Tumor Microenvironment-Responsive Nanodrug for Embolotherapy and Enhanced Chemotherapy

Embolotherapy is an effective antitumor method, which essentially blocks the oxygen supply and induces hypoxia to treat tumors; however, traditional practices demand high expertise and harbor risks of complications. This study presents a mesoporous polydopamine-based (MPDA) drug delivery platform modified by engineered fusion proteins, which can specifically embolize tumor blood vessels and deliver the hypoxia-activated prodrug tirapazamine (TPZ). The fusion protein consists of an affibody targeting HER-2, a substrate for MMP-2, an RGD tripeptide, and a truncated tissue factor (tTF), which is then connected to MPDA loaded with TPZ. This nanodrug can actively target HER-2, interact with MMP-2 in the tumor microenvironment (TME), and embolize blood vessels; then, under TME acidic circumstances, MPDA releases TPZ, which is activated by hypoxia aggravated by embolization, and kills tumors. This embolization strategy, which is activated only under specific conditions, is extremely safe, and it compensates for the inadequacies of conventional embolization therapy, while also addressing the issue of hypoxia deficiency in hypoxia-activated prodrug therapy.