RESUMO
Cancer stem cells (CSCs) are responsible for malignant tumor initiation, recurrences, and metastasis. Therefore, targeting CSCs is a promising strategy for the development of cancer therapies. A big challenge for CSC-based cancer therapy is the overexpression of therapeutic stress protein, heat shock protein 90 (Hsp90), which protects CSCs from further therapeutic-induced damage, leading to the failure of treatment. Thus, efficient strategies to target CSCs are urgently needed for cancer therapy. To this end, a multifunctional nanoparticle (MNP) for CSC-based combined thermotherapy and chemotherapy is reported. This strategy dramatically suppresses tumor growth in breast CSC xenograft-bearing mice. Furthermore, a new mechanism is present that the MNP exerts its striking effects on CSCs by inhibiting the secretion of extracellular Hsp90 (eHsp90), resulting in the interruption of several key signaling pathways. These findings open new perspectives on the use of an MNP for effective CSC-based cancer treatment by inhibiting the function of eHsp90.
Assuntos
Proteínas de Choque Térmico HSP90/metabolismo , Nanopartículas de Magnetita/química , Animais , Anticorpos/química , Anticorpos/imunologia , Anticorpos/farmacologia , Anticorpos/uso terapêutico , Apoptose/efeitos dos fármacos , Benzoquinonas/química , Benzoquinonas/farmacologia , Benzoquinonas/uso terapêutico , Linhagem Celular Tumoral , Óxido Ferroso-Férrico/química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Humanos , Receptores de Hialuronatos/imunologia , Hipertermia Induzida , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/farmacologia , Lactamas Macrocíclicas/uso terapêutico , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/metabolismo , Porosidade , Transdução de Sinais/efeitos dos fármacos , Dióxido de Silício/química , Transplante HeterólogoRESUMO
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.