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Multi-functional nanoparticles delivering siRNA and doxorubicin overcome drug resistance in cancer.

J Biol Chem. 2010 May 11;

Authors: Chen Y, Bathula SR, Li J, Huang L

Drug resistance is a major challenge to the effective treatment of cancer. We have developed two nanoparticle formulations cationic liposome polycation DNA (LPD) and anionic liposome polycation DNA (LPD II) for systemic codelivery of doxorubicin (Dox) and a therapeutic siRNA to multiple drug resistance (MDR) tumors. In this study, we have provided four strategies to overcome drug resistance. First, we formed the LPD nanoparticles with a guanidinium containing cationic lipid, i.e. DSAA which can induce reactive oxygen species (ROS), down regulate MDR transporter expression and increase Dox uptake. Second, to block angiogenesis and increase drug penetration, we have further formulated LPD nanoparticles to co deliver vascular endothelial growth factor (VEGF) siRNA and Dox. An enhanced Dox uptake and therapeutic effect were observed when combined with VEGF siRNA in the nanoparticles. Third, to avoid Pgp mediated drug efflux, we further designed another delivery vehicle, LPD II, which showed much higher entrapment efficiency of Dox than LPD. Finally, we delivered a therapeutic siRNA to inhibit MDR transporter. We demonstrated the first evidence of c Myc siRNA delivered by the LPD II nanoparticles down-regulating MDR expression and increasing Dox uptake in vivo. Three daily intravenous injections of therapeutic siRNA and Dox (1.2 mg/kg) coformulated in either LPD or LPD II nanoparticles showed a significant improvement in tumor growth inhibition. This study highlights a potential clinical use for the multifunctional nanoparticles with an effective delivery property and a function to overcome drug resistance in cancer. The activity and the toxicity of LPD and LPD II mediated therapy are compared.

PMID: 20460382 [PubMed - as supplied by publisher]