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

Junyoung Seo,Soyoun Kim,Byungheon Lee,In-San Kim,Gayong Shim,Yu-Kyoung Oh,Rang-Woon Park,Minseong Kim,Jae Do Yoo

doi:10.1038/s12276-021-00688-7

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.

Highlights

Cancer patients exhibit an abnormal plasma clot profile, increased clot formation potential, and a decreased fibrinolytic ability to resolve clots
Our study demonstrated that the clot-targeting peptides (CLT)-small version of the ferritin (sFt)-μP nanocage, named fibrinolytic nanocage (FNC), is a promising tool to resolve fibrin-induced interstitial fluid pressure and improve drug penetration into tumors
FNC (CLT-sFt-μP) is significantly bound to clots in a dose-dependent manner when compared to controls, indicating that FNC can bind to clots via CLT peptides (Fig. 1c)

Summary

Introduction

Cancer patients exhibit an abnormal plasma clot profile, increased clot formation potential, and a decreased fibrinolytic ability to resolve clots. Patients with cancer are at risk of both tumor progression and venous thromboembolism (VTE) and arterial thrombotic (ATE) complications. The risk of VTE is especially high in those receiving chemotherapy, which is the second leading cause of death in cancer patients[1,2,3]. Significant fibrin deposition has been observed in many solid tumor biopsies, including those from breast, colon, esophageal, kidney, liver, lung, melanoma, and stomach tumors. The degree of deposition is heterogeneous among tumor types and stages: 20–90% of the tumor area is positively stained for fibrin in all examined tumor biopsies[4]. The tumor-specific presence of fibrin makes it an attractive target for anticancer therapeutics[5]

Methods

Results

Conclusion