Trastuzumab targeted micellar delivery of docetaxel using dendron–polymer conjugates

Abstract

Incorporation of a therapeutic antibody into nanosized drug delivery systems can improve their target specificity. This work reports an antibody-conjugated targeted delivery system composed of polymer–dendron conjugates. Trastuzumab is chosen as the targeting moiety, since it is clinically used against tumor cells expressing HER2 receptors. A micellar delivery system was generated using amphiphilic polymer–dendron conjugates containing a fourth-generation polyester dendron as the hydrophobic block and a linear poly(ethylene glycol) (PEG) chain as the hydrophilic block. After preparation of docetaxel loaded (ca. 10% wt) micelles, trastuzumab was conjugated onto the micellar shell using an amidation reaction. Micelles remained stable after conjugation of the antibody, with a slight increase in size from 179 nm to 185 nm upon functionalization. Docetaxel release was determined to be responsive to acidic pH, and over the course of 30 h, 54% drug release was measured in acidic media, whereas it was around 30% under neutral conditions. Cytotoxicity experiments on MCF-7 and SK-OV-3 cell lines displayed improved toxicity levels for targeted micelles in comparison with the non-targeted counterparts, whereas pulse-chase experiments indicated effectiveness of micellar formulations and the presence of targeting groups. Cellular internalization experiments using fluorescence microscopy and flow cytometry further demonstrated the enhanced cellular uptake of antibody conjugated targeted micelles.