriers that can release their payload upon a stimulus, such as an increase in temperature from 37 -- 40 °C, may provide a means of controlling the drug release. Aliphatic polyesters, and poly(caprolactone)s in particular, are common components in drug delivery applications largely due to their biodegradable backbones. As discussed in Chapter 1, the ease with which caprolactone monomers can be substituted with functional groups and polymerized has contributed to their widespread use in polymeric drug carriers that have tunable properties like micelle stability, drug loading, and stimuli-responsive behavior. While many copolymers have been explored as micellar drug carriers, very few amphiphilic diblock copolymers exhibit both a fully biodegradable backbone and thermoresponsive behavior. First reported by the Stefan group, block copolymers featuring poly{gamma-2-[2-(2-methoxyethoxy)ethoxy]ethoxy-epsilon-caprolactone} (PME 3CL) have showcased the great potential of PME3CL as a thermoresponsive, biodegradable hydrophilic block in micellar assemblies. Presented in Chapter 2 is the synthesis and characterization of new micelle-forming amphiphilic, biodegradable, and thermosensitive diblock copolymers featuring gamma-(2-methoxyethoxy)-epsilon-caprolactone (ME1CL) and ME3CL. Highly tunable lower critical solution temperatures (LCSTs) in the range of 31 -- 43 °C were achieved by synthesizing a series of PME3CL-b-PME1CL copolymers with varying block ratios. Chapter 3 discusses the design and synthesis of block terpolymers from ME3CL, ME1CL, and unsubstituted caprolactone as potential a route to micelles with enhanced thermodynamic stability and drug loading capacity. Compared to previous PME 3CL-type diblock copolymers, these diblock terpolymers demonstrated lower critical micelle concentrations by one order of magnitude and more than a two-fold increase in doxorubicin drug loading capacity. Preliminary in viitro biological studies including micelle cytotoxicity, stability in protein-containing serum, and uptake by HeLa cells also are presented. The findings suggest that using a combination of substituted and unsubstituted caprolactones in the micelle core may greatly enhance the drug loading in other PME3CL-based thermoresponsive block copolymers.