Novel CD44-targeting and pH/redox-dual-stimuli-responsive core–shell nanoparticles loading triptolide combats breast cancer growth and lung metastasis

Journal of Nanobiotechnology

Yihan Wu¹  Chaomei Fu¹  Huan Gu¹  Jinming Zhang¹  Zhixing Cao¹  Jinfeng Shi¹  Jiaqi Ma¹  Xi Luo¹  Jiaxin Li¹  Yali Ren¹ 

[1] State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, College of Pharmacy, Chengdu University of Traditional Chinese Medicine, No. 1166 Liutai Avenue, Wenjiang District, Chengdu, China;

关键词: Triptolide;    Nanoparticles;    Breast cancer;    Lung metastasis;    Low toxicity;   

DOI  :  10.1186/s12951-021-00934-0

来源: Springer

【 摘 要 】

BackgroundThe toxicity and inefficient delivery of triptolide (TPL) in tumor therapy have greatly limited the clinical application. Thus, we fabricated a CD44-targeting and tumor microenvironment pH/redox-sensitive nanosystem composed of hyaluronic acid-vitamin E succinate and poly (β-amino esters) (PBAEss) polymers to enhance the TPL-mediated suppression of breast cancer proliferation and lung metastasis.ResultsThe generated TPL nanoparticles (NPs) had high drug loading efficiency (94.93% ± 2.1%) and a desirable average size (191 nm). Mediated by the PBAEss core, TPL/NPs displayed a pH/redox-dual-stimuli-responsive drug release profile in vitro. Based on the hyaluronic acid coating, TPL/NPs exhibited selective tumor cellular uptake and high tumor tissue accumulation capacity by targeting CD44. Consequently, TPL/NPs induced higher suppression of cell proliferation, blockage of proapoptotic and cell cycle activities, and strong inhibition of cell migration and invasion than that induced by free TPL in MCF-7 and MDA-MB-231 cells. Importantly, TPL/NPs also showed higher efficacy in shrinking tumor size and blocking lung metastasis with decreased systemic toxicity in a 4T1 breast cancer mouse model at an equivalent or lower TPL dosage compared with that of free TPL. Histological immunofluorescence and immunohistochemical analyses in tumor and lung tissue revealed that TPL/NPs induced a high level of apoptosis and suppressed expression of matrix metalloproteinases, which contributed to inhibiting tumor growth and pulmonary metastasis.ConclusionCollectively, our results demonstrate that TPL/NPs, which combine tumor active targeting and pH/redox-responsive drug release with proapoptotic and antimobility effects, represent a promising candidate in halting breast cancer progression and metastasis while minimizing systemic toxicity.Graphic Abstract

【 授权许可】

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