Mitochondrial metabolism blockade nanoadjuvant reversed immune-resistance microenvironment to sensitize albumin-bound paclitaxel-based chemo-immunotherapy  

作　　者：Zaigang Zhou Wenjuan Luo Chunjuan Zheng Haoxiang Wang Rui Hu Hui Deng Jianliang Shen 

机构地区：[1]National Engineering Research Center of Ophthalmology and Optometry,Eye Hospital,Wenzhou Medical University,Wenzhou 325027,China [2]School&Hospital of Stomatology,Wenzhou Medical University,Wenzhou 325027,China [3]Zhejiang Engineering Research Center for Tissue Repair Materials,Wenzhou Institute,University of Chinese Academy of Sciences,Wenzhou 325001,China [4]Department of the Second Affiliated Hospital of Wenzhou Medical University,Wenzhou 325000,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第9期4087-4101,共15页药学学报（英文版）

基　　金：the National Natural Science Foundation of China(22377093);the Zhejiang Provincial Natural Science Foundation for Distinguished Young Scholar(LR23C100001,China);the Zhejiang Qianjiang Talent Plan(QJD20020224,China).

摘　　要：Currently, the efficacy of albumin-bound paclitaxel (PTX@Alb) is still limited due to theimpaired PTX@Alb accumulation in tumors partly mediated by the dense collagen distribution. Meanwhile,acquired immune resistance always occurs due to the enhanced programmed cell death-ligand 1(PD-L1) expression after PTX@Alb treatment, which then leads to immune tolerance. To fill these gaps,we newly revealed that tamoxifen (TAM), a clinically widely used adjuvant therapy for breast cancer withmitochondrial metabolism blockade capacity, could also be used as a novel effective PD-L1 and TGF-bdual-inhibitor via inducing the phosphorylation of adenosine 5ʹ-monophosphate-activated protein kinase(AMPK) protein. Following this, to obtain a more significant effect, TPP-TAM was prepared by conjugatingmitochondria-targeted triphenylphosphine (TPP) with TAM, which then further self-assembledwith albumin (Alb) to form TPP-TAM@Alb nanoparticles. By doing this, TPP-TAM@Alb nanoparticleseffectively decreased the expression of collagen in vitro, which then led to the enhanced accumulation ofPTX@Alb in 4T1 tumors. Besides, TPP-TAM@Alb also effectively decreased the expression of PD-L1 and TGF-b in tumors to better sensitize PTX@Alb-mediated chemo-immunotherapy by enhancing T cellinfiltration. All in all, we newly put forward a novel mitochondrial metabolism blockade strategy toinhibit PTX@Alb-resistant tumors, further supporting its better clinical application。

关 键 词：CHEMO-IMMUNOTHERAPY Collagen Transforming growth factor-b Mitochondrial metabolism Programmed cell deathligand 1 Drug accumulation Albumin-bound paclitaxel Immune-resistance microenvironment 

分 类 号：R730.53[医药卫生—肿瘤]