Development of synthetic and semi-synthetic transporters for drug and gene delivery
Abstract/Contents
- Abstract
- The delivery of small molecules, probes, and nucleic acids across impenetrable biological barriers represents a challenge for many current clinical strategies. Nucleic acids are of particular interest for delivery with potential clinical applications in cancer immunotherapy, gene editing and vaccines. Chapters 2-5 describe the development and use of charge-altering materials for the delivery of nucleic acids. The charge-altering materials described are dubbed Charge-Altering Releasable Transporters (CARTs), diblock or triblock oligomers consisting of a lipid-modified oligocarbonate block(s) followed by a charge-altering block. The charge-altering blocks, derived from either morpholinones or poly(serine esters), are initially cationic for complexation of the polyanionic nucleic acid cargo but degrade under basic conditions over time to neutral byproducts, providing a mechanism for nucleic acid release. These chapters describe the use of CARTs to deliver a range of nucleic acid cargos (plasmid DNA, messenger RNA, small interfering RNA) across a variety of cell types, including lymphocytes, as well as for in vivo gene delivery. Chapter 6 explores vault proteins as another scaffold for drug or probe delivery. Vaults are naturally occurring, large (13 MDa), hollow ribonucleic protein complexes. These proteins have the potential to be promising delivery agents based on their biocompatibility, size, and internal compartment that can encapsulate hundreds to thousands of molecules. In this chapter, we systematically study the chemical modification of vault proteins and used the developed strategies to prepare vaults modified with cell penetrating peptides for enhanced uptake into cells. Chapter 7 describes the synthesis and evaluation of prodrugs of PKC modulators. Prostratin, bryostatin 1, ingenol esters and their analogs, are potent PKC modulators and have been identified as latency reversing agents (LRAs) for HIV eradication. LRAs can be used to activate the HIV provirus in latent viral reservoir cells, which can then be subject clearance using a "kick and kill" approach. While promising agents, a major challenge associated with the clinical use of LRAs is sustaining therapeutically meaningful levels of the active agent while minimizing side effects. In this chapter, we describe the synthesis of PKC modulator prodrugs designed to slowly release the active drug over time. These PKC modulator prodrugs exhibit comparable but delayed in vitro activity relative to the parent compounds and avoid the problems associated with bolus administration in vivo.
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 | Benner, Nancy Lynn |
|---|---|
| Degree supervisor | Wender, Paul A |
| Thesis advisor | Wender, Paul A |
| Thesis advisor | Dassama, Laura |
| Thesis advisor | Khosla, Chaitan, 1964- |
| Degree committee member | Dassama, Laura |
| Degree committee member | Khosla, Chaitan, 1964- |
| Associated with | Stanford University, Department of Chemistry. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Nancy L. Benner. |
|---|---|
| Note | Submitted to the Department of Chemistry. |
| Thesis | Thesis Ph.D. Stanford University 2019. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2019 by Nancy Lynn Benner
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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