A toolbox of peptide-drug conjugates for targeted chemotherapy
Abstract/Contents
- Abstract
- Traditional cancer chemotherapeutics often have narrow ranges between their effective and toxic doses. To improve efficacy and minimize side effects, protein-drug conjugates (PDCs) can be used to selectively deliver chemotherapeutics to cancerous tissue. Existing targeting agents rely nearly exclusively on high molecular weight (MW) proteins, namely antibodies. Low MW targeting agents offer a dramatically altered pharmacokinetic profile and have potential to overcome historical limitations of antibody-drug conjugates including limited efficacy against solid tumors and difficulty targeting brain tumors due to an inability to cross the blood-brain-barrier. Despite the theoretical advantages of low MW targeting proteins, there exists some skepticism that this class of PDCs would be highly effective due to rapid systemic clearance or toxicity. The work presented here includes the development and testing of a toolbox of PDCs comprising an identical tumor targeting moiety and toxic warhead but having diverse molecular properties including varying MW and valency. This set of PDCs enables investigation of the impact of varying features on circulatory half-life, tumor penetration, and therapeutic efficacy. Chapter 1 provides background on tumor-targeting and motivation for this work. Chapter 2 discusses the engineering of a broadly specific tumor targeting agent, a detailed investigation of the structural basis of its targeting mechanism, and an exploration of its use as a tumor imaging agent. Chapter 3 describes the development of an ultra-low MW PDC from this tumor targeting agent and an investigation of its mechanism of drug delivery. Chapter 4 focuses on the development and in vivo testing of an intermediate MW PDC with pharmacokinetic properties between an antibody-drug conjugate and an ultra-low MW PDC. Chapter 5 presents the entire toolbox of PDCs and demonstrates the in vivo potency of monovalent, low MW targeting proteins as alternative scaffolds for drug delivery. Finally, Chapter 6 summarizes the existing clinical landscape of PDCs and highlights the role of this work in promoting further research into targeted chemotherapy.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2019; ©2019 |
| Publication date | 2019; 2019 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Kintzing, James Reese |
|---|---|
| Degree supervisor | Cochran, Jennifer R |
| Thesis advisor | Cochran, Jennifer R |
| Thesis advisor | Bertozzi, Carolyn R, 1966- |
| Thesis advisor | Huang, Possu |
| Degree committee member | Bertozzi, Carolyn R, 1966- |
| Degree committee member | Huang, Possu |
| Associated with | Stanford University, Department of Bioengineering. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | James Reese Kintzing. |
|---|---|
| Note | Submitted to the Department of Bioengineering. |
| Thesis | Thesis Ph.D. Stanford University 2019. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2019 by James Reese Kintzing
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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