α3 integrin-binding peptide-functionalized polymersomes loaded with volasertib for dually-targeted molecular therapy for ovarian cancer.
Acta Biomater
; 124: 348-357, 2021 04 01.
Article
en En
| MEDLINE
| ID: mdl-33561562
ABSTRACT
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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias Ováricas
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Integrina alfa3
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Acta Biomater
Año:
2021
Tipo del documento:
Article