Date of Award
Doctor of Philosophy (PhD)
Professor Harald D. Stöver
Professor Shiping Zhu
The newly emerged biotechnology of liposome-based drug delivery has drawn great interest in research and pharmaceuticals. Lipsomes are potential candidates to carry highly toxic drugs to target cells in order to minimize the damage to normal cells and side effects. In the past two decades, extensive work has improved the stability of phospholipid lipsomes in physiological fluids as drug carriers.
My research on developing controlled release drug delivery systems started with the synthesis of a highly reliable anchor for water-soluble polymers, which will serve as an anchor with a high affinity towards lipid bilayers and can be monitored by fluorescence. A new family of hydrophobic building block, namely cholesterol and fluorescence. A new family of hydrophobic building block, namely cholesterol and fluorescence group, was prepared and characterization. The conformation study suggests that intramolecular hydrogen bonds form via amide proton of these compounds in methanol-d3 and DMSO-d6. Furthermore, an efficient synthetic route was developed to synthesize the corresponding pyrenylbutyl cholestrol lysine derivative.
These functional hydrophobic building blocks were successfully attached to water-soluble polymers such as poly(N-isopropylacrylamide). Solution properties of the modified polymers were investigated by fluorescence, time-resolved fluorescence, and dynamic light scattering. The cholesterol bearing PNIPAM exhibited the lower critical solution temperature (LCST), which was close to that of the precursor polymer. The polymers formed micellar aggregates in water via inter or/and intrapolymeric associations, which depended on the polymer architecture and solution tempeprature.
Interaction of phospholipid and nonphospholipid liposomes with these thermoresponsive polymers was followed in order to develop controlled release systems based on cholesterol-bearing poly(N-isopropylacrylamide) coated liposomes. The strong interaction between the polymer and liposomes was found via fluorescence and gel-filtration chromatography measurement. As expected, the cholesterol-bearing polymers remained on the liposome surfaces as increasing temperature up to 60°C. In contrast, above the LCST of PNIPAM, octadecyl group modified PNIPAM escaped from lipsosome surfaces and left liposome unprotected. Interesting results were also found in the study of temperature controlled release and target fusion of these polymers coated liposomes.
In addition, controlled release systems based on hybrid polymeric nanoparticles formed by self-assembled cholestrol-bearing pullulan and poly(N-isopropylacrylamide) (PNIPAM) were studied. The hybrid nanoparticles further proved that cholesterol was a reliable anchor, which remained in hydrophobic microdomains of the hybrid nanoparticles in the studied temperature range from 20 to 45°C. In comparison, octadecyl group modified PNIPAM escaped from hybrid nanoparticles at the temperature above the LCST of PNIPAM.
Finally, these hydrophobic building blocks were attached to polysaccharide, hyaluronan (HA), to develop targeting delivery systems. Synthesis, characterization, solution properties of cholesterol bearing HA and interaction of the polymer with liposomes were conducted. The highly reliable liposomes as site-specific carriers were developed by coating the cholesterol-bearing hyaluronan onto lipsomes.
Li, Ming, "Development of Controlled Release Drug Delivery Systems" (2002). Open Access Dissertations and Theses. Paper 966.