A New Paclitaxel Formulation with a Cationic Cyclotriphosphazene

Abstract

Recently the inter-polyelectrolyte complexes (IPECs) have received considerable attention. IPECs represent a special class of chemical compounds formed as a result of cooperative electrostatic interactions between cations and anions. The properties of IPECs depend strongly on the feeding ratio of the oppositely charged polyions. First studies on the utilization of IPECs were reported on gene delivery in the late 1980s. Paclitaxel is one of the most important antitumor agents currently in clinical use, since it exhibits effective antitumor activity against various cancers. However, its clinical applications are limited due to its extremely low water solubility (< 1 μg/mL) as well as its serious side effects. Therefore, a great deal of efforts has been made to overcome such problems. There are numerous studies on solubilization of paclitaxel by chemical conjugation to hydrophilic polymers or micellar encapsulation using amphiphilic polymers. However, to our knowledge, there is no report on the formulation of paclitaxel based on IPEC. In this paper we report a novel formulation method for paclitaxel by incorporation of 2'succinylpaclitaxel (2'-SPTX) into a cationic cyclotriphosphazene resulting in chemically stable micelles. A cationic and water soluble cyclotriphosphazene drug carrier bearing a hydrophilic poly(ethylene glycol) (PEG) with a molecular weight of 350 and lysine ethyl ester as cationic moiety was prepared according to the same procedure as described in our previous work with modification. Instead of an oligopeptide, lysine ethyl ester (LysEt) was employed as a cationic moiety for electrostatic interaction with anionic 2'-SPTX. The synthetic schemes for the anionic 2'-SPTX (I) and the cationic cyclotriphosphazene carrier (II) are shown along with their final ion paired IPEC in Scheme 1. The final paclitaxel IPEC could easily be prepared by a direct feeding method as follows. The 2'-SPTX (1 mg) solution in ethanol was added to the cyclotriphosphazene carrier (20 mg) in ethanol. The mixed solution was evaporated to dryness and then the residue was dissolved in distilled water. After sonication for 10 min, the resulting solution was filtered with 0.45 μm syringe filter to obtain a clear solution of the paclitaxel-loaded IPEC, which was fully characterized by multinuclear (H, P) NMR spectroscopy along with its dynamic light scattering (DLS) and critical micelle concentration (CMC) measurements. The H-NMR spectra of the paclitaxel IPEC in CDCl3 displayed in Figure 1(a) clearly show all the proton resonances both of the hydrophilic methoxy poly(ethylene glycol) (MPEG) and the LysEt group forming an ionic pair with 2'SPTX with good resolution, but in D2O most proton