Orally Active Heparin Conjugate Augments Drug Distribution and Alleviates the Immunosuppressive Microenvironment by Promoting Tumor Perfusion
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초록
내용
Formation of blood clots is common in solid tumors, however their impact on limiting tumor perfusion and drug distribution have not been well established. Here, this study verifies that tumor perfusion is highly limited by cancer-associated thrombosis (CAT), which results in restricted drug distribution and accelerated hypoxia. Administration of an oral heparin conjugate (STP3725) demonstrates prevention of CAT and improves tumor perfusion, potentiating the efficacy of gemcitabine/oxaliplatin by enhancing drug distribution. Furthermore, this decreases hypoxia-related cytokines and MDSCs while increasing the infiltration of effector lymphocytes, leading to transformation into an immune-supportive tumor microenvironment. Collectively, these findings establish a rationale for a new combination strategy of oral anticoagulation therapy with chemotherapy/immunotherapy, which can lead to substantial improvements of current approaches in the clinic.