Fibrinolytic nanocages dissolve clots in the tumor microenvironment, improving the distribution and therapeutic efficacy of anticancer drugs
서준영, 유재도, 김민성, 심가용, 오유경, 박랑운, 이병현, 김인상, Kim So-Youn,
소속 상세정보
서준영 ( Seo Jun-Young )
Kyungpook National University School of Medicine Department of Biochemistry and Cell Biology
유재도 ( Yoo Jae-Do )
Kyungpook National University School of Medicine Department of Biochemistry and Cell Biology
김민성 ( Kim Min-Seong )
Kyungpook National University School of Medicine Department of Biochemistry and Cell Biology
심가용 ( Shim Ga-Yong )
Soongsil University School of Systems Biomedical Science
오유경 ( Oh Yu-Kyoung )
Seoul National University College of Pharmacy
박랑운 ( Park Rang-Woon )
Kyungpook National University School of Medicine Department of Biochemistry and Cell Biology
이병현 ( Lee Byung-Heon )
Kyungpook National University School of Medicine Department of Biochemistry and Cell Biology
김인상 ( Kim In-San )
Korea Institute of Science and Technology Biomedical Research Institute
( Kim So-Youn )
Kyungpook National University School of Medicine Department of Biochemistry and Cell Biology
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.
키워드
Drug delivery; Drug development
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SCI(E)
MEDLINE
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KoreaMed
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