Here, we suggest in the first time that the cancer associated thrombosis(CAT) might be one of the major factor which limit the tumor blood perfusion and drug distribution inside the tumor tissue by reducing the effective radius of blood vessels. In order to prevent CAT and achieve enhanced drug distribution, we developed orally active heparin to be combined with other anti-cancer therapies. We injected dye conjugated fibrinogen and chitosan nanoparticles to mice which were bearing highly thrombotic tumor to visualize CAT and nanoparticle distribution inside the tumor tissue. When CAT is prevented by heparin, we found that nanoparticle distribution and accumulation were significantly enhanced compared to the group not treated with heparin. This results signify that the CAT can limit the tumor perfusion and prevention of CAT can enhance the drug accumulation and distribution. We used highly thrombotic cancer models such as melanoma and pancreatic cancer to evaluate the therapeutic efficacy of the doxorubicin containing nanoparticle and the combination of oxaliplatin and gemcitabine when they are combined with heparin. We have found that when heparin is combined with each therapy, their tumor inhibition efficacy increased about 25% and also confirmed that this synergistic effect comes from enhanced drug distribution inside the tumor tissue by preventing the CAT using anticoagulant. These results were also supported by histological analysis.
We have validated our hypothesis by showing that CAT can limit the tumor perfusion, which in turn brings reduced drug distribution inside the tumor tissue. We also confirmed that our oral heparin could enhance the tumor perfusion and the efficacy of anti-cancer therapeutics by preventing the CAT in the tumor tissue.
Citation Format: Jeong Uk Choi, Taslim A. Al-Hilal, Seung Woo Chung, Jisuk Yun, Hwajung Nam, Myungyun Lee, Jinha Hwang, Kyungjin Kim, Youngro Byun, Youngseok Cho, Seong Wook Lee. Enhancing tumor blood perfusion using orally active heparin to increase the distribution of anticancer therapeutics inside the tumor tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5154. doi:10.1158/1538-7445.AM2017-5154