Heparanase-responsive nanomaterial for anaplastic thyroid cancer chemotherapy

Abstract

Anaplastic thyroid cancer (ATC) is aggressive and has a high mortality rate. Doxorubicin (DOX), the first-line chemotherapy drug for ATC, has an insufficient effective concentration and severe cardiac toxicity, limiting its clinical application. Therefore, it is urgent to enhance the efficacy of DOX and reduce its toxicity. Designing stimulus-responsive drug delivery systems (DDSs) based on the characteristics of the tumor microenvironment may be a promising approach for the treatment of ATC. We found that heparanase (HPSE) is highly expressed in the tumor microenvironment of ATC, but not in normal thyroid tissue. In this study, we successfully constructed and characterized a HPSE-responsive self-assembled carrier, TET-HS-NI, which was modified with 3,3,5,5-tetraiodothyroacetic acid (TET) that targets α_vβ₃. DOX was loaded into TET-HS-NI to construct TET-HS-NI/DOX. Zebrafish cell-derived xenograft (CDX) and ATC orthotopic models showed that TET-HS-NI/DOX significantly improved the antitumor efficacy and safety of DOX. In a word, we have constructed a drug delivery system that sensitively releases DOX in the ATC environment where HPSE is overexpressed, increasing DOX's effective concentration at the tumor site and providing a new method for the treatment of ATC.