PEG-epirubicin Conjugates with High Drug Loading

Abstract

PEG is used as a polymeric carrier for low molecular weight drugs, but limitations arise from the fact that only one or two hydroxyl residues are on each polymer. Therefore, the synthesis of dendrimeric structures, based on amino adipic acid or beta-glutamic acid, as a branching molecule, built on a PEG diol of Mw 10,000Da was investigated. The large polycyclic drug epirubicin molecule was chosen as a model to investigate the influence of structure branching and drug steric hindrance during coupling reactions. Several derivatives with increased numbers of drug molecules linked to each PEG chain were synthesized and their physical, chemical and biological properties were studied. The use of specific amino bicarboxylic acids (amino adipic acid or -glutamic acid), as the branching moiety for the dendrimer synthesis, allowed linking the hindered molecule epirubicin to multibranched PEG. Most drug loaded conjugates only dissolve in water following dissolution in DMSO. This solubility problem was solved by adding a hydrophilic peptide linker between the drug and the polymer. The conjugates, synthesized in good yield and purity, showed better stability than free epirubicin in different pH buffers and in plasma as well as prolonged residence time in blood. Dynamic light scattering investigation showed that these products have a high tendency to aggregate forming stable micelles.