Deep tumor‐penetrated nanosystem eliminates cancer stem cell for highly efficient liver cancer therapy

Abstract

Cancer stem cells (CSCs), which are resistant to the traditional therapies, have been considered to account for the development, metastasis, and relapse of various malignant tumors, and therefore, must be eliminated to cure cancer. However, they can reside in deep tumor regions away from the blood vessels, and are typically inaccessible owing to the low delivery efficiency and limited tumor penetrating ability of drug carriers. To overcome these problems, we designed a tumor-penetrating peptide (tLyP-1)-conjugated ZIF-90 nanosystem loaded with doxorubicin (DOX) and N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine t-butyl ester (DAPT) to penetrate and eradicate differentiated cancer cells and CSCs simultaneously. The nanosystem exhibited beneficial biocompatibility, enhanced tissue penetration, high blood circulation stability, and pH-responsive drug release for favoring cancer therapy. It was found that the nanosystem could kill both cancer cells and CSCs in vitro. The in vivo results demonstrated that the ZIF-90 nanosystem can effectively accumulate in tumor tissues after long blood circulation and flexibly permeate throughout the tumor tissues. In the HCCLM3 xenograft model, the ZIF-90 nanosystem presented high-efficiency tumor suppression and drastically eradicated the CSCs in the tumor tissues with low systemic toxicity. Overall, the deep tumor-penetrating nanosystem exhibits outstanding potential for improving curative effect.