Polymeric micelles containing reversibly phospholipid-modified anti-survivin siRNA: A promising strategy to overcome drug resistance in cancer

Abstract

The discovery that survivin, a small anti-apoptotic protein, is involved in chemoresistance, opens a new scenario to overcome the drug resistance in cancer. It was shown that siRNA can efficiently inhibit the expression of survivin in cancer cells. However, the clinical use of siRNA is still hampered by an unfavorable pharmacokinetic profile. To address this problem, earlier we developed a novel system to deliver siRNA into cancer cells. Namely, we reversibly modified the survivin siRNA with a phosphothioethanol (PE) portion via a reducible disulfide bond and incorporated the resulting siRNA-S-S-PE conjugate into nanosized polyethyelene glycol2000-phosphatidyl ethanolamine (PEG2000-PE)-based polymeric micelles (PM), obtaining survivin siRNA PM. The activity of these nanopreparations was evaluated by survivin protein down-regulation, tumor cell growth inhibition, and chemosensitization of the treated tumor cells to paclitaxel (PXL). We found a significant decrease of cell viability and down-regulation of survivin protein levels after treatment with survivin siRNA PM in several cancer cell lines. In addition, the down-regulation of survivin by treating cells with survivin siRNA PM, elicited a significant sensitization of the cells to PXL, in both sensitive and resistant cancer cell lines. Finally, we demonstrate successful co-delivery of PXL and survivin siRNA in the same PM leading to superior therapeutic activity compared to their sequential administration. Our results support the use of this new platform for the treatment of the most aggressive tumors.

Nanocarriers for Delivery of siRNA and Co-Delivery of siRNA and Other Therapeutic Agents

“…The co-delivery micelles demonstrated significantly better control of tumor volume than a mixture of single agent-loaded micelles, when tested on MCF-7 xenografts [87] Dox and BCL-2 siRNA FA-PEG-PGA/PEI-PCL layer-by-layer polymeric micelle FA The co-delivery micelles were shown to cause a higher level of cell apoptosis compared with micelles loaded with Dox and scrambled siRNA on human Bel-7402 hepatic cancer cells [95] Paclitaxel and Survivin siRNA siRNA-S-S-PE/P EG 2000 -PE micelle -Cytotoxicity test on paclitaxel-resistant SKOV3 cells showed that the co-delivery system led to a significant improvement in the paclitaxel chemosensitivity [96] Dox and PLK1 siRNA…”

The effect of co-delivery of paclitaxel and curcumin by transferrin-targeted PEG-PE-based mixed micelles on resistant ovarian cancer in 3-D spheroids and in vivo tumors

“…There are numerous reports showing increased P-gp overexpression and related drug resistance in spheroids compared to monolayers in various cancer cell lines including breast, lung and ovarian ones (Doublier et al, 2012, Kolchinsky and Roninson, 1997, Ponce de Leon and Barrera-Rodriguez, 2005, Walker et al, 2004). It has been shown earlier that co-delivery of anticancer agents with resistance modifiers (Patil et al, 2009, Patel et al, 2011, Wong et al, 2006, Sarisozen et al, 2012a) or therapeutic siRNA molecules (Salzano et al, 2014) in nanocarrier formulations could enhance the cytotoxicity and reverse the MDR on 2D monolayers.…”

Nanoparticle-mediated inhibition of survivin to overcome drug resistance in cancer therapy

“…To facilitate the delivery of survivin siRNA, survivin siRNA was linked with a phosphothioethanol (PE) moiety through a reducible disulfide bond to form a siRNA-S-S-PE conjugate [93]. The survivin siRNA-S-S-PE conjugate was then incorporated into PEG-phosphatidyl ethanolamine (PEG-PE) micelles along with PTX.…”