A Biodegradable Polymeric Carrier Based on PEG for Drug Delivery

A biodegradable copolymer (PEG-fum), based on poly(ethylene glycol) (PEG) and fumarate (fum) units, was synthesised and studied as a drug carrier. PEG and fum were linked together by ester bonds to confer biodegradability to the polymeric backbone in vivo. Hence, this copolymer can be used with molecular weights above the kidney clearance threshold for PEG without body accumulation. The PEG-fum was designed to be a high drug loading carrier due to the fumarate units, thus, overcoming the limitations of linear PEGs. Suitable reactive groups for drug coupling were added by reacting fumarate with tioglycolic acid (TGA). The pendant TGA carboxylic groups were conjugated to the camptothecin derivative, SN38, taxol and epirubicin, respectively. The SN38 and taxol linked to the PEG-fum-(TGA) increased their solubility 15 and 100 fold, respectively. The rate of 2 SN38 release in plasma was adequate for prolonged circulation in vivo, while taxol was rapidly hydrolysed. This relatively fast degradation could hamper the conjugate from accumulating in the tumor tissue by enhanced permeability and retention effect (EPR). Instead, EPR effect could be exploited with the epirubicin conjugate coupled by means of a hydrazone bond. This linkage provides good blood stability, while readily cleaved in acidic environment like those in endosomes and lysosomes. Therefore, the drug is released intercellularly in its active form only after, thus reducing toxic effects.