Targeted co-delivery of docetaxel and siPlk1 by herceptin-conjugated vitamin E TPGS based immunomicelles

• Published in: Biomaterials 2013-04, Vol.34 (13), p.3411-3421
• Main Authors: Zhao, Jing, Mi, Yu, Feng, Si-Shen
• Format: Article
• Language: English
• Subjects: Advanced Basic Science; Animals; Antibodies, Monoclonal, Humanized - pharmacology; Anticancer drugs; Biodegradable polymers; Biomedical materials; Biotechnology; Bonding; Cancer nanotechnology; Cell Cycle Proteins - metabolism; Cell Division - drug effects; Cell Line; Cell Survival - drug effects; Chromatography, High Pressure Liquid; Conjugates; Cytoplasm - drug effects; Cytoplasm - metabolism; Dentistry; Docetaxel; Drug Delivery Systems; Drugs; Gene Transfer Techniques; Humans; Inhibitory Concentration 50; Kinases; Light; Mice; Micelles; Microscopy, Electron, Transmission; Molecular biomaterials; Nanomedicine; Particle Size; Polo-Like Kinase 1; Polyethylene Glycols - pharmacology; Protein Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; RNA, Small Interfering - metabolism; Scattering, Radiation; SiRNA; Taxoids - administration & dosage; Taxoids - chemistry; Taxoids - pharmacology; Time-Lapse Imaging; Transfection; Trastuzumab; Vitamin E; Vitamin E - analogs & derivatives; Vitamin E - pharmacology
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2013.01.009

Abstract We developed a drug delivery system of herceptin-conjugated micelles, which consist of vitamin E TPGS and TPGS–siRNA conjugates, for targeted co-delivery of docetaxel and polo-like kinase 1 siRNA to achieve synergistic effects between the anticancer drug and the small interfering RNA responsible for multidrug resistance. The TPGS–siRNA conjugate is made through disulfide bond that could enable a pH-sensitive intracellular release. The load ratio between siPlk1 and docetaxel could be controlled by adjusting the siPlk1–TPGS to TPGS ratio as well as the drug to polymer ratio. NIH3T3, MCF7, and SK-BR-3 cell lines, which are of low, moderate and high HER2 overexpression, were employed to obtain proof-of-concept experimental results for the advantages of such a design. It has been shown that the IC50 , which is the drug concentration needed to kill 50% of the cancer cells in a designated time period, was 1.72, 0.042, 0.0032 and 0.000671 μg/mL for SK-BR-3 cells after 24 h treatment by Taxotere® , and docetaxel formulated in the TPGS micelles, the TPGS–siPlk1/TPGS micelles and the herceptin-conjugated TPGS–siPlk1/TPGS micelles, respectively.