Application of lipoprotein as drug delivery system for anticancer drug and DNA-based vaccine
Alanazi, Fars Kaed
MetadataShow full item record
Various advanced drug delivery systems such as lipoprotein, red blood cell, and albumin have been investigated to overcome the limitation of the conventional systems. One of the advantages of using these advanced drug delivery systems is that they are natural plasma components. The main focus of this research is to study the application of lipoprotein as drug delivery system for cancer therapy and for DNA based vaccines. The high requirement of LDL by malignant cells and thus the overexpression of LDL receptor can be utilized for developing a novel targeted drug delivery system. This can be achieved by targeting of the LDL particle in vivo and allowing the anticancer drugs to be transfered to the natural LDL inside of the body. Basically, LDL will function as a secondary carrier of anticancer molecules in vivo and deliver these molecules selectively toward cancerous cells via elevated LDL receptors. This approach requires the anticancer molecules to have affinity of the LDL particle endogenously and to have certain special physicochemical properties. We hypothesized that mimicking the cholesterol ester can facilitate targeting of the LDL particle and cancer cells. Therefore, we synthesized new cholesterol boron conjugates. Liposomes were prepared as the first carrier of these compounds and the factors affecting the incorporation in liposomes were studied. We also investigated the distribution of one of these compounds, BCH, in the brain after intracerebral administration using a tumor-bearing rat model. Since these compounds will face hydrolytic enzymes in vivo that limit their targeting activity, by liberating cholesterol from anticancer moiety, stability studies of a representative compound, BCH, in simulated biological media were carried out. Inductively Coupled Plasma (ICP), an analytical technique for determining concentration in liposomal formulation and tissue samples was evaluated. To examine the transfer of these compounds from liposomal formulation to low density lipoprotein (LDL) in vitro, an ultra-centrifugation method was developed and optimized. An artificial lipoprotein system mimicking natural lipoprotein in the human body was evaluated as a novel DNA based vaccine delivery system. The artificial lipoprotein is composed of an oil-in-water emulsion, hydrophobic polyamine polymer and plasmid DNA. Characterization of the complex with DNA as well as transfection efficiency was studied.