|M.Sc Thesis||Department of Chemistry|
|Supervisors:||Prof. Eisen Moris|
|Prof. Emeritus Lotan Noah|
|Full Thesis text|
There is a continuous demand for optimizing drug administration procedures, thus improving the patient health and quality of life. The traditional methods of drug administration suffer from significant disadvantages. In order to overcome these disadvantages, controlled drug delivery systems are developed. In these systems the rate of the drug release is controlled, therefore a constant concentration of the drug in the blood is maintained. More intelligent drug delivery systems have been developed, since there are clinical situations where even such an approach is insufficient. These include drug targeting systems, from which the drug is preferentially released in the tissue or organ of interest, thus allowing for more effective treatment while not affecting other parts of the body.
In this research, a drug delivery system that combines the controlled release rate and targeting was designed and synthesized. The suggested system is built from drug-containing particles. These are connected to one another with chemical bonds, thus generating clusters.
The clusters will be injected into the blood vessel just upstream of the target organ. As the cluster approaches the organ, the blood vessels narrow, the cluster plugs the blood vessel and the drug is released locally. The bonds connecting the particles break over time; the cluster disintegrates and, finally, unplugs the blood vessel. This system allows for the majority of the drug to be released while the cluster plugs the blood vessel and targeting is achieved based on the cluster size.
A mathematical analysis, dealing with the disintegration course of the clusters and based on the percolation theory, was carried out by Prof. Larry Wein from the Stanford University.
Based on the basic concepts outlined above, a model drug delivery system was successfully synthesized using commercially available poly(styrene-co-divinylbenzene) particles. To these particles sulfhydryl groups were attached using different reaction routes. The clusters were then assembled using a novel homobifunctional cross-linker, namely sebacic acid-bis-hydroxymaleimide, which was synthesized as part of this research. This cross-linker has maleimide moieties at both ends and they react rapidly with the sulfhydryl groups on the particles surface to give thiosuccinimide ester linkages. These esters, resembling the known N-hdroxysuccinimide (NHS) ones, are highly reactive towards nucleophilic reagents and, as such, are hydrolyzed fast. We used basic hydrolysis in order to successfully disintegrate the clusters. The experimental results thus obtained, together with the stipulations of the mathematical model, confirm the validity of the basic concepts underlying the system considered.