DESIGN AND CHARACTERIZATION OF PACLITAXEL-LOADED PCL-TPGS NANOPARTICLES FOR CANCER THERAPY

BERNABEU E.; HELGUERA G.; CHIAPPETTA D.A.

Rosario

Encuentro; RICIFA 2012. The 2nd International Meeting on Pharmaceutical Sciences; 2012

Introduction Paclitaxel (PTX) is one of the most effective antineoplastic drugs used to treat ovarian and breast cancer patients (1). Clinical toxicity of PTX is associated with Cremophor EL®, the solvent of the market formulation, but a great number of side effects are associated with this excipient. Nanoparticulate systems may provide an advantageous alternative to the use of toxic excipients to improve solubility and favor an extended chemotherapy. We have synthesized a poly(ε-caprolactone)–tocopheryl polyethylene-glycol-succinate (PCL–TPGS) copolymer with an hydrophobic–hydrophilic balance adequate for the nanoparticle (NP) formulation of anticancer drugs. In addition, the polyethylene glycol repulsive properties present in TPGS provide the advantage of higher stability of NPs in biological fluids (2). The present work is focused on the design and characterization of PTX-loaded PCL-TPGS NPs for cancer chemotherapy. Materials and Methods ε-caprolactone (CL), D-α-tocopheryl polyethylene-glycol (PEG) 1000 succinate (TPGS, ~1513 kg/mol), tin(II) 2-ethylhexanoate Sn(Oct)2, PTX and solvents were obtained from donors. A PCL-TPGS copolymer was synthesized by the ring opening polymerization of CL by TPGS in presence of Sn(Oct)2. PTX-loaded PCL-TPGS nanoparticles were prepared by: a) nanoprecipitation (NPr-method); b) emulsion-solvent evaporation homogenized with an Ultra-Turrax® (UT-method); and c) with an ultrasonicator (US-method). The size, size distribution, and zeta potential of the systems were measured with a Zetasizer Nano-Zs. Drug loading and in vitro drug release profiles were measured by HPLC-UV. In vitro release studies were performed in phosphate buffer (pH 7.4) USP 30 with 0.5% tween-80 using dialysis bag diffusion technique. Results NPr-method and US-method produced smaller nanoparticles (~260 and ~240nm, respectively) compared to those produced by UT-method (~440nm). All formulations showed zeta potential values between -30.0 and -37.8mV. SEM images showed nanoparticles of spherical shape with all techniques. NPs prepared by NPr-method and UT-method had low values of drug loading (1.24 and 1.45%, respectively), while the particles prepared by US-method was 5.73% (a 4.6 and 4.0-fold increase). The amount of drug released from the NPs at 48h was ~30% and ~50% for US-method and NPr-method, respectively. Conclusions PTX-loaded PCL-TPGS nanoparticles prepared by US-method had smaller size and higher drug content than those prepared by NPr-method and UT-method. This is probably due to the higher energy released in the emulsification process by US-method, leading to the formation of a more stable emulsion which was directly related to the size and drug loading of the nanoparticles. In vitro release assay indicates that PCL-TPGS nanoparticles prepared by US-method released the drug more slowly than nanoparticles prepared by NPr-method. These results suggest that the US-method is a more efficient method to prepare a controlled release particulate system. Future studies will evaluate the in vitro cytotoxicity of PTX-PCL-TPGS nanoparticles. Acknowledgements Authors thank the UBA (Grant UBACyT 20020100300088). EB is supported by the PFDT fellowship from the National Agency for Promotion of Science and Technology (ANPCyT-FONARSEC PICT-PRH 2008-00315), Argentina. DAC and GH are partially supported by CONICET, Argentina.