Administration of the optimized beta-Lapachone-poloxamer-cyclodextrin ternary system induces apoptosis, DNA damage and reduces tumor growth in a human breast adenocarcinoma xenograft mouse model

作者：Seoane Samuel; Diaz Rodriguez Patricia; Sendon Lago Juan; Gallego Rosalia; Perez Fernandez Roman; Landin Mariana^*

来源：European Journal of Pharmaceutics and Biopharmaceutics, 2013, 84(3): 497-504.

DOI：10.1016/j.ejpb.2012.12.019

• beta-Lapachone
• Genetic algorithms
• Artificial neural networks
• Breast cancer
• MCF-7 cells

beta-Lapachone (beta-Lap) is a 1,2-orthonaphthoquinone that selectively induces cell death in human cancer cells through NAD(P)H: quinone oxidoreductase-1 (NQO1). NQO1 is overexpressed in a variety of tumors, as compared to normal adjacent tissue. However, the low solubility and non-specific distribUtion of beta-Lap limit its suitability for clinical assays. We formulated beta-Lap in an optimal random methylated-beta-cyclodextrin/poloxamer 407 mixture (i.e., beta-Lap ternary system) and, using human breast adenocarcinoma MCF-7 cells and immunodeficient mice, performed in vitro and in vivo evaluation of its anti-tumor effects on proliferation, cell cycle, apoptosis, DNA damage, and tumor growth. This ternary system is fluid at room temperature, gels over 29 degrees C, and provides a significant amount of drug, thus facilitating intratumoral delivery, in situ gelation, and the formation of a depot for time-release. Administration of beta-Lap ternary system to MCF-7 cells induces an increase in apoptosis and DNA damage, while producing no changes in cell cycle. Moreover, in a mouse xenograft tumor model, intratumoral injection of the system significantly reduces tumor volume, while increasing apoptosis and DNA damage without visible toxicity to liver or kidney. These anti-tumoral effects and lack of visible toxicity make this system a promising new therapeutic agent for breast cancer treatment.

• 出版日期2013-8