Multifunctional polymeric micelles co-loaded with anti-survivin siRNA and paclitaxel overcome drug resistance in an animal model of ovarian cancer

摘要

Ovarian cancer is a dreadful disease estimated to be the second most common gynecological malignancy worldwide. Its current therapy, based on cytoreductive surgery followed by the combination of platinum and taxanes, is frequently complicated by the onset of multidrug resistance (MDR). The discovery that survivin, a small anti-apoptotic protein, is involved in chemo-resistance, provided a new prospect to overcome MDR in cancer, since siRNA could be used to inhibit the expression of survivin in cancer cells. With this in mind, we have developed self-assembly polymeric micelles (PM) able to efficiently co-load an anti-survivin siRNA and a chemotherapeutic agent, such as Paclitaxel (PXL) (survivin siRNA/PXL PM). Previously, we have successfully demonstrated that the down-regulation of survivin by using siRNA-containing PM strongly sensitizes different cancer cells to PXL. Here, we have evaluated the applicability of the developed multifunctional PM in vivo. Changes in survivin expression, therapeutic efficacy and biological effects of the nanopreparation were investigated in an animal model of PXL-resistant ovarian cancer. The results obtained in mice xenografed with SKOV3-tr revealed a significant down-regulation of survivin expression in tumor tissues together with a potent anticancer activity of survivin siRNA/PXL PM, while the tumors remained unaffected with the same quantity of free PXL alone. These promising results introduce a novel type of non-toxic and easy-to-obtain nano-device for the combined therapy of siRNA and anti-cancer agents in the treatment of chemo-resistant tumors.