SiRNA Nanoparticles Dramatically Reduce Ovarian Tumor Growth in Mouse Model

If siRNA is not protected within a nanoparticle, it is broken down and excreted before it can be effective. The challenge has been to construct the best nanoparticle structure for siRNA transport.

Investigators at The Methodist Hospital Research Institute (Houston, TX, USA) had previously described the development of a multistage vector (MSV) system, composed of discoidal porous silicon particles loaded with anticancer drugs that directed effective delivery and sustained release of siRNA into tumors.

In the current study they evaluated the therapeutic efficacy of MSV-loaded EphA2 (the gene that encodes the protein ephrin type-A receptor 2) siRNA (MSV/EphA2) with mouse models of metastatic ovarian cancers as a first step towards development of a new class of nanotherapeutics for the treatment of ovarian cancer.

They treated mice with ovarian tumors with intravenous injections of MSV/siRNA. Tumor accumulation of MSV/EphA2 and sustained release of siRNA from MSV were analyzed. Nude mice with metastatic SKOV3ip2 tumors were treated with MSV/EphA2 and paclitaxel, and therapeutic efficacy was assessed. Mice with chemotherapy-resistant HeyA8 ovarian tumors were treated with a combination of MSV/EphA2 and docetaxel, and enhanced therapeutic efficacy was evaluated.

Results published in the February 5, 2013, online edition of the journal Clinical Cancer Research revealed that treatment of SKOV3ip2 tumor mice with MSV/EphA2 biweekly for six weeks resulted in a dose-dependent reduction of tumor weight of up to 83% and reduction of the number of tumor nodules compared with the control groups. In addition, tumor growth was completely inhibited when mice were treated with MSV/EphA2 in combination with paclitaxel. Furthermore, combination treatment with MSV/EphA2 and docetaxel inhibited growth of HeyA8-MDR tumors, which were otherwise resistant to docetaxel treatment. The nanoparticles safe to use, being no more toxic to the mice than was treatment with paclitaxel or docetaxel alone at clinically relevant doses.

"Drug resistance is a huge problem in the clinic," said contributing author Dr. Mauro Ferrari, professor of biomedical engineering in medicine at The Methodist Hospital Research Institute. "Our work shows that protecting the RNA longer so that it can get to where it must go and do its work inside cancer cells not only increases the RNA's impact, but also makes drug-resistant cancer cells once again sensitive to commonly used chemotherapy drugs."

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