The design, synthesis, and biological evaluation of molecular transporter conjugates and their encapsulation inside nanoparticles for drug delivery applications
Abstract/Contents
- Abstract
- Biological barriers prevent the uptake of many potentially harmful xenobiotics yet also limit the delivery and cellular entry of a variety of drugs to their targets. One approach to this problem selects only those compounds with appropriate properties, namely solubility in polar biological fluids yet also able to pass through the nonpolar cellular membrane. This restriction would therefore preclude the use of many polar (e.g. siRNA) and nonpolar (e.g. Taxol) compounds whose inherent physical properties cause problems with formulation, distribution or bioavailability. The research described herein utilizes an alternative strategy that involves molecular transporters, which are agents that, when attached to poorly soluble or poorly bioavailable drugs, produce conjugates that exhibit excellent water solubility and simultaneously an increased ability to cross tissue and cell barriers. Bioactivatable molecular transporter conjugates of the immunosuppressant drug Cyclosporin A incorporating disulfide linkers were developed, evaluated for their biological activity in vitro, and administered topically in an in vivo mouse model. In addition to the inherent physical properties limitation that prevents drug passage across the cell membrane, another significant contributor to the failure of many therapeutics is the overexpression of membrane proteins (e.g. P-glycoprotein or Pgp) that mediate the unidirectional efflux of drugs out of target cells, often doing so prior to the drug reaching its intracellular target. Bioactivatable oligoarginine transporter conjugates of Taxol, a substrate for Pgp, were prepared and shown to overcome efflux-mediated resistance in primary human ovarian cancer tissue ex vivo. The encapsulation of transporter conjugates inside biodegradable polymeric nanoparticles was also investigated as a way to achieve sustained release of transporter drug conjugates over extended periods of time, thereby avoiding metabolism or toxicity problems associated with a bolus administration of therapeutic agents. Nanoparticles encapsulating transporter-probe conjugates were formed using two different methods, and shown to release their encapsulated cargo over time under biologically relevant conditions.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2010 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Galliher, Wesley Charles | |
|---|---|---|
| Associated with | Stanford University, Department of Chemistry. | |
| Primary advisor | Wender, Paul A | |
| Thesis advisor | Wender, Paul A | |
| Thesis advisor | Cegelski, Lynette | |
| Thesis advisor | Trost, Barry M | |
| Advisor | Cegelski, Lynette | |
| Advisor | Trost, Barry M |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Wesley Charles Galliher. |
|---|---|
| Note | Submitted to the Department of Chemistry. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2010. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2010 by Wesley Charles Galliher
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