Combination of Dendrimer-Nanovector-Mediated Small Interfering RNA Delivery to Target Akt with the Clinical Anticancer Drug Paclitaxel for Effective and Potent Anticancer Activity in Treating Ovarian Cancer

• Published in: Journal of medicinal chemistry 2014-03, Vol.57 (6), p.2634-2642
• Main Authors: Kala, Shashwati, Mak, Abby Sin Chi, Liu, Xiaoxuan, Posocco, Paola, Pricl, Sabrina, Peng, Ling, Wong, Alice Sze Tsai
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents, Phytogenic - chemical synthesis; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis - drug effects; Blotting, Western; Cell Death - drug effects; Cells, Cultured; Coloring Agents; Dendrimers; Drug Delivery Systems; Female; Gene Silencing - drug effects; Genetic Vectors - genetics; Humans; Mice; Mice, Nude; Models, Molecular; Nanotechnology; Nuclease Protection Assays; Oncogene Protein v-akt - drug effects; Oncogene Protein v-akt - genetics; Ovarian Neoplasms - drug therapy; Paclitaxel - analogs & derivatives; Paclitaxel - chemical synthesis; Paclitaxel - pharmacology; Phosphatidylinositol 3-Kinases - metabolism; RNA, Small Interfering - administration & dosage; Signal Transduction - drug effects; Tetrazolium Salts; Thiazoles; Transfection
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm401907z

The recently discovered small interfering RNA (siRNA) holds great promise in cancer therapy. However, efficient and safe delivery systems are required for the development of new therapeutic paradigms. Ovarian cancer has the highest mortality of all gynecologic tumors, and there is an urgent need for specific and effective therapies. The phosphatidylinositol 3-kinase/Akt pathway, which is strongly implicated in the biology of ovarian cancer, constitutes an attractive therapeutic target. In this study, we describe a triethanolamine-core poly­(amidoamine) dendrimer which forms stable nanoparticles with the Akt siRNA, protects siRNA against RNase digestion, and is highly effective for initiating Akt target-gene silencing both in vitro and in vivo, while being minimally toxic. Most importantly, it could potentiate the antitumor effect of the anticancer drug paclitaxel. These results represent the proof-of-concept, demonstrating that dendrimer-mediated Akt siRNA delivery, in combination with a chemotherapeutic regimen, may constitute a promising nanomedicine approach in cancer therapy.