The goal of this research is to study how the cholesterol content in liposomal formulations affects the anticancer activity (e.g., cell growth suppression) of combretastatin A4 phosphate (CA4P). CA4P is a powerful antivascular agent currently under clinical trials for treating solid tumors. Liposomal CA4P has several advantages over free CA4P, including the reduced toxicities and the increased overall drug efficacy. In this thesis work, I have demonstrated that the proliferation of breast cancer MCF-7 cells varies with the cholesterol mole fraction in the formulation of liposomal CA4P in a biphasic manner, displaying a local minimum at the critical sterol mole fractions (Cr) for maximal superlattice formation. Cell proliferation was monitored using a fluorescence-based assay. Since cholesterol content determines membrane lateral organization, my results imply that membrane lateral organization plays an important role in regulating the anti-cancer activity of liposomal CA4P. This finding provides a new concept in the rational design of liposomal anti-cancer drugs. More than 20 anticancer drug formulations are in the market or under clinical trials. Most of them include cholesterol as a major component. My present study indicates that cholesterol is not just serving as a vesicle stabilizing agent, but also modulates the activity of liposomal drugs. The principle learned from CA4P can be extended to other liposomal anti-cancer drugs. This study is also significant from the membrane biophysics point of view. The data provide additional support for the sterol superlattice model and illustrate that the concept of sterol superlattice can be applied to biotechnology development. / Biochemistry
| Identifer | oai:union.ndltd.org:TEMPLE/oai:scholarshare.temple.edu:20.500.12613/3946 |
| Date | January 2010 |
| Creators | Zhu, Weiwei |
| Contributors | Chong, Parkson Lee-Gau, Collins, Jimmy H., Merali, Salim, Chan, Marion M. |
| Publisher | Temple University. Libraries |
| Source Sets | Temple University |
| Language | English |
| Detected Language | English |
| Type | Thesis/Dissertation, Text |
| Format | 88 pages |
| Rights | IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available., http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | http://dx.doi.org/10.34944/dspace/3928, Theses and Dissertations |
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