Suppressing Wnt signaling of the blood-tumor barrier to intensify drug delivery and inhibit lipogenesis of brain metastases

扫码查看

原文链接

NETL
NSTL
万方数据

外文摘要：Lipogenesis is often highly upregulated in breast cancer brain metastases to adapt to intracra-nial low lipid microenvironments.Lipase inhibitors hold therapeutic potential but their intra-tumoral dis-tribution is often blocked by the blood-tumor barrier(BTB).BTB activates its Wnt signaling to maintain barrier properties,e.g.,Mfsd2a-mediated BTB low transcytosis.Here,we reported VCAM-1-targeting nano-wogonin(W@V-NPs)as an adjuvant of nano-orlistat(O@V-NPs)to intensify drug delivery and inhibit lipogenesis of brain metastases.W@V-NPs were proven to be able to inactivate BTB Wnt signaling,downregulate BTB Mfsd2a,accelerate BTB vesicular transport,and enhance tumor accumula-tion of O@V-NPs.With the ability to specifically kill cancer cells in a lipid-deprived environment with IC50 at 48 ng/mL,W@V-NPs plus O@V-NPs inhibited the progression of brain metastases with pro-longed survival of model mice.The combination did not induce brain edema,cognitive impairment,and systemic toxicity in healthy mice.Targeting Wnt signaling could safely modulate the BTB to improve drug delivery and metabolic therapy against brain metastases.

外文关键词：

LipogenesisBrain metastasesBlood-tumor barrierWnt signalingDrug deliveryFatty acid synthaseNanoparticlesCombination therapy

作者：

Yang Tong、Pei An、Puxian Tang、Rui Mu、Yuteng Zeng、Hang Sun、Mei Zhao、Ziyan Lv、Pan Wang、Wanjun Han、Chunshan Gui、Xuechu Zhen、Liang Han

展开 >

作者单位：

Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences,Soochow University,Suzhou 215123,China

Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development,Soochow University,Suzhou 215123,China

基金：

National Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Innovation of Science and Technology-2030(Program of Brain Science and Brain-Inspired Intelligence Technology)grantJiangsu Key Laboratory of Neuropsychiatric Diseases Research Major Program,ChinaPriority Academic Program Development of the Jiangsu Higher Education Institutes(PAPD)Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain DiseasesSuzhou Science and Technology Development Project,China

项目编号：

32171381819732542021ZD0204004ZZ2101SJC2022021

出版年：

2024

DOI：

10.1016/j.apsb.2024.03.024

药学学报(英文版)

CSTPCD

ISSN：

年,卷(期)：2024.14(6)

参考文献量75