Nanotherapeutics in Angiogenesis: Synthesis and in Vivo Assessment of Drug Efficacy and Biocompatibility in the Zebrafish Embryos

Great progress has been made in the last few years in the development of nanomedicine. Studies have provided proof-in-principle that nanomaterials, such as carbon nanotubes (CNTs), could be a new class of therapeutics delivering drugs or targeting tissues without much toxic side effects. Carbon nanotubes have been made aqueous-dispersable, and coupled with various synthesis and conjugation strategies, which have produced prototypes of highly reactive and mobile nanotherapeutics for antimicrobial or anticancer treatment. The wide range of nanotherapeutics and their small sizes, however, adds to the difficulty of in vivo assessment in animal models on their fate, efficacy and biological interactions. Apart from batch to batch variations in the synthesis of these carbon nanotubes, they also differ in size, surface area, surface coating, attached functional groups and contaminants from their specific production processes. Furthermore, before these compounds can be used in the clinic, it is crucial to find out where these carbon nanotubes go and end up once they are being introduced into the body. In this application, the researchers propose to explore a new type of nanotherapeutics, namely, the functionalized single-walled carbon nanotubes (f-SWNTs), to be used as anti-angiogenic agents. These studies will combine the expertise in both chemistry and molecular biology to generate and assess nanotherapeutics with an interdisciplinary approach. New classes of nanotherapeutics will be generated by conjugating aqueous dispersable f-SWNT with a tracking dye, molecules targeting newly formed blood vessels and anti-angiogenic drugs. The biodistribution, efficacy and biocompatibility will be tested in the transparent zebrafish embryos and the anti-angiogenic activities will be further validated in the nude mouse model of tumors. This project will represent one of the first attempts to generate anti-angiogenic agents by attaching anti-angiogenic drug, together with targeting moieties and a tracking dye, onto the same carbon nanotubes. The research team has expertise on the synthesis of different nanomaterials and conjugation strategies on the loading of different functional groups. The researchers have also been investigating the biocompatibility of various nanomaterials, such as nanotubes, quantum dots and silicon nanoparticles, with extensive experience in tracking their fate in vitro and in vivo. For example, they have experienced the difficulty in tracking the presence of carbon nanotubes with electron microscopy and hence they have decided to use a tracking dye here to locate the carbon based nanotubes. The zebrafish system is an important model for studying human development and diseases. The researchers have also shown that drugs causing anti-angiogenesis in human have the same effect in the developing zebrafish embryo. They have successfully applied the zebrafish system to screen for angiogenic modulating activities in Chinese herbs and derived compounds. The researchers are confident that their work will contribute to the understanding of how artificial nanomaterials interact with the biological systems and will produce data on synthesis strategies suitable for generating efficient and safe nanotherapeutics. Moreover, they will be able to extend the application of the zebrafish system to be used as a novel screening platform for the new nanotherapeutics.