期刊
PHARMACEUTICS
卷 13, 期 11, 页码 -出版社
MDPI
DOI: 10.3390/pharmaceutics13111959
关键词
bladder cancer; polymeric nanoparticles; combined nano-therapies; paclitaxel; survivin
资金
- MINECO/FEDER [RTC-2015-3751-1, SAF2015-64927C2-1-R, SAF2015-64927-C2-2-R]
- Generalitat de Catalunya (Agencia de Gestio d'Ajuts Universitaris i de Recerca-AGAUR) [SGR 2017 1559]
The dual nano-treatment for bladder cancer based on survivin inhibition and paclitaxel did not show the expected synergistic effect, possibly due to cell cycle arrest caused by nuclear survivin silencing, which is incompatible with the action of paclitaxel.
Bladder cancer is the 10th most diagnosed cancer, with almost 10 M cancer deaths last year worldwide. Currently, chemotherapy is widely used as adjuvant therapy after surgical transurethral resection. Paclitaxel (PTX) is one of the most promising drugs, but cancer cells acquire resistance, causing failure of this treatment and increasing the recurrence of the disease. This poor chemotherapeutic response has been associated with the overexpression of the protein survivin. In this work, we present a novel dual nano-treatment for bladder cancer based on the hypothesis that the inhibition of survivin in cancer cells, using a siRNA gene therapy strategy, could decrease their resistance to PTX. For this purpose, two different polymeric nanoparticles were developed to encapsulate PTX and survivin siRNA independently. PTX nanoparticles showed sizes around 150 nm, with a paclitaxel loading of around 1.5%, that produced sustained tumor cell death. In parallel, siRNA nanoparticles, with similar sizes and loading efficiency of around 100%, achieved the oligonucleotide transfection and knocking down of survivin expression that also resulted in tumor cell death. However, dual treatment did not show the synergistic effect expected. The root cause of this issue was found to be the cell cycle arrest produced by nuclear survivin silencing, which is incompatible with PTX action. Therefore, we concluded that although the vastly reported role of survivin in bladder cancer, its silencing does not sensitize cells to currently applied chemotherapies.
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