Co-delivery of doxorubicin and siRNA by a simplified platform with oligodeoxynucleotides as a drug carrier

The greatest challenge in combining chemotherapy and gene therapy is the construction of a suitable platform for the co-delivery of the drug and the therapeutic gene. In this study, a simplified and effective system for the co-loading and intracellular co-delivery of doxorubicin (Dox) and siRNA was developed. Oligodeoxynucleotides with CGA repeating units (CGA-ODNs) were introduced to load Dox. The loading mechanism was based on the ability of Dox to intercalate within double-stranded 5′-GC-3′ or 5′-CG-3′ sequences. Poly(ethyleneimine) (PEI) was used to condense siRNA and Dox loaded CGA-ODNs (CGA-ODNs-Dox) to obtain Dox and siRNA co-loaded nanocomplexes (PEI/CGA-ODNs-Dox&siRNA, PDR). The cellular uptake of PDR in A549 and HepG2 cells was 39.52% and 36.78%, respectively, indicating that the co-loading and co-delivery effect was achieved through the mono-loading method. An in vitro drug release study indicated that CMCS-poly(ethylene glycol) (PEG)-NGR (CPN) modified PDR (CPN-PDR) displayed a pH-triggered drug release property due to the reversed surface charge of CMCS in an acidic environment. Cellular uptake studies also confirmed that the disassembly of CPN-PDR was induced by an acidic pH in the extracellular matrix. Moreover, lysosomal escape of both Dox and siRNA was observed. Successful accumulation of Dox in the cell nucleus and siRNA in the cytoplasm was also demonstrated. Consequently, the novel construction of a simplified loading method and high co-delivery efficiency was proven to be a promising platform for the co-delivery of drug and siRNA.