Co-delivery Of Drugs With Nanoparticies For Cancer Stem Cell Therapy

Cancer stem cells (CSCs), also called tumor-initiating cells or stem-like cancer cells, are known to be resistant to chemotherapy and radiotherapy and are associated with tumor metastasis and recurrence after treatments; as such, they have attracted increasing attention in recent years with regard to the development of advanced therapeutic methods, including directly killing, inhibition of self-renewal, differentiation, regulation of their niche. However, existed evidences indicated that non-CSCs in the tumor can spontaneously and stochastically turn into CSCs de novo, undermining the efficacy of therapeutic strategies that only target CSCs. Hence, it is crucial to eliminate CSCs and non-CSCs simultaneously for effective cancer therapy. Recently, delivering drugs with different mechanisms to the tumor tissue and cancer stem cells by combination therapy, can overcome the instability, promote the blood circulation, and improve the synergistic effect of drugs, which is promising in cancer stem cells therapy. Therefore, we used polyethylene glycol-polylactic acid-based nanoparticles to simultaneously encapsulate drug targeting cancer stem cells and traditional chemotherapeutic agents, achieving prolonged circulation time, which can increase the enrichment of drugs in tumor tissue and cancer stem cells, further promote inhibiton for cancer stem cells and tumor cells and ultimate efficient tumor treatment.1. We proposed a promising co-delivery strategy of all-trans-retinoicacid and doxorubicin for both CSCs and non-CSCs therapy. All-trans-retinoicacid and doxorubicin-loaded nanoparticles were prepared by a single emulsion method, and the effective drug uptake by breast CSCs was successfully demonstrated. Meanwhile, treatment with obtained nanoparticles induced breast CSC differentiation via all-trans-retinoic acid, which attenuated their tumor initiating ability and eventually enhanced the cytotoxicity of doxorubicin. Furthermore, intravenous administration of the nanoparticles enhanced the enrichment of the drugs both in tumor tissue and cancer stem cells, and co-delivery of all-trans-retinoicacid and doxorubicin remarkably impoved the suppression of tumor growth while decreasing breast CSCs ratio through a synergistic manner.2. Thinking about the crucial role of autophagy in cancer stem cells, we developed another strategy to inhibit the cancer stem cells through autophagy inhibition, which was combined with doxorubicin or docetaxel treatment for synergistic suppression of cancer stem cells and tumor growth using co-delivery system. Firstly, we demonstrated that inhibition of autophagy by chloroquine reduced the stemness of cancer stem cells, and increased the suppression of cancer stem cells with the help of chemotherapeutic drugs in vitro. On the other hand, using nanocarriers simultaneously delivered chloroquine and chemotherapeutic agents to the tumor tissue and cancer stem cells. Finally, inhibition of autophagy promoted sensitivity of cancer stem cells and ordinary tumor cells to chemotherapeutic drugs, which achieved more effective inhibition of cancer stem cells and improved tumor therapy in vivo.