Ian Wark Research Institute
ARC Special Research Centre
ARC Special Research Centre
Research Area: Colloid and nanostructures, biointerfaces, pharmaceutical delivery
Degree: Honours
Supervisors: Prof Clive Prestidge
and Dr Tim Barnes (School of Pharmacy)
Description: Dendrimers are a novel class of nanoparticulate biomaterials with highly branched, tree-like structures. They arise from the repeated addition of series (or generations) of polyfunctional units to a central core. The last layer of terminal groups can be capped with any of a variety of surface reagents to provide a vast array of surface chemistry. Dendrimers are molecules of a similar scale to proteins, and as such they offer a mode of interaction with biological systems that is distinct from the typical small molecule therapies, in that they can act through a multivalent mechanism, whereby multiple surface ligands
interact simultaneously with multiple receptors at the biological site
of action. This binding mode has the advantage of amplifying what can be
a weak "monovalent" recognition to a therapeutically useful strong, and specific
"multivalent" recognition.
Right:
Dendrimer interaction
With this in mind, dendrimer molecules are being developed for biological/pharmaceutical applications, e.g. anti-viral for sexually transmitted disease, anti-bacterial products, anti-cancer, drug delivery, etc. The high level of biological activity for dendrimers compared with conventional drug molecules is considered to be a result of their multiple functional groups and hence their strong surface activities with cell and virus particle surfaces. Previous work has lead to the ability to surface modify dendrimers for targeting and to attach them to surfaces for specific applications.
Right:
Traditional drug interaction
Schematic representation of drug
interaction with cell receptors (from http://www.starpharma.com)
However, limited information is available concerning the physicochemical properties of dendrimers in solution or the kinetics and thermodynamics of their interactions at the solid-liquid interface. An improved understanding of the solution and interfacial activity of dendrimer molecules is critical for optimising their formulation, controlling their delivery and gaining an improved understanding of their biological activities. The aims of the proposed project are to:
Approach: The physicochemical properties of dendrimers will be determined as a function of their type, surface modification and the solution conditions (i.e. pH, salt and temperature). Scattering techniques will be employed to characterize the size and electrical properties of dendrimer molecules in solution. Cryo- electron microscopy techniques will be employed for imaging dendrimers in solution and atomic force microscopy (AFM) used to image the size, shape and structure of surface-immobilised dendrimers, with nanometre scale resolution.
The successful utilisation of dendrimers as therapeutics will also require a detailed understanding of how these molecules can be made bioavailable. In order for a dendrimer to reach an intracellular target, it must first find passage through the cell membrane. Investigations will be undertaken to gain insight into how the surface properties of the dendrimer control the interaction between dendrimers and lipid bilayers that model the properties of biological membranes.
References
D�Emanuele, A.; Attwood, D.; Abu-Rmaileh, R. Dendrimers. Encyclopaedia of Pharmaceutical Technology; Marcel Dekker, NY, 2003,
1-21
Liu, M.; Frechet, J. N. J. Designing dendrimers for drug delivery. Pharm. Sci. and Technol. Today. 1999, 2(10),
393-401
Frechet, J. N. J.; Tomalia, D. A. Dendrimers and other dendritic polymers. John Wiley & Sons Ltd,
2001
