Enhanced antitumor activity of doxorubicin in breast cancer through the use of poly(butylcyanoacrylate) nanoparticles

Laura Cabeza,1,* Raúl Ortiz,1,2,* José L Arias,3 Jose Prados,1,4 Maria Adolfina Ruiz Martínez,3 José M Entrena,5,6 Raquel Luque,7 Consolación Melguizo1,4 1Institute of Biopathology and Regenerative Medicine (IBIMER), Granada, Spain; 2Department of Health Science, University of Jaén, Jaén, Spain; 3Department of Pharmacy and Pharmaceutical Technology, University of Granada, Granada, Spain; 4Biosanitary Institute of Granada (ibs GRANADA), SAS-Universidad de Granada, Granada, Spain; 5Institute of Neuroscience, Biomedical Research Center, 6Animal Behavior Research Unit, Scientific Instrumentation Center, University of Granada, Armilla, Granada, Spain; 7Service of Medical Oncology, Virgen de las Nieves Hospital, Granada, Spain *These authors contributed equally to this work Abstract: The use of doxorubicin (DOX), one of the most effective antitumor molecules in the treatment of metastatic breast cancer, is limited by its low tumor selectivity and its severe side effects. Colloidal carriers based on biodegradable poly(butylcyanoacrylate) nanoparticles (PBCA NPs) may enhance DOX antitumor activity against breast cancer cells, thus allowing a reduction of the effective dose required for antitumor activity and consequently the level of associated toxicity. DOX loading onto PBCA NPs was investigated in this work via both drug entrapment and surface adsorption. Cytotoxicity assays with DOX-loaded NPs were performed in vitro using breast tumor cell lines (MCF-7 human and E0771 mouse cancer cells), and in vivo evaluating antitumor activity in immunocompetent C57BL/6 mice. The entrapment method yielded greater drug loading values and a controlled drug release profile. Neither in vitro nor in vivo cytotoxicity was observed for blank NPs. The 50% inhibitory concentration (IC50) of DOX-loaded PBCA NPs was significantly lower for MCF-7 and E0771 cancer cells (4 and 15 times, respectively) compared with free DOX. Furthermore, DOX-loaded PBCA NPs produced a tumor growth inhibition that was 40% greater than that observed with free DOX, thus reducing DOX toxicity during treatment. These results suggest that DOX-loaded PBCA NPs have great potential for improving the efficacy of DOX therapy against advanced breast cancers. Keywords: biodegradable polymer, carcinoma, cytotoxicity, chemotherapeutic drug, drug delivery, nanopolymer