Recent advancements in pharmaceutical technology based on principles of nanotechnology, polymer chemistry, and biomedical engineering have resulted in the creation of novel drug delivery systems with the potential to revolutionize current strategies in cancer chemotherapy. In oncology, realization of significant improvements in therapeutic efficacy requires minimization of drug exposure to healthy tissues and concentration of the drug within the tumor. As such, encapsulation of chemotherapeutic agents inside nanoparticles capable of enhancing tumor-targeted drug delivery is a particularly promising innovation. Yet, initial investigations into the intratumoral fate of nanomedicines have suggested that they may be heterogeneously distributed and achieve limited access to cancer cells located distant from the tumor vasculature. As such, uncovering the determinants of nanoparticle transport at the intratumoral level is critical to the development of optimized delivery vehicles capable of fully exploiting the therapeutic potential of nanomedicines. In this work, the chemotherapeutic agent, docetaxel (DTX), was incorporated into nano-sized, biocompatible PEG-b-PCL block copolymer micelles (BCMs). Encapsulation of DTX in micelles via chemical conjugation or physical entrapment resulted in a dramatic increase in drug solubility and customizable drug release rate. The use of multicellular tumor spheroids (MCTS) was established as a viable platform for assessing the efficacy and tumor tissue penetration of nanomedicines in vitro. A series of complementary assays was validated for analysis of DTX-loaded micelle (BCM+DTX) toxicity in monolayer and spheroid cultures relative to Taxotere®. Cells cultured as spheroids were less responsive to treatment relative to monolayer cultures due to mechanisms of drug resistance associated with structural and microenvironmental properties of the 3-D tissue. Computational, image-based methodologies were used to assess the spatial and temporal penetration of BCMs in spheroids and corresponding human tumor xenografts. Using this approach, the tumor penetration of micelles was found to be nanoparticle-size-, tumor tissue type- and time- dependent. Furthermore, spheroids were found to be a valuable platform for the prediction of trends in nanoparticle transport in vivo. Overall, the results reported herein serve to demonstrate important determinants of nanoparticle intratumoral transport and to establish computational in vitro and in vivo methodologies for the rational design and optimization of nanomedicines.

Recent advancements in pharmaceutical technology based on principles of nanotechnology, polymer chemistry, and biomedical engineering have resulted in the creation of novel drug delivery systems with the potential to revolutionize current strategies in cancer chemotherapy. In oncology, realization of significant improvements in therapeutic efficacy requires minimization of drug exposure to healthy tissues and concentration of the drug within the tumor. As such, encapsulation of chemotherapeutic agents inside nanoparticles capable of enhancing tumor-targeted drug delivery is a particularly promising innovation. Yet, initial investigations into the intratumoral fate of nanomedicines have suggested that they may be heterogeneously distributed and achieve limited access to cancer cells located distant from the tumor vasculature. As such, uncovering the determinants of nanoparticle transport at the intratumoral level is critical to the development of optimized delivery vehicles capable of fully exploiting the therapeutic potential of nanomedicines. In this work, the chemotherapeutic agent, docetaxel (DTX), was incorporated into nano-sized, biocompatible PEG-b-PCL block copolymer micelles (BCMs). Encapsulation of DTX in micelles via chemical conjugation or physical entrapment resulted in a dramatic increase in drug solubility and customizable drug release rate. The use of multicellular tumor spheroids (MCTS) was established as a viable platform for assessing the efficacy and tumor tissue penetration of nanomedicines in vitro. A series of complementary assays was validated for analysis of DTX-loaded micelle (BCM+DTX) toxicity in monolayer and spheroid cultures relative to Taxotere®. Cells cultured as spheroids were less responsive to treatment relative to monolayer cultures due to mechanisms of drug resistance associated with structural and microenvironmental properties of the 3-D tissue. Computational, image-based methodologies were used to assess the spatial and temporal penetration of BCMs in spheroids and corresponding human tumor xenografts. Using this approach, the tumor penetration of micelles was found to be nanoparticle-size-, tumor tissue type- and time- dependent. Furthermore, spheroids were found to be a valuable platform for the prediction of trends in nanoparticle transport in vivo. Overall, the results reported herein serve to demonstrate important determinants of nanoparticle intratumoral transport and to establish computational in vitro and in vivo methodologies for the rational design and optimization of nanomedicines.

ABSTRACT Effective drug delivery to ocular tissues is an unmet challenge that has significant potential to improve the treatment of ocular diseases. Whether the intended drug delivery target is the anterior or posterior segment, the eye’s efficient natural protection mechanisms prevent effective and sustained drug delivery. Anatomical and physiological barriers including the rapid tear turnover that effectively washes away topically applied drugs, the impermeable characteristics of the cornea, conjunctiva, and sclera, and the tight junctions in the blood-ocular barriers make conventional drug delivery methods ineffective. New materials that are able to overcome these barriers are essential to improving the sustained delivery of ophthalmic therapeutics to the intended targets within the eye. This thesis will explore two polymeric drug delivery systems that have the potential to improve therapeutic delivery to ocular tissues. Chapter 1 will discuss the anatomical and physiological barriers to ophthalmic drug delivery and overview current research in this area. Chapter 2 will discuss the synthesis of N-isopropylacrylamide-based copolymers with adjustable gelation temperatures based on composition and molecular weight. Chapter 3 will discuss further development of these copolymers into an injectable, thermoresponsive, and resorbable polymeric drug delivery system intended for the treatment of diseases in the posterior segment. Chapter 4 will discuss the development of mucoadhesive polymeric micelle nanoparticles based on phenylboronic acid intended for topical administration of ophthalmic therapeutics. Finally, Chapter 5 will provide an overview of potential future work on these materials that could further develop and broaden their therapeutic use. / Thesis / Master of Science in Biomedical Engineering