Abstract

Melphalan has been shown to effectively improve cancers by inhibiting deoxyribonucleic acid synthesis. However, it has some obvious drawbacks such as short plasma half-life, non-target selectivity and serious adverse reactions. Because of these shortcomings, its clinical application is limited. In the present research work, we have tried to obtain polyethylene glycol-hyaluronic acid by modifying hyaluronic acid with activated polyethylene glycol; polyethylene glycol-hyaluronic acid was then connected to melphalan to prepare the polyethylene glycol-hyaluronic acid-melphalan prodrug. Polyethylene glycol-hyaluronic acid was obtained by modifying hyaluronic acid with activated polyethylene glycol and it was then connected with melphalan to prepare the polyethylene glycol-hyaluronic acid-melphalan prodrug. The prodrug generates micelles by self-assembly in aqueous solution and was characterized by nuclear magnetic resonance and infrared spectroscopy. Changes of tumor cell morphology and cytotoxicity were observed by an inverted microscope. Dynamic light scattering and transmission electron microscope showed that the prodrug formed micelle and was evenly distributed in 100-130 nm. Tumor cells treated with polyethylene glycol-hyaluronic acid-melphalan (10⁻⁷ and 10⁻⁶ mol/l respectively) showed significant changes in cell proliferation compared with the control group (p<0.05, p<0.01) with half-maximal inhibitory concentration values of 0.53 μM/48 h. Tumor cells treated with polyethylene glycol-hyaluronic acid-melphalan (10⁻⁶ mol/l) were condensed and rounded, aggregated into clumps, and the number of cells was significantly reduced at both 24 h and 48 h after treatment. The polyethylene glycol-hyaluronic acid-melphalan prodrug was synthesized successfully and characterized by fourier-transform infrared spectroscopy, proton nuclear magnetic resonance, dynamic light scattering and transmission electron microscope. It can form micelle with the average size of about 100-130 nm. It was demonstrated that these natural, biocompatible and biodegradable particles can be used as drug delivery system and found that this compound play potent inhibitory role on tumor cells, and indicated that the polyethylene glycol-hyaluronic acid-melphalan prodrug could be very useful on release of control targeted drug.