Tumor microenvironment specific nanostructure-based drug delivery

Abstract

<br/> Tumor microenvironment (TME) is composed of tumor tissue and its related immune cells, extracellular matrix and secreted proteins. TME is one of the critical factors for disease treatment and it has been attracting the interest of scientists. Targeted drug delivery originally has the highly expressed proteins on tumor cells and its targetable range has been expanded to TME. Recently, TME specific targeted drug delivery has been rising as promising strategy for improving anticancer treatment efficiency and the applicable field is getting bigger. First, DNA nanostructure was formed by self-assembly suing successive 15 guanine sequence extended to the end of DNA aptamer sequence which can specifically bind to protein tyrosine Kinase 7 (PTK7). Methylene blue (MB) was loaded into the G-quadruplex based DNA nanostructure and the complex showed significantly high delivery effect only to PTK7 overexpressing cancer cells. Then the LED irradiation was followed to generate reactive oxygen species (ROS) and resulting in effective cancer cell killing. Secondly, chlorin e6 (Ce6) having cyclic peptide was designed for loading onto reduced graphene oxide (rGO) nanosheets. The peptide was delivered to and cleaved at cathepsin L enzyme-rich TME.Then targetable peptide was activated to recognized the cancer cell surface proteins and receptor mediated endocytosis occurred. NIR irradiation generated hyperthermia at rGO accumulated tumor cell. The photothermal therapy (PTT) showed complete tumor ablation. Lastly, tight junction (TJ) was selected for targeted drug delivery. TJ is the main protein which limits drug delivery to center of tumor mass. TJ binding peptide was loaded onto rGO nanosheets and the TJ disruption-mediated drug delivery efficiency was evaluated in cell spheroid models and tumor bearing mice models. <br/> Keywords: Tumor microenvironment, targeted drug delivery, DNA nanostructure, reduced graphene oxide, photodynamic therapy, photothermal therapy, tight junction, penetration depth