MACROMOLECULAR SYSTEMS FOR CHEMOTHERAPY AND MAGNETIC-RESONANCE-IMAGING

The potential of macromolecular pro-drugs in drug delivery and diagnos tic imaging lies in their ability to modify the pharmacokinetic distri bution of low molecular weight drugs or diagnostic agents. At a simple level this may provide a means of sustaining release of drug from a s oluble macromolecule which is retained in the circulation, perhaps avo iding distribution of active drug to a toxicity compartment in the pro cess. There is greater potential in applications which make use of the intrinsic biodistribution of inert macromolecules, in relation to the ir hydrodynamic radius and net charge. Long circulating macromolecular systems may have advantages in magnetic resonance imaging of the bloo d circulation and diagnosis of damaged or inflamed tissues, which may take up the macromolecule to a greater extent than normal tissues. A r elated technology is developing based on the concept that circulating macromolecules accumulate passively in tumours, due to enhanced endoth elial permeability and retention of the macromolecule due to poor lymp hatic drainage. A secondary advantage potentially could be gained by t argeting macromolecules to specific cells by receptor-mediated endocyt osis, and designing systems which are degraded by lysosomal enzymes to release active drug in the target cell. The drawbacks of macromolecul es are their limited penetration into tissues and the relatively slow rates of internalisation by endocytosis, which have discouraged drug d elivery scientists in the recent past. Yet this field is still in its infancy. The tissue distribution of macromolecules with regard to poly mer chemistry, molecular weight and charge are not yet fully understoo d, and advances in this field will depend on the synthesis of well-def ined 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 degradati on, developments in synthetic approaches within the field, and discuss how macromolecular pro-drug chemistry affects their biological proper ties. We pay particular attention to the rationale for their use in ma gnetic resonance imaging and the selection of MRI contrast agents for coupling to polymers.