Macromolecular Systems for Chemotherapy and Magnetic Resonance Imaging

The potential of macromolecular pro-drugs in drug delivery and diagnostic imaging lies in their ability to modify the pharmacokinetic distribution of low molecular weight drugs or diagnostic agents. At a simple level this may provide a means of sustaining release of drug from a soluble macromolecule which is retained in the circulation, perhaps avoiding distribution of active drug to a toxicity compartment in the process. There is greater potential in applications which make use of the intrinsic biodistribution of inert macromolecules, in relation to their hydrodynamic radius and net charge. Long circulating macromolecular systems may have advantages in magnetic resonance imaging of the blood circulation and diagnosis of damaged or inflamed tissues, which may take up the macromolecule to a greater extent than normal tissues. A related technology is developing based on the concept that circulating macromolecules accumulate passively in tumours, due to enhanced endothelial permeability and retention of the macromolecule due to poor lymphatic drainage. A secondary advantage potentially could be gained by targeting macromolecules to specific cells by receptor-mediated endocytosis, and designing systems which are degraded by lysosomal enzymes to release active drug in the target cell. The drawbacks of macromolecules are their limited penetration into tissues and the relatively slow rates of internalisation by endocytosis, which have discouraged drug delivery scientists in the recent past. Yet this field is still in its infancy. The tissue distribution of macromolecules with regard to polymer chemistry, molecular weight and charge are not yet fully understood, and advances in this field will depend on the synthesis of well-defined polymers, and careful characterisation of their properties. Here we review the rationale for the use of macromolecules in chemotherapy, the susceptibility of macromolecular pro-drugs to lysosomal degradation, developments in synthetic approaches within the field, and discuss how macromolecular pro-drug chemistry affects their biological properties. We pay particular attention to the rationale for their use in magnetic resonance imaging and the selection of MRI contrast agents for coupling to polymers.