A Novel Combined Micellar System of Lapatinib and Paclitaxel with Enhanced Antineoplastic Effect Against Human Epidermal Growth Factor Receptor‐2 Positive Breast Tumor In Vitro

ABSTRACT: Lapatinib (LPT) could sensitize human epidermal growth factor receptor-2 (HER-2) positive breast cancer to paclitaxel (PTX) and induce synergetic action with PTX in preclinical test and phase II/III trial. In this study, LPT-conjugated poly (ethylene glycol) (PEG) and poly (lactic acid) (PLA) (LPT–PEG–PLA) was first synthesized and confirmed with 1 H Nuclear Magnetic Resonance and Matrix-Assisted Laser Desorption/ Ionization Time of Flight Mass Spectrometry, which was used for the preparation of a novel PEG–PLA combined micelles of LPT and PTX (PPM-LP). The obtained PPM-LP exhibited uniform, spherical shape with a size of 25.80 ± 0.47 nm and zeta potential of −3.17 ± 0.15 mv. PTX existed in molecular or amorphous forms in the micelles and superficial LPT could better delay PTX release. The cytotoxicity of PPM-LP with LPT conjugation against SKBr-3 cells (HER-2 positive) was found to be significantly increasing as compared with PPM–PTX, whereas there was no significant difference against MDA-MB-231 cells (HER-2 negative). PPM-LP could escape from endosomes and be distributed into cytoplasm and led to cell arrest in G2/M and G1/S phases simultaneously. Results of nucleus staining and flow cytometry confirmed that LPT could remarkably increase antineoplastic effect of PTX against SKBr-3 cells. All these results demonstrated that PPM-LP may be a promising drug delivery system for HER-2 positive breast cancer. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:165–177, 2015