ATB0,+-targeted nanoparticles initiate autophagy suppression to overcome chemoresistance for enhanced colorectal cancer therapy

Abstract

Oxaliplatin (OXA) resistance remains the major obstacle to the successful chemotherapy of colorectal cancer (CRC). As a self-protection mechanism, autophagy may contribute to tumor drug resistance, therefore autophagy suppression could be regarded as a possible treatment option in chemotherapy. Cancer cells, especially drug-resistant tumor cells, increase their demand for specific amino acids by expanding exogenous supply and up-regulating de novo synthesis, to meet the needs for excessive proliferation. Therefore, it is possible to inhibit cancer cell proliferation through pharmacologically blocking the entry of amino acid into cancer cells. SLC6A14 (ATB0,+) is an essential amino acid transporter, that is often abnormally up-regulated in most cancer cells. Herein, in this study, we designed oxaliplatin/berbamine-coloaded, ATB0,+-targeted nanoparticles ((O + B)@Trp-NPs) to therapeutically target SLC6A14 (ATB0,+) and inhibit cancer proliferation. The (O + B)@Trp-NPs utilize the surface-modified tryptophan to achieve SLC6A14-targeted delivery of Berbamine (BBM), a compound that is found in a number of plants used in traditional Chinese medicine, which could suppress autolysosome formation though impairing autophagosome-lysosome fusion. We verified the feasibility of this strategy to overcome the OXA resistance during colorectal cancer treatment. The (O + B)@Trp-NPs significantly inhibited the proliferation and decreased the drug resistance of resistant colorectal cancer cells. In vivo, (O + B)@Trp-NPs greatly suppressed the tumor growth in tumor-bearing mice, which is consistent with the in vitro data. This research offers a unique and promising chemotherapeutic treatment for colorectal cancer.