线粒体代谢阻断纳米佐剂逆转免疫耐受微环境以增强白蛋白结合紫杉醇基础的化疗免疫治疗

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

DOI 原文链接

用sci-hub下载

Acta Pharmaceutica Sinica B

影响因子:14.6

分区:医学1区 Top / 药学1区

发表日期:2024 Sep

作者: Zaigang Zhou, Wenjuan Luo, Chunjuan Zheng, Haoxiang Wang, Rui Hu, Hui Deng, Jianliang Shen

DOI: 10.1016/j.apsb.2024.05.028

摘要

目前，白蛋白结合紫杉醇（PTX@Alb）的疗效仍然受到限制，部分原因是由致密胶原蛋白分布介导的PTX@Alb在肿瘤中的积累受损。同时，PTX@Alb治疗后常发生获得性免疫耐受，这是由于程序性细胞死亡配体1（PD-L1）表达增加，导致免疫耐受。为弥补这些空白，我们新发现他莫昔芬（TAM）作为临床广泛应用于乳腺癌辅助治疗、具有线粒体代谢阻断能力的药物，也可以作为新型有效的PD-L1和TGF-β双重抑制剂，通过诱导腺苷酸活化蛋白激酶（AMPK）磷酸化实现。随后，为获得更显著的效果，制备了TPP-TAM，将线粒体靶向的三苯基膦（TPP）与TAM偶联，再与白蛋白（Alb）自组装形成TPP-TAM@Alb纳米粒子。通过这种方式，TPP-TAM@Alb纳米粒子在体外有效降低胶原蛋白的表达，从而增强了PTX@Alb在4T1肿瘤中的积累。此外，TPP-TAM@Alb还能有效降低肿瘤中的PD-L1和TGF-β的表达，通过增强T细胞的渗透性，从而更好地增强PTX@Alb介导的化疗免疫治疗。总之，我们提出了一种新颖的线粒体代谢阻断策略，以抑制PTX@Alb耐药性肿瘤，进一步支持其临床应用的潜力。

Abstract

Currently, the efficacy of albumin-bound paclitaxel (PTX@Alb) is still limited due to the impaired 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 with mitochondrial metabolism blockade capacity, could also be used as a novel effective PD-L1 and TGF-β dual-inhibitor via inducing the phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK) protein. Following this, to obtain a more significant effect, TPP-TAM was prepared by conjugating mitochondria-targeted triphenylphosphine (TPP) with TAM, which then further self-assembled with albumin (Alb) to form TPP-TAM@Alb nanoparticles. By doing this, TPP-TAM@Alb nanoparticles effectively decreased the expression of collagen in vitro, which then led to the enhanced accumulation of PTX@Alb in 4T1 tumors. Besides, TPP-TAM@Alb also effectively decreased the expression of PD-L1 and TGF-β in tumors to better sensitize PTX@Alb-mediated chemo-immunotherapy by enhancing T cell infiltration. All in all, we newly put forward a novel mitochondrial metabolism blockade strategy to inhibit PTX@Alb-resistant tumors, further supporting its better clinical application.