Abstract
The inherent or acquired resistance to paclitaxel and cisplatin, which are commonly used chemotherapeutic agents for ovarian cancer treatment, remains an important issue in chemotherapy of multidrug resistant ovarian cancer. Currently, it is still challenging to deal with the recurrent or advanced stage ovarian cancer. When drug efflux and anti-apoptotic pathways are highly interdependent and also involved in developing the resistance of multidrug resistant ovarian cancer, simultaneous inhibition of both pathways represents the potential targets to enhance the efficacy of chemotherapy. Here, we introduce PLGA nanoparticles system as a “dual RNAi delivery system” to contain both MDR1 and BCL2 siRNA, which is designed for simultaneous inhibition of drug efflux and cell death defense pathways. In the present studies, siRNA-loaded PLGA nanoparticles efficiently elicit the simultaneous suppression of both genes, which consequently shows more enhanced drug-sensitivity than sole suppression of drug efflux or anti-apoptosis in the resistant ovarian cancer cells, owing to the interdependence of both pathways. Our siRNA-loaded PLGA nanoparticles for co-delivering MDR1 and BCL2 siRNA provide an efficient combination therapy strategy to overcome the chemoresistance of paclitaxel and cisplatin on the paclitaxel-resistant SKOV3-TR and cisplatin-resistant A2780-CP20 ovarian cancer respectively.
Highlights
Multidrug resistance (MDR) that reduces the cytotoxic effects of chemotherapeutics is common and most likely to associate with a relapse of cancer and a failure in the chemotherapy
As an effort to enhance the drug-sensitivity in the ovarian cancer, previous studies have reported that the combination therapy comprising doxorubicin and BCL2 siRNA increased the apoptosis of SKOV3 ovarian cancer cells, the selected cancer cell lines were drug-sensitive, rather than drug-resistant[7]
Flow cytometry analysis showed 64.7% of intracellular accumulation of Alexa-CP20 drugs within the siRNA@Poly(DL-lactide-co-glycolide acid) (PLGA) NPs-pretreated A2780-CP20 cells with respect to the untreated cells or scRNA@PLGA NPs-treated cells (Supplementary Fig. S5B). These results show that siRNA@ PLGA NPs can efficiently suppress the function of P-glycoproteins in the MDR ovarian cancer cells and increase the accumulation of intracellular drugs, which is highly associated with potential tumor responsiveness to chemotherapeutics
Summary
Multidrug resistance (MDR) that reduces the cytotoxic effects of chemotherapeutics is common and most likely to associate with a relapse of cancer and a failure in the chemotherapy. As an effort to enhance the drug-sensitivity in the ovarian cancer, previous studies have reported that the combination therapy comprising doxorubicin and BCL2 siRNA increased the apoptosis of SKOV3 ovarian cancer cells, the selected cancer cell lines were drug-sensitive, rather than drug-resistant[7] Such “sole RNAi suppressor” strategy is not an efficient strategy to block the development of chemoresistance on MDR ovarian cancer, because multidrug resistance on the MDR cancer is often determined by a variety of resistance mechanisms, in which pump and non-pump types of resistance is highly interdependent[8]. PLGA nanoparticles for delivering siRNA oligo have attracted great interests as an alternative delivery system to the commonly used polycationic delivery systems that are unavoidably toxic and/or non-biodegradable[12]
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