Fibrinolytic nanocages dissolve clots in the tumor microenvironment, improving the distribution and therapeutic efficacy of anticancer drugs

Abstract

Fibrin, one of the components of the extracellular matrix (ECM), acts as a transport barrier within the core of tumors by constricting the blood vessels and forming clots, leading to poor intratumoral distribution of anticancer drugs. Our group previously developed a microplasmin-based thrombolytic ferritin nanocage that efficiently targets and dissolves clots without causing systemic fibrinolysis or disrupting hemostatic clots. We hypothesized that the thrombolytic nanocage-mediated degradation of fibrin clots in the tumor ECM can lead to enhanced intratumoral drug delivery, especially for nanosized anticancer drugs. Fibrin clot deposition worsens after surgery and chemotherapy, further hindering drug delivery. Moreover, the risk of venous thromboembolism (VTE) also increases. Here, we used thrombolytic nanocages with multivalent clot-targeting peptides and fibrin degradation enzymes, such as microplasmin, to dissolve fibrin in the tumor microenvironment and named them fibrinolytic nanocages (FNCs). These FNCs target tumor clots specifically and effectively. FNCs efficiently dissolve fibrin clots inside of the tumor vessels, suggesting that they can mitigate the risk of VTE in cancer patients. Coadministration of FNC and doxorubicin led to improved chemotherapeutic activity in a syngeneic mouse melanoma model. Furthermore, the FNCs increased the distribution of Doxil/doxorubicin nanoparticles within mouse tumors. These results suggest that fibrinolytic cotherapy might help improve the therapeutic efficacy of anticancer nanomedicines. Thus, microplasmin-based fibrinolytic nanocages are promising candidates for this strategy due to their hemostatic safety and ability to home in on the tumor. Cancer: Improving treatment by dissolving clots Engineered "nanocages" that deliver clot-busting enzymes to tumors can improve the potency of chemotherapy and potentially reduce the risk of life-threatening complications. Many tumors form capillary-constricting clots composed of the protein fibrin, which impede drug penetration and create the potential for fatal venous thromboembolism. Researchers led by Soyoun Kim of Kyungpook National University, Daegu, South Korea, have devised a promising intervention that uses fibrin-degrading enzymes to clear these clogged vessels. The enzyme is delivered in nanocages composed of the protein ferritin coupled to short peptides that selectively bind fibrin, essentially targeting the treatment to clots. When they administered these nanocages to a mouse model of melanoma, the researchers observed a significantly improved response to chemotherapy and greater tumor penetration. This selective fibrin degradation should also eliminate the conditions that predispose patients to thrombembolism.