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Dendrosome-based delivery of siRNA against E6 and E7 oncogenes in cervical cancer
Tathagata Dutta1, Melinda Burgess, Nigel A J McMillan
1School of Pharmacy, University of Queensland, Brisbane, Australia.
Abstract:
Although small interfering RNA (siRNA) treatment holds great promise for the treatment of cancers, the field has been held back by the availability of suitable delivery vehicles. For cervical cancer the E6 and E7 oncogenes are ideal siRNA targets for treatment. The purpose of the present study was to explore the potential of dendrosomes for the delivery of siRNA targeting E6 and E7 proteins of cervical cancer cells in vitro. Optimization of dendrimer generation and nitrogen-to-phosphate (N/P) ratio was carried out using dendrimer-fluorescein isothiocyanate oligo complexes. The optimized N/P ratios were used in formulating complexes between dendrimers and siRNA targeting green fluorescence protein (siGFP). Although formulation 4D100 (dendrimer-siRNA complex) displayed the highest GFP knockdown, it was also found to be highly toxic to cells. In the final formulation 4D100 was encapsulated into dendrosomes so as to mask these toxic effects. The optimized dendrosomal formulation (DF), DF3 was found to possess a siGFP-entrapment efficiency of 49.76% +/- 1.62%, vesicle size of 154 +/- 1.73 nm, and zeta potential of +3.21 +/- 0.07 mV. The GFP knockdown efficiency of DF3 (dendrosome) was found to be almost identical to that of 4D100, but the former was completely nontoxic to the cells. DF3 containing siRNA against E6 and E7 was found to knock down the target genes considerably, as compared with the other formulations tested. Our results imply that dendrosomes hold potential for the delivery of siRNA and that a suitable targeting strategy could be useful for applications in vivo.
From The Clinical Editor:
siRNA treatment holds great promise for the treatment of cancers, but overall, the availability of suitable delivery vehicles remains a major issue. The purpose of this study was to explore the potential of dendrosomes for the delivery of siRNA targeting specific proteins in cervical cancer cells in vitro. The results suggest that dendrosomes hold potential for the delivery of siRNA and a suitable targeting strategy could be useful for applications in vivo.
Insights
Dendrosomes effectively deliver small interfering RNA (siRNA) to cervical cancer cells, overcoming toxicity issues associated with earlier formulations. This advance offers a promising strategy for cancer treatment delivery systems.
Area of Science:
- Nanotechnology in Medicine
- Cancer Therapeutics
- Gene Silencing
Background:
- Small interfering RNA (siRNA) shows therapeutic potential for cancers but faces delivery challenges.
- Effective delivery vehicles are crucial for translating siRNA's promise into clinical cancer treatments.
- Cervical cancer presents ideal targets with E6 and E7 oncogenes for siRNA-based therapy.
Purpose of the Study:
- To investigate dendrosomes as a novel delivery system for siRNA targeting cervical cancer.
- To optimize dendrosome formulations for efficient and non-toxic siRNA delivery in vitro.
- To evaluate the efficacy of dendrosome-encapsulated siRNA against E6 and E7 oncogenes.
Main Methods:
- Dendrimer generation and nitrogen-to-phosphate (N/P) ratios were optimized using dendrimer-fluorescein isothiocyanate oligo complexes.
- Complexes of dendrimers with siRNA targeting green fluorescence protein (siGFP) were formulated.
- Optimized dendrosomal formulations (DF) were characterized for entrapment efficiency, vesicle size, and zeta potential.
- siGFP and E6/E7 gene knockdown efficiencies were assessed, along with cellular toxicity.
Main Results:
- An initial dendrimer-siRNA complex (4D100) showed high GFP knockdown but significant cellular toxicity.
- Encapsulating 4D100 into dendrosomes created a non-toxic formulation (DF3) with comparable gene knockdown.
- DF3 exhibited a siGFP-entrapment efficiency of 49.76%, a vesicle size of 154 nm, and a zeta potential of +3.21 mV.
- DF3 demonstrated considerable knockdown of E6 and E7 genes in cervical cancer cells.
Conclusions:
- Dendrosomes are a viable and non-toxic delivery vehicle for siRNA in cancer therapy.
- Optimized dendrosomal formulations can effectively deliver siRNA to target oncogenes in vitro.
- Further development with targeting strategies could enable in vivo applications for cancer treatment.
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