Nucleus-targeted nano delivery system eradicates cancer stem cells by combined thermotherapy and hypoxia-activated chemotherapy

• Published in: Biomaterials Vol. 200; pp. 1 - 14
• Main Authors: Li, Hongjuan, Yan, Weixiao, Suo, Xiaomin, Peng, Haotong, Yang, Xinjian, Li, Zhenhua, Zhang, Jinchao, Liu, Dandan
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.04.2019
• Subjects: Cancer stem cells; Combined therapy; Hypoxia-activated; Nucleus-targeted; Signaling pathway; Nucleus-targeted; Signaling pathway; Cancer stem cells; Hypoxia-activated; Combined therapy
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2019.01.048

Many efforts have focused on the cancer stem cell (CSC) targeting nano delivery system, however, the anticancer therapy efficacy is relative low due to the highly drug-resistance and drug efflux. Nucleus-targeted drug delivery is a promising strategy for reverse the drug resistance and drug efflux of CSCs, but in vivo nucleus-targeted drug delivery has been challenging. Herein, we designed a mesoporous silica nanoparticle (MSN)-based nucleus-targeted system, which could directly target the CSCs and further enter the nucleus by the surface modification of anti-CD133 and thermal-triggered exposure of TAT peptides under an alternating magnetic field (AMF). The nucleus-targeted drug release ultimately leads to an exhaustive apoptosis of the CSCs through combined thermotherapy and hypoxia-activated chemotherapy. In vivo, the nucleus-targeted nano delivery system efficiently inhibits the tumor growth without notable side effects during the course of treatment. Molecular mechanism study illustrates that the system effectively eliminates the CSCs by blocking the hypoxia signaling pathway. This designed nucleus-targeted nano delivery system is expected to provide new insights for developing efficient platforms for CSC-targeted cancer therapy. The nucleus-targeted nano delivery system with capacity of vasculature-to membrane-to nucleus displays an extraordinarily high in vivo tumor targeting efficacy and especially to tumor nuclear, and thus is highly desired in promoting the therapeutic efficacy by combined thermotherapy and hypoxia-activated chemotherapy. [Display omitted] •The nanosystem has a core/shell structure with four layers that delivers the drug into nucleus.•Positive target to CSCs by specific antibody as the first layer.•Exposure of TAT peptide under AMF treatment facilitates the nucleus-targeting.•Supressing the growth of CSCs through releasing the hypoxic responsed drug in the nucleus.