Novel CD44-targeting and pH/redox-dual-stimuli-responsive core–shell nanoparticles loading triptolide combats breast cancer growth and lung metastasis
Abstract Background The 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-amin...
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doaj-c1fcd1edb56749a7ba354e50087b280a2021-06-27T11:07:27ZengBMCJournal of Nanobiotechnology1477-31552021-06-0119112210.1186/s12951-021-00934-0Novel CD44-targeting and pH/redox-dual-stimuli-responsive core–shell nanoparticles loading triptolide combats breast cancer growth and lung metastasisJinfeng Shi0Yali Ren1Jiaqi Ma2Xi Luo3Jiaxin Li4Yihan Wu5Huan Gu6Chaomei Fu7Zhixing Cao8Jinming Zhang9State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, College of Pharmacy, Chengdu University of Traditional Chinese MedicineState Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, College of Pharmacy, Chengdu University of Traditional Chinese MedicineState Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, College of Pharmacy, Chengdu University of Traditional Chinese MedicineState Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, College of Pharmacy, Chengdu University of Traditional Chinese MedicineState Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, College of Pharmacy, Chengdu University of Traditional Chinese MedicineState Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, College of Pharmacy, Chengdu University of Traditional Chinese MedicineState Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, College of Pharmacy, Chengdu University of Traditional Chinese MedicineState Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, College of Pharmacy, Chengdu University of Traditional Chinese MedicineState Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, College of Pharmacy, Chengdu University of Traditional Chinese MedicineState Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, College of Pharmacy, Chengdu University of Traditional Chinese MedicineAbstract Background The 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. Results The 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. Conclusion Collectively, 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 Abstracthttps://doi.org/10.1186/s12951-021-00934-0TriptolideNanoparticlesBreast cancerLung metastasisLow toxicity |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jinfeng Shi Yali Ren Jiaqi Ma Xi Luo Jiaxin Li Yihan Wu Huan Gu Chaomei Fu Zhixing Cao Jinming Zhang |
spellingShingle |
Jinfeng Shi Yali Ren Jiaqi Ma Xi Luo Jiaxin Li Yihan Wu Huan Gu Chaomei Fu Zhixing Cao Jinming Zhang Novel CD44-targeting and pH/redox-dual-stimuli-responsive core–shell nanoparticles loading triptolide combats breast cancer growth and lung metastasis Journal of Nanobiotechnology Triptolide Nanoparticles Breast cancer Lung metastasis Low toxicity |
author_facet |
Jinfeng Shi Yali Ren Jiaqi Ma Xi Luo Jiaxin Li Yihan Wu Huan Gu Chaomei Fu Zhixing Cao Jinming Zhang |
author_sort |
Jinfeng Shi |
title |
Novel CD44-targeting and pH/redox-dual-stimuli-responsive core–shell nanoparticles loading triptolide combats breast cancer growth and lung metastasis |
title_short |
Novel CD44-targeting and pH/redox-dual-stimuli-responsive core–shell nanoparticles loading triptolide combats breast cancer growth and lung metastasis |
title_full |
Novel CD44-targeting and pH/redox-dual-stimuli-responsive core–shell nanoparticles loading triptolide combats breast cancer growth and lung metastasis |
title_fullStr |
Novel CD44-targeting and pH/redox-dual-stimuli-responsive core–shell nanoparticles loading triptolide combats breast cancer growth and lung metastasis |
title_full_unstemmed |
Novel CD44-targeting and pH/redox-dual-stimuli-responsive core–shell nanoparticles loading triptolide combats breast cancer growth and lung metastasis |
title_sort |
novel cd44-targeting and ph/redox-dual-stimuli-responsive core–shell nanoparticles loading triptolide combats breast cancer growth and lung metastasis |
publisher |
BMC |
series |
Journal of Nanobiotechnology |
issn |
1477-3155 |
publishDate |
2021-06-01 |
description |
Abstract Background The 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. Results The 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. Conclusion Collectively, 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 |
topic |
Triptolide Nanoparticles Breast cancer Lung metastasis Low toxicity |
url |
https://doi.org/10.1186/s12951-021-00934-0 |
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