Anti-lymphangiogenesis for boosting drug accumulation in tumors  

作　　者：Chunling Wang Junchao Xu Xiaoyu Cheng Ge Sun Fenfen Li Guangjun Nie Yinlong Zhang 

机构地区：[1]CAS Key Laboratory for Biomedical Effects of Nanomaterials&Nanosafety,CAS Center for Excellence in Nanoscience,National Center for Nanoscience and Technology,Beijing 100190,China [2]Sino-Danish College,University of Chinese Academy of Sciences,Beijing 100190,China [3]Sino-Danish Center for Education and Research,Beijing 100190,China [4]Department of Bioengineering,University of Pennsylvania,Philadelphia,PA 19104,USA [5]School of Nanoscience and Engineering,University of Chinese Academy of Sciences,Beijing 100049,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第5期2161-2175,共15页信号转导与靶向治疗（英文）

基　　金：This work was supported by grants from the National Key Research and Development Program of China(2022YFA1206800,2021YFA1201103);the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB36000000,G.N.);the National Natural Science Foundation of China(32371520);the Beijing Natural Science Foundation(Z210017);the Key Research Program of Frontier Sciences CAS(ZDBS-LY-SLH039),the Youth Innovation Promotion Association CAS(2022166);the Fundamental Research Funds for the Central Universities.The authors thank Han Ouyang(School of Nanoscience and Engineering,University of Chinese Academy of Sciences)for the help of intratumoral interstitial fluid pressure(IFP)assay.

摘　　要：The inadequate tumor accumulation of anti-cancer agents is a major shortcoming of current therapeutic drugs and remains an even more significant concern in the clinical prospects for nanomedicines.Various strategies aiming at regulating the intratumoral permeability of therapeutic drugs have been explored in preclinical studies,with a primary focus on vascular regulation and stromal reduction.However,these methods may trigger or facilitate tumor metastasis as a tradeoff.Therefore,there is an urgent need for innovative strategies that boost intratumoral drug accumulation without compromising treatment outcomes.As another important factor affecting drug tumor accumulation besides vasculature and stroma,the impact of tumor-associated lymphatic vessels(LVs)has not been widely considered.In the current research,we verified that anlotinib,a tyrosine kinase inhibitor with anti-lymphangiogenesis activity,and SAR131675,a selective VEGFR-3 inhibitor,effectively decreased the density of tumor lymphatic vessels in mouse cancer models,further enhancing drug accumulation in tumor tissue.By combining anlotinib with therapeutic drugs,including doxorubicin(Dox),liposomal doxorubicin(Lip-Dox),and anti-PD-L1 antibody,we observed improved anti-tumor efficacy in comparison with monotherapy regimens.Meanwhile,this strategy significantly reduced tumor metastasis and elicited stronger anti-tumor immune responses.Our work describes a new,clinically transferrable approach to augmenting intratumoral drug accumulation,which shows great potential to address the current,unsatisfactory efficacies of therapeutic drugs without introducing metastatic risk.

关 键 词：DRUGS ANGIOGENESIS METASTASIS 

分 类 号：R96[医药卫生—药理学]