Linear and Star-Like Substituted Polycaprolactones for Enhanced Delivery of Doxorubicin
Washington, Katherine E.
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Doxorubicin is a poorly water soluble chemotherapeutic drug used in the treatment of many cancers. However, due to its toxic side effects, there has been a lot of effort to develop better delivery methods for this drug to alleviate some of the toxicity and to improve its efficacy. Encapsulation of doxorubicin in polymeric micellar drug delivery systems offer an opportunity to improve this delivery by improved solubility and a more controlled release of the drug to tumor sites. Substituted poly(caprolactone)s are a desirable material to use to form amphiphilic block copolymers due to their tunable properties. Depending on the substituent used, the size, stability, degradation rate, and hydrophilicity or hydrophobicity of the micelle can be adjusted. One drawback of micelle drug delivery systems is their tendency to have low drug loading capacities. In this dissertation, several drug delivery systems were designed in order to increase the amount of doxorubicin loading in polymeric micelles. The design and recent advances of polymeric drug delivery systems featuring polyesters is discussed in Chapter 1. Polyesters are attractive drug delivery materials due to their biocompatibility and biodegradability. Many systems have been designed using these systems including those that are stimuli-responsive, designed for a more controlled release of the encapsulated cargo, and those that have targeting to allow for a better accumulation of the drug delivery vehicles at tumor sites. Different systems that have been developed in recent years using polyesters are discussed in this chapter. Chapter 2 describes a comparison of linear and 4-arm star-like block copolymers synthesized from amphiphilic polycaprolactones with a tri(ethylene glycol) substituted polycaprolactone as the hydrophilic block and unsubstituted poly(caprolactone) as the hydrophobic segment. The linear and star-like block copolymers are compared in terms of their thermodynamic stability, degradation, size, and drug loading capabilities, with the star-like structure used as a way to improve the loading of doxorubicin. In Chapter 3, two star-like polycaprolactones featuring either four or six arms are compared in terms of their properties and drug loading abilities. In addition, these polymers are synthesized with a tri(ethylene glycol) substituted poly(caprolactone) hydrophilic block and a ethoxy substituted hydrophobic block, which are shown to have thermally controlled drug release. Chapter 4 focuses on improving the loading of doxorubicin in polymeric micelles through the combination loading of doxorubicin with resveratrol, a polyphenolic compound that has cardioprotective and chemosensitizing properties. Resveratrol, when loaded in combination with doxorubicin, increases the amount of doxorubicin encapsulated in the micelle significantly. This can be a way to improve loading of the chemotherapeutic drug, while also decreasing some of its toxic side effects.