Ovarian cancer (OC) is a high-mortality
malignancy in women with a five-year survival rate of 30-40%. There is an urgent need to develop high-efficacy and low toxic treatments for OC. Herein, we report an appealing strategy that combines α3
integrin targeted polymersomes (A3-Ps) and targeted molecular drug,
polo-like kinase 1 (PLK1) inhibitor
volasertib (Vol) for dually
targeted molecular therapy of OC in vivo. A3-Ps had good Vol loading of 7.7-8.0 wt.% and small size of 25-32 nm, depending on the density of α3
integrin binding
peptide A3. Interestingly, cellular uptake studies using
FITC-labeled Vol revealed that A3-Ps with 20%
peptide gave 2.3 and 3.3-fold better internalization in SKOV-3 OC cells compared with non-targeted Ps and free Vol, respectively. Accordingly, Vol loaded in A3-Ps showed the best inhibitory activity to SKOV-3 cells with an IC50 of 49 nM, which was 3.5 times lower than free Vol. Importantly, the in vivo experiments demonstrated that A3-Ps-Vol proficiently repressed the growth of SKOV-3
tumors in mice while continuous
tumor growth was observed for Ps-Vol and free Vol-treated mice. A3-Ps-Vol besides boosting anti-OC activity also reduced the systemic toxicity of Vol. This dually targeted molecular drug nanoformulation has appeared to be an especially potent and low toxic treatment modality for human
ovarian cancers. STATEMENT OF SIGNIFICANCE:
Volasertib provides a potential molecular
therapy for PLK1-positive advanced OC patients. The initial clinical outcomes, nevertheless, showed a suboptimal efficacy, possibly resulting from its fast clearance, deficient
tumor deposition and dose-limiting toxicities. Here, we show for the first time that dually
targeted molecular therapy of OC using α3
integrin-binding
peptide-modified polymersomes as a vehicle gives markedly improved potency, better toleration, and depleted adverse effects in SKOV-3
tumor models, greatly outperforming free
volasertib. This dually targeted strategy has emerged as an appealing treatment for malignant PLK1-positive ovarian
tumors.