Synthesis and Biological Evaluation of a Thermosensitive Phosphazene-Peptide Derivative and Its Doxorubicin Conjugate

Abstract

In order to overcome disadvantages of conventional doxorubicin drug such as severe toxicity and narrow spectrum of activity, a new class of phosphazene trimer-doxorubicin conjugate was synthesized, and their bioavailability, tumor targeting properties and biodegradability were studied. Thermosensitive phosphazene trimer with MPEG and AAE as side group was employed as a carrier for doxorubicin. Phosphazene trimer with side groups tetrapeptide and methoxy-poly(ethylene glycols) is potentially biocompatible and biodegradable to harmless product. Incubation of phosphazene trimer-doxorubicin conjugates with plasmin is showed highest enzymatic release (58%, for 48 hr,) of the drug when the peptide side-chain Gly-Phe-Leu-Gly was used as spacer. We have shown that the poly(organophosphazenes) bearing methoxy-poly(ethylene glycol) (MPEG) and amino acid ester (AAE) as side groups are allowed to be variable in a wide range of LCST by composition. Especially, those with LCST near or below the body temperature in the range of 0 to 40°C are also of interest for the biomedical applications such as local drug delivery and body temperature sensitive drug release. Novel octopus-shape thermosensitive cyclotriphosphazene of cis-nongeminal structures bearing MPEG and AAEs as side group have been synthesized and their LCST behavior was investigated. The LCST of the trimers was affected by several factors such as chain length of MPEG, kind of amino acids and ester groups. Generally, a more hydrophilic composition of the trimers exhibited the higher LCST. Such results indicate that the LCST of the tirmers can be controlled by appropriate design of the trimers. Thermosensitive trimers are expected to be useful for application to local drug delivery system. Phosphazene trimer-doxorubicin conjugate showed remarkable antitumor inactivity against YCC-3 human cell line in vitro (ED_(50)>40 μg/ml ).