Selective in vivo metabolic labeling for cell targeting and immune regulation

Bo, Yang

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https://hdl.handle.net/2142/121240 Copy

Description

Title

Selective in vivo metabolic labeling for cell targeting and immune regulation

Author(s)

Bo, Yang

Issue Date

2023-07-13

Director of Research (if dissertation) or Advisor (if thesis)

Cheng, Jianjun

Doctoral Committee Chair(s)

• Cheng, Jianjun
• Wang, Hua

Committee Member(s)

• Leal, Cecília
• Chen, Qian
• Lau, Gee

Department of Study

Materials Science & Engineerng

Discipline

Materials Science & Engr

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• Metabolic labeling
• click chemistry
• cancer targeting
• drug delivery

Abstract

My Ph.D. research is focused on developing innovative metabolic glycoengineering techniques that can be used to target cells in vivo and modulate the immune system in selective and controlled manners to provide new solutions for unmet medical needs. In the first part of my research, I developed a cancer targeting and treatment strategy to utilize intracellular non-lethal enzymes through a combination of selective cancer stem-like cell (CSC) labeling and Click chemistry-mediated drug delivery. A de novo designed compound selectively labeled cancer CSCs in vitro and in vivo through enzymatic oxidation by intracellular aldehyde dehydrogenase 1A1 (ALDH1A1). This approach enabled the identification, isolation, and targeting of tumorigenic CSCs. The azido-labeled CSCs could further mediate targeted conjugation of dibenzocyclooctyne (DBCO)-bearing therapeutics via efficient bioorthogonal click chemistry, resulting in significantly improved anticancer efficacy and reduced toxicity against multi-drug resistant colon cancer, triple-negative breast cancer, and metastatic breast cancer. In the second part of my research, by taking advantage of the host cell-pathogen interactions or bacteria-specific enzymes, I for the first time developed unnatural sugars that can selectively label bacteria-infected host cells with chemical tags (e.g., azido groups). The azido-labeled host cells can mediate targeted conjugation of DBCO-bearing imaging and therapeutic agents via efficient click chemistry for the detection and treatment of drug-resistant pathogens. This technique has substantiated an unprecedented approach for intracellular bacteria treatment by using a complete small molecule-based targeting platform of infected host cells and is transferable to other bactericidal agents’ delivery for various lethal infectious diseases. Furthermore, several independent projects under the scope of controlled metabolic glycoengineering for in vivo targeting are also recorded in this dissertation. I demonstrated that fully differentiated mature adipocytes can be metabolically labeled with chemical tags (e.g., azido groups) via metabolic glycoengineering processes of unnatural sugars, which can act as targetable drug depot to prevent post-surgical breast cancer recurrence. I also explored unnatural sialic acid analog modification strategies to achieve in vivo sialic acid remodeling and targeting.

Graduation Semester

2023-08

Type of Resource

Thesis

Copyright and License Information

Copyright 2023 Yang Bo

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