A co-delivery nanosystem of chemotherapeutics and DNAzyme overcomes cancer drug resistance and metastasis

Abstract

Multidrug resistance (MDR) constitutes a major problem in the management of cancer and cancer metastasized from primary-source tumor causes cancer-related deaths. Our new approach is the co-delivery of chemotherapy drugs with a transcription-factor-targeting genetic agent to simultaneously inhibit the growth and metastasis of cancer cells. C-Jun is a transcription factor that regulates multidrug resistance-associated protein 1 (MRP1) pump efflux transcription and tumor metastasis. In this work, we reported that mesoporous silica nanoparticles (MSNs) can be functionalized to co-deliver doxorubicin (Dox) and DNAzyme (Dz) to increase cancer cell killing in an additive fashion. The MSNs were sequentially conjugated with Dox into the MSNs’ nanochannels and Dz onto the MSNs’ outermost surface to target c-Jun as the Dox@MSN-Dz co-delivery system. The Dox-resistant PC-3 cells treated with Dox@MSN-Dz efficiently enhanced the intracellular Dox concentration due to the abrogation of Dox-induced MRP1 expression through the downregulation of c-Jun expression by Dz. Additionally, significant reductions in invasion and migration related to metastasis were also observed in cells treated with Dox@MSN-Dz. Therefore, our results contribute new insight to the treatment of MDR combined metastatic cancer cells, worthwhile for studying its potential for development in clinical translation.

Advances in Delivery Systems for Doxorubicin

“…To advance the efficacy of Dox against resistant cells, one study evaluated incorporation of Dox with a DNAzyme (Dx), which targeted the transcriptional factor C-Jun, into a nanoparticle (Fig 2) [28]. This report was in part stimulated by a previous study that the combination of free Dox and a nanoparticle transporting C-Jun DNAzyme (Dx) almost completely inhibited tumor growth [29].…”

RNA-cleaving DNAzymes for accurate biosensing and gene therapy

“…The results showed that the co-delivery system effectively increased intracellular Dox concentration in Dox-resistant PC-3 cells, due to RNA-cleaving DNAzyme-mediated downregulation of c-jun expression and subsequent inhibition of MRP1 expression. 95 In a word, although MDR is a thorny problem in cancer chemotherapy, RNA-cleaving DNAzymes show a good synergistic effect by the silencing of drug-resistant genes, showing great application potential in reversing the MDR.…”

Recent advances of DNAzyme-based nanotherapeutic platform in cancer gene therapy

“…In addition, MDR can also be reversed by reducing non-MDR-associated proteins, such as pro-apoptotic c-jun protein. Sun et al used mesoporous silica nanoparticles (MSNs) to deliver c-jun targeting DNAzyme to attenuate the drug efflux because silencing c-jun mRNA mediated the downregulation of multidrug resistance-associated protein 1 (MRP1), which is bound up with the acquired MDR in metastatic prostate cancer (Sun et al 2017). Dass et al also indicated the role of DNAzymes-mediated silencing c-jun gene in reversing the drug resistance of osteosarcoma.…”