Sustained release of growth factors

With the identification, characterization and cloning of specific growth factors, recombinant proteins are now widely used in the clinic. The use of recombinant hematopoietic growth factors has, for example, allowed the clinical manipulation of the hematopoietic system. Recombinant human granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are now widely used to mobilize hematopoietic stem cells (HSC) thereby providing a source of HSC for autologous or allogeneic transplantation, in addition to treating congenic, iatrogenic and disease-related neutropenia. However, one disadvantage associated with the use of most recombinant molecules is their rapid clearance. Clearance mechanisms include glomerular filtration, receptor binding and/or enzymatic degradation. Because of the rapid clearance, of recombinant molecules they require repeated administration to achieve biological efficacy. Initially, continuous infusion (CI) was used to address this pharmacological deficiency. CI has the advantage of delivering drugs in a controlled manner and is particularly appropriate when it is important to maintain constant plasma drug concentrations. However, the requirement for continuous venous access and the use of ambulatory pumps limits its use. Thus other approaches have been developed to improve the pharmacokinetic and pharmacodynamic properties of recombinant proteins in vivo. These have included the addition of polyethylene glycol (PEG) to the recombinant molecules (PEGylation) and the use of sustained release delivery matrices and liposomes. One goal of these approaches is to achieve clinical efficacy with significantly fewer, possibly single injections, thereby increasing patient compliance. In addition to improving the pharmacokinetic and pharmacodynamic profile of recombinant molecules, sustained release may also increase the biological activity of the molecules.