Anticancer Therapeutics Based on Tubulin-based Nanotubes and Surface-engineered Gold Nanorods

Abstract

Although the paradigm for anticancer therapy is continuously changing, chemotherapy is still a gold standard for cancer treatment and being broadly used as single or combinatorial therapy. A variety of drug delivery carriers have been developed for reducing the side effect and enhancing the therapeutic efficacy of conventional chemotherapeutics, and for improving the combinatorial effect with other types of cancer therapies. Among them, nanoparticles are being widely studied as anticancer drug carriers due to their high tumor permeation and retention ability. In chapter 1, the benefits of nanoparticles in anticancer drug delivery and the nanoparticles approved for clinical use or under preclinical study are briefly described.In chapter 2, the development of tubulin-based drug carrier which is generally applicable for microtubule-targeting agents (MTAs) was demonstrated. MTAs bind to intracellular microtubules and suppress dynamic instability of microtubules which is crucial in cell division and motility. MTAs inhibit cell division resulting in apoptosis of cancer cells and suppress the proliferation and migration of vascular endothelial cells which are critical in angiogenesis. This dual mode of action of MTAs is suitable for cancer treatment, but the clinical use of these drugs is limited due to low water-solubility, off-target toxicity in normal tissue, and insufficient therapeutic efficacy. Here, a novel nanocarrier made up of tubulins was developed for MTAs based on the facts that 1) multiple MTAs bind to different binding sites on a tubulin and 2) tubulins can self-assemble to superstructures such as protofilaments and microtubules. A block copolymer of polyethylene glycol (PEG) and poly-L-lysine (PEG-b-PLL) was used for the complexation with negatively charged tubulins by electrostatic interactions, and tubulin-based nanotubes (TNTs) were consequentially formed with optimized size of PEG-b-PLLs. Both of microtubule-stabilizing agents and microtubule-destabilizing agents could be loaded on TNTs causing changes in architecture and properties of TNTs, which was profoundly investigated in this study. Also, MTAs occupying different binding sites could be concurrently loaded on TNTs, exerting synergistic effect on anticancer and ant-angiogenesis. In in vitro and in vivo tests, it was shown that MTAs loaded on TNTs were more efficiently delivered to cancer cells, resulting in enhanced therapeutic effects compared to free drugs.In chapter 3, gold nanorods (GNRs) were surface-engineered with a novel coating method and exploited in combinatorial chemo-photothermal therapy for cancer treatment. GNRs are being widely used in cancer theranostics due to their high absorbance at NIR region and superior conversion efficiency to thermal energy or light energy. However, since GNRs are easily aggregated in aqueous solution, some surface modifications are required for their use in biological conditions. In this study, GNRs were surface-engineered with triblock copolymer, poly(TMSMA-r-PEGMA-r-NAS), and the functional group of this polymeric shell was utilized for conjugating cancer targeting ligands or loading anticancer drugs, improving the stability and usefulness of GNRs in cancer imaging and therapy. In specific, this polymer-coated GNRs loaded with Doxorubicin showed synergistic anticancer effect through the combinatorial chemo-photothermal therapy in vitro and in vivo.