Controlled drug delivery can influence the performance of a drug by manipulating its concentration, location and duration. Therefore, it provides a promising way to minimize side effects and increase therapeutic efficacy. In the past decades, controlled drug delivery technology has represented one of the frontier areas of science, which involves multidisciplinary scientific approach. This thesis describes the development and characterization of new nanoparticles-based drug carriers with unique release properties.
Chapter 3 describes the development of a polymeric nanoparticle-based drug delivery system for the anticancer drug doxorubicin. Biodegradable poly (lactide-co-glycolide) (PLGA) particles of various sizes were prepared by changing the polymer concentration. Transmission electron microscopy (TEM) images revealed that the particles had smooth spherical morphology with a mean size ranging from 110nm to 180nm. The in vitro release profile showed that small particles (110nm) had a higher release rate compared to larger particles (180nm). For all nanoparticles prepared with different polymer concentration, an initial burst release, followed by a slow release, were observed. These results indicated that the drugs were released through a diffusion-controlled release mechanism. Fluorescence imaging studies showed that the nanoparticles could be internalized by MCF-7 human breast cancer cells. Interestingly, different intracellular distribution of free drugs and the drug-loaded nanoaprticles were observed. It
indicated that they were taken up by different mechanism. Probably free drugs were taken up by diffusion and nanoparticles were internalized by non-specific endocytosis. The bioactivity of the drugs was also tested against MCF-7 cell culture. In vitro cytotoxicity study showed that drug activity had been maintained in these particles.
In Chapter 4, we reported the preparation of mesoporous silica nanoparticles and their use in triggered drug release system. Silica nanoparticles, which can be prepared with a desired size, tunable pore size and surface properties, were previously used as hosts of proteins and catalysts. We loaded the mesoporous silica nanopartilces with the tetramethylrhodamine dextran (TMR- Dex), which was used as a fluorescent drug analog. We then coated the nanoparticles with a phospholipid membrane to seal drug molecules inside the nanoparticles. Temporal release profiles showed that 95% of the TMR-Dex molecules were retained in phospholipids coated silica nanoparticles over 12 hours. In contrast about 90%of the TMR-Dex molecules leaked from uncoated silica particles during the same time period. The release of TMR-Dex molecules from phospholipids coated silica particles was triggered by adding the antimicrobial peptide cecropin-melittin to the particle suspension. About 70% of TMR-Dex molecules were released in 2 hours following the addition of 0.175mg/mL cecropin-melittin (final concentration). The regulated release of the encapsulated content was realized by adjusting the level of the antiimicrobial peptide cecropin (1-8)-melittin (1-18). Further studies will focus on optimizing the composition of lipids membrane to selectively destroy the coating without inducing toxicity to living cells.
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VITA
The author was born in Henan, China. In 1989, she began her undergraduate study in Zhengzhou University, where she obtained her B.S. degree in Chemistry Department in 1993. She continued her graduate study in organic chemistry at Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences and earned a M.S. degree in 1996. In 2000, she joined the Department of Chemistry at the University of New Orleans and became a member of Professor Zeev Rosenzweig’s research group.