Controlled metabolic cell labeling and bioorthogonal click chemistry for cancer targeting

cancer targeting;sugar;cell labeling;Click chemistry;nanomedicine;drug delivery;cancer;ultrasound

Wang, Hua

关键词: cancer targeting;    sugar;    cell labeling;    Click chemistry;    nanomedicine;    drug delivery;    cancer;    ultrasound;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/90943/WANG-DISSERTATION-2016.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

The aim of my Ph.D. research is to develop a new, transformative cancer targeted therapy via the combination of unnatural sugar-mediated controlled metabolic cell labeling and bioorthogonal Click chemistry. By controlling the metabolic glycoengineering processes of unnatural sugars via rational chemistry designs, I was able to design a library of trigger-activatable sugar precursors that can label cell surface with chemical groups (e.g., azides) only in the presence of either exogenous triggers (ultraviolet (UV)) or endogenous triggers (H2O2, tumor hypoxia, NAD(P)H dehydrogenase quinone 1 (NQO1), and histone deacetylase (HDAC)/cathepsin L (CTSL)). Among them, HDAC/CTSL-responsive acetylated azidomannose (DCL-AAM) mediated excellent cancer-specific labeling in vitro and in vivo, which enhanced tumor accumulation of dibenzocyclooctyne (DBCO)-drug conjugates via efficient Click Chemistry between azides and DBCO and consequently exerted robust anticancer activities against LS174T colon cancer, MDA-MB-231 triple-negative breast cancer, and 4T1 metastatic breast cancer in murine models. DCL-AAM coupled with DBCO-drug conjugates, a new cancer targeted therapy which I name as Active Tissue Targeting via Anchored ClicK Chemistry (ATTACK), is essentially the small molecule version of antibody/antigen targeting technology and shows multiple advantages. Apart from the efforts in rational chemical designs of azido-sugars, I also developed sugar-loaded micelles and microbubbles for tumor labeling and targeting, in an effort to fully evaluate the advantages of Click chemistry-based cancer targeting strategy. Last but not least, I demonstrated that different types of unnatural sugars (e.g., azido-mannose and azido-galactose) have distinct labeling efficiencies in varying cancer types and that the use of reversible chemistries can impart the recyclability of cell-surface chemical receptors.