Enhanced Lysosomal Escape of pH-Responsive Polyethylenimine–Betaine Functionalized Carbon Nanotube for the Codelivery of Survivin Small Interfering RNA and Doxorubicin

Abstract

The combination of gene therapy and chemotherapy has recently received considerable attention for cancer treatment. However, low transfection efficiency and poor endosomal escape of genes from nanocarriers strongly limit the success of the clinical use of small interfering RNA (siRNA). In this study, a novel pH-responsive, surface-modified single-walled carbon nanotube (SWCNT) was designed for the codelivery of doxorubicin (DOX) and survivin siRNA. Polyethylenimine (PEI) was covalently conjugated with betaine, and the resulting PEI–betaine (PB) was further synthesized with the oxidized SWCNT to form SWCNT–PB (SPB), which exhibits an excellent pH-responsive lysosomal escape of siRNA. SPB was modified with the targeting and penetrating peptide BR2 (SPBB), thereby achieving considerably higher uptake of siRNA than SWCNT-PEI (SP) or SPB. Furthermore, SPBB–siRNA presented substantially lower survivin expression and higher apoptotic index than Lipofectamine 2000. DOX and survivin siRNA were adsorbed onto SPB to form DOX–SPBB–siRNA, and siRNA/DOX was released into the cytoplasm and nuclei of adenocarcinomic human alveolar basal epithelial (A549) cells without lysosomal retention. Compared with SPBB–siRNA or DOX–SPBB treatment alone, DOX–SPBB–siRNA significantly reduced tumor volume in A549 cell-bearing nude mice, demonstrating the synergistic effects of DOX and survivin siRNA. Pathological analysis also indicated the potential therapeutic effects of DOX–SPBB–siRNA on tumors without distinct damages to normal tissues. In conclusion, the novel functionalized SWCNT loaded with DOX and survivin siRNA was successfully synthesized, and the nanocomplex exhibited effective antitumor effects both in vitro and in vivo, thereby providing an alternative strategy for the codelivery of antitumor drugs and genes.

Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study?

“…However, after review of this specialized area, we found that while the ribozyme approach was used for some time in research [111][112][113], further studies toward the use of this approach for cancer therapeutics were not progressing; this is likely due to the much easier approach of siRNA technology being available. Consistent with this notion, the survivin siRNA approach was used throughout the history of survivin studies [114][115][116][117][118]; the survivin siRNA studies in recent years show a clear trend of developing and using various new delivery technologies of survivin siRNA with or without combination of a cancer drug for therapeutics in vitro [119][120][121][122][123] and in vivo [124][125][126][127][128][129][130][131]. Although clinical trials using a type of nanotechnology to deliver survivin siRNA with or without combination of a cancer therapeutic drug remain to be seen, survivin siRNA formulated in a novel delivery system as an anticancer product will likely come into clinical trials in the near future.…”

“…Whether the toxicity came from the unique locked modification of the EZN-3042 oligonucleotides, as discussed in the case of LY2181308, is unknown. Nevertheless, a breakthrough to find survivin mRNA inhibitors may come from the siRNA approach in combination with the development of nanotechnology for delivery [119][120][121][122][123][124][125][126][127][128][129][130][131], since survivin siRNA design in the coming years might take inspiration from various miRNA-mediated survivin mRNA inhibition. Currently miRNA regulation of survivin mRNA/transcripts is a hot research area, which has room for further in depth, extended studies (see Table 1) [146][147][148][149].…”

Recent Advances in Nanocarrier-Assisted Therapeutics Delivery Systems

“…To overcome certain disadvantages of some pH-sensitive polymers, such as uncontrolled drug-loading or drug-releasing rate as well as undesired toxicity, non-polymer pH-sensitive carbon dots were also developed for cancer therapy [94]. In addition, recently surface modified pH-responsive SWCTs have also been developed to co-deliver anti-cancer drugs and genes [95].…”

<p>The Applications of Carbon Nanotubes in the Diagnosis and Treatment of Lung Cancer: A Critical Review</p>

“…The carrier was functionalized with polyethyleneimine (PEI) besides betaine. 93 Gemcitabine Also, Gemcitabine is among the anti-cancer drugs for nonsmall cell lung cancer. In a clinical trial on B6-mice, the drug was tested with an SWCNT carrier.…”