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

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ACTA PHARMACEUTICA SINICA B 2024年第9期14卷 4087-4101页

作者： Zhou, Zaigang Luo, Wenjuan Zheng, Chunjuan Wang, Haoxiang Hu, Rui Deng, Hui Shen, Jianliang Wenzhou Med Univ Eye Hosp Natl Engn Res Ctr Ophthalmol & Optometry Wenzhou 325027 Peoples R China Univ Chinese Acad Sci Wenzhou Inst Zhejiang Engn Res Ctr Tissue Repair Mat Wenzhou 325001 Peoples R China Wenzhou Med Univ Sch & Hosp Stomatol Wenzhou 325027 Peoples R China Wenzhou Med Univ Dept Affiliated Hosp 2 Wenzhou 325000 Peoples R China

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-beta 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-beta 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. (c) 2024 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. This is an open access article under the CC BY-NC-ND license (http://***/licenses/by-nc-nd/4.0/).

关键词： Chemo-immunotherapy Collagen Transforming growth factor-beta Mitochondrial metabolism Programmed cell death-ligand 1 Drug accumulation Albumin-bound paclitaxel immune-resistance microenvironment BREAST-CANCER TAMOXIFEN NANOPARTICLES PENETRATION EFFICACY

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