Overcoming doxorubicin resistance in cancer: siRNA-loaded nanoarchitectures for cancer gene therapy

Gene therapy can be used as a cancer therapy by affecting signaling networks participating in the aggressive behavior of tumors. Small interfering RNA (siRNA) is a genetic tool employed for gene silencing. The siRNA molecules have a length of 21–22 nucleotides, and are synthetic, short non-coding RNAs. The siRNA molecule should be loaded into the RISC complex to carry out its function to degrade mRNA and reduce protein expression. By targeting oncogenic pathways, siRNA can also promote chemosensitivity and reduce resistance. Doxorubicin (DOX) is an anthracycline family member capable of triggering cell cycle arrest via binding to topoisomerase II and inhibiting DNA replication. The present review focuses on the design of siRNA for increasing DOX sensitivity and overcoming resistance. Molecular pathways such as STAT3, Notch1, Mcl-1 and Nrf2 can be down-regulated by siRNA to promote DOX sensitivity. Furthermore, siRNA can be used to suppress the activity of P-glycoprotein as a cell membrane transporter of drugs, leading to enhanced accumulation of DOX. The co-delivery of DOX and siRNA both incorporated into nanoparticles can increase the intracellular accumulation in cancer cells, and protect siRNA against degradation by enzymes. Furthermore, the circulation time of DOX is lengthened to boost cytotoxicity against cancer cells. The surface modification of nanocarriers with ligands such as RGD or folate increases their selectivity towards cancer cells. Moreover, smart nanostructures, including pH-, redox- and light-responsive are optimized for siRNA and DOX delivery and tumor treatment.