Hypoxia-cleavable and specific targeted nanomedicine delivers epigenetic drugs for enhanced treatment of breast cancer and bone metastasis

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Abstract

Breast cancer bone metastasis has become a common cancer type that still lacks an effective treatment method. Although epigenetic drugs have demonstrated promise in cancer therapy, their nontargeted accumulation and drug resistance remain nonnegligible limiting factors. Herein, we first found that icaritin had a strong synergistic effect with an epigenetic drug (JQ1) in the suppression of breast cancer, which could help to relieve drug resistance to JQ1. To improve tumor-targeted efficacy, we developed a hypoxia-cleavable, RGD peptide-modified poly(D,L-lactide-co-glycolide) (PLGA) nanoparticle (termed ARNP) for the targeted delivery of JQ1 and icaritin. The decoration of long cleavable PEG chains can shield RGD peptides during blood circulation and reduce cellular uptake at nonspecific sites. ARNP actively targets breast cancer cells via an RGD-αvβ3 integrin interaction after PEG chain cleavage by responding to hypoxic tumor microenvironment. In vitro and in vivo assays revealed that ARNP exhibited good biodistribution and effectively suppressed primary tumor and bone metastasis. Meanwhile, ARNP could alleviate bone erosion to a certain extent. Furthermore, ARNP significantly inhibited pulmonary metastasis secondary to bone metastasis. The present study suggests that ARNP has great promise in the treatment of breast cancer and bone metastasis due to its simple and practical potential.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12951-023-01939-7.

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Most cited references 40

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Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)

This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.

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The skeleton is the most common organ to be affected by metastatic cancer and the site of disease that produces the greatest morbidity. Skeletal morbidity includes pain that requires radiotherapy, hypercalcemia, pathologic fracture, and spinal cord or nerve root compression. From randomized trials in advanced cancer, it can be seen that one of these major skeletal events occurs on average every 3 to 6 months. Additionally, metastatic disease may remain confined to the skeleton with the decline in quality of life and eventual death almost entirely due to skeletal complications and their treatment. The prognosis of metastatic bone disease is dependent on the primary site, with breast and prostate cancers associated with a survival measured in years compared with lung cancer, where the average survival is only a matter of months. Additionally, the presence of extraosseous disease and the extent and tempo of the bone disease are powerful predictors of outcome. The latter is best estimated by measurement of bone-specific markers, and recent studies have shown a strong correlation between the rate of bone resorption and clinical outcome, both in terms of skeletal morbidity and progression of the underlying disease or death. Our improved understanding of prognostic and predictive factors may enable delivery of a more personalized treatment for the individual patient and a more cost-effective use of health care resources.

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Response and resistance to BET bromodomain inhibitors in triple negative breast cancer

Shaokun Shu, Charles Y Lin, Housheng He … (2016)

Triple negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy 1-3 . BET bromodomain inhibitors, which have shown efficacy in several models of cancer 4-6 , have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyllysine recognition modules, leading to inhibition of oncogenic transcriptional programs 7-9 . Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance.

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Author and article information

Contributors

Dong Ma: tmadong@jnu.edu.cn

Huile Gao: gaohuile@scu.edu.cn , gaohuilescu@163.com

Yi Qin: qinyi0225@163.com

Journal

Journal ID (nlm-ta): J Nanobiotechnology

Journal ID (iso-abbrev): J Nanobiotechnology

Title: Journal of Nanobiotechnology

Publisher: BioMed Central (London )

ISSN (Electronic): 1477-3155

Publication date (Electronic): 12 July 2023

Publication date PMC-release: 12 July 2023

Publication date Collection: 2023

Volume: 21

Electronic Location Identifier: 221

Affiliations

[1 ]GRID grid.452930.9, ISNI 0000 0004 1757 8087, Department of Orthopedic, , Zhuhai People’s Hospital (Zhuhai hospital affiliated with Jinan University, ; Zhuhai, 519000 Guangdong China

[2 ]GRID grid.13291.38, ISNI 0000 0001 0807 1581, Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, , Sichuan University, ; Chengdu, 610041 China

[3 ]GRID grid.258164.c, ISNI 0000 0004 1790 3548, Department of Biomedical Engineering, , Jinan University, ; Guangzhou, 510632 China

[4 ]GRID grid.452209.8, ISNI 0000 0004 1799 0194, Department of Orthopaedic Surgery, , Third Hospital of Hebei Medical University, ; Shijiazhuang, China

Article

Publisher ID: 1939

DOI: 10.1186/s12951-023-01939-7

PMC ID: 10337106

SO-VID: ad0824e6-a420-471d-ac1b-114615bd3763

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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 3 April 2023

Date accepted : 25 May 2023

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 82174142

Funded by: FundRef http://dx.doi.org/10.13039/501100003453, Natural Science Foundation of Guangdong Province;

Award ID: 2021A1515410001

Funded by: Zhuhai Xiangshan Talent Project

Award ID: 2021XSYC-01

Funded by: Cultivation Project of Zhuhai People’s Hospital

Award ID: 2019PY-14

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ScienceOpen disciplines: Biotechnology

Keywords: bone metastasis,epigenetic drug,nanomedicine,drug delivery,hypoxia responsive

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ScienceOpen disciplines: Biotechnology

Keywords: bone metastasis, epigenetic drug, nanomedicine, drug delivery, hypoxia responsive

Hypoxia-cleavable and specific targeted nanomedicine delivers epigenetic drugs for enhanced treatment of breast cancer and bone metastasis

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Most cited references 40

Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Clinical features of metastatic bone disease and risk of skeletal morbidity.

Response and resistance to BET bromodomain inhibitors in triple negative breast cancer

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