5-FU@DHA-UIO-66-NH <sub>2</sub> potentiates chemotherapy sensitivity of breast cancer cells through a microRNA let-7a-dependent mechanism

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Abstract

Background

Drug delivery systems with magnetization facilitate the accumulation of drug at the target site. This study aimed to explore the mechanism by which docosahexaenoic acid (DHA)-modified porous metal-organic framework (MOF) UIO-66-NH ₂ loads chemotherapeutic drug 5-fluorouracil (5-FU) and reduces the chemotherapy resistance of breast cancer (BC) cells.

Methods

UIO-66-NH ₂ was synthesized and DHA with carboxyl end was used to modify the surface of UIO-66-NH ₂. 5-FU was incorporated to UIO-66-NH ₂ or DHA-UIO-66-NH ₂ by a post-synthesis method. The loading and release of 5-FU by @DHA-UIO-66-NH ₂ was investigated with ultraviolet (UV) spectroscopy. RT-qPCR was conducted to detect the expression of let-7a in cells. The uptake of DHA-UIO-66-NH ₂ by MCF-7 BC cells was observed by confocal laser scanning microscope (CLSM). Cell counting kit-8 (CCK-8), flow cytometry, and live/dead cell staining were applied to investigate the effects of 5-FU@DHA-UIO-66-NH ₂ on BC cells, and a BC mouse model was established to explore its effects on tumorigenesis. HE staining and routine blood index analysis were applied for determination of the biological safety of 5-FU@DHA-UIO-66-NH ₂.

Results

5-FU@DHA-UIO-66-NH ₂ was successfully constructed and characterized. The loading amount of DHA-UIO-NH ₂ for 5-FU reached 30.31%. DHA-UIO-66-NH ₂ was effectively taken up by MCF-7 cells. Further, 5-FU@DHA-UIO-66-NH ₂ exhibited stronger inhibitory effects on MCF-7 cell viability in vitro as well as tumorigenesis in vivo than 5-FU and 5-FU@UIO-66-NH ₂. DHA up-regulated let-7a to reduce the resistance of MCF-7 cells to 5-FU. Moreover, the biosafety of 5-FU@DHA-UIO-66-NH ₂ was identified.

Conclusions

5-FU@DHA-UIO-66-NH ₂ increased the level of let-7a in BC cells, repressed cell viability and augmented apoptosis, and thus reduced the chemotherapy resistance of BC cells.

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Controlled drug delivery vehicles for cancer treatment and their performance

Sudipta Senapati, Arun Mahanta, Sunil Kumar … (2018)

Although conventional chemotherapy has been successful to some extent, the main drawbacks of chemotherapy are its poor bioavailability, high-dose requirements, adverse side effects, low therapeutic indices, development of multiple drug resistance, and non-specific targeting. The main aim in the development of drug delivery vehicles is to successfully address these delivery-related problems and carry drugs to the desired sites of therapeutic action while reducing adverse side effects. In this review, we will discuss the different types of materials used as delivery vehicles for chemotherapeutic agents and their structural characteristics that improve the therapeutic efficacy of their drugs and will describe recent scientific advances in the area of chemotherapy, emphasizing challenges in cancer treatments.

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Exosome-mediated microRNA signaling from breast cancer cells is altered by the anti-angiogenesis agent docosahexaenoic acid (DHA)

Bethany Hannafon, Karla Carpenter, William L. Berry … (2015)

Background Docosahexaenoic acid (DHA) is a natural compound with anticancer and anti-angiogenesis activity that is currently under investigation as both a preventative agent and an adjuvant to breast cancer therapy. However, the precise mechanisms of DHA’s anticancer activities are unclear. It is understood that the intercommunication between cancer cells and their microenvironment is essential to tumor angiogenesis. Exosomes are extracellular vesicles that are important mediators of intercellular communication and play a role in promoting angiogenesis. However, very little is known about the contribution of breast cancer exosomes to tumor angiogenesis or whether exosomes can mediate DHA’s anticancer action. Results Exosomes were collected from MCF7 and MDA-MB-231 breast cancer cells after treatment with DHA. We observed an increase in exosome secretion and exosome microRNA contents from the DHA-treated cells. The expression of 83 microRNAs in the MCF7 exosomes was altered by DHA (>2-fold). The most abundant exosome microRNAs (let-7a, miR-23b, miR-27a/b, miR-21, let-7, and miR-320b) are known to have anti-cancer and/or anti-angiogenic activity. These microRNAs were also increased by DHA treatment in the exosomes from other breast cancer lines (MDA-MB-231, ZR751 and BT20), but not in exosomes from normal breast cells (MCF10A). When DHA-treated MCF7 cells were co-cultured with or their exosomes were directly applied to endothelial cell cultures, we observed an increase in the expression of these microRNAs in the endothelial cells. Furthermore, overexpression of miR-23b and miR-320b in endothelial cells decreased the expression of their pro-angiogenic target genes (PLAU, AMOTL1, NRP1 and ETS2) and significantly inhibited tube formation by endothelial cells, suggesting that the microRNAs transferred by exosomes mediate DHA’s anti-angiogenic action. These effects could be reversed by knockdown of the Rab GTPase, Rab27A, which controls exosome release. Conclusions We conclude that DHA alters breast cancer exosome secretion and microRNA contents, which leads to the inhibition of angiogenesis. Our data demonstrate that breast cancer exosome signaling can be targeted to inhibit tumor angiogenesis and provide new insight into DHA’s anticancer action, further supporting its use in cancer therapy. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0400-7) contains supplementary material, which is available to authorized users.

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Metal–Organic Framework Nanocarriers for Drug Delivery in Biomedical Applications

Yujia Sun, Liwei Zheng, Yu. Yang … (2020)

Recent advances in biomedical applications of metal–organic framework (MOF) nanocarriers for drug delivery are summarized. State-of-the-art strategies to functionalize MOFs with therapeutic agents, as well as their merits and drawbacks, are comprehensively discussed. Investigation of metal–organic frameworks (MOFs) for biomedical applications has attracted much attention in recent years. MOFs are regarded as a promising class of nanocarriers for drug delivery owing to well-defined structure, ultrahigh surface area and porosity, tunable pore size, and easy chemical functionalization. In this review, the unique properties of MOFs and their advantages as nanocarriers for drug delivery in biomedical applications were discussed in the first section. Then, state-of-the-art strategies to functionalize MOFs with therapeutic agents were summarized, including surface adsorption, pore encapsulation, covalent binding, and functional molecules as building blocks. In the third section, the most recent biological applications of MOFs for intracellular delivery of drugs, proteins, and nucleic acids, especially aptamers, were presented. Finally, challenges and prospects were comprehensively discussed to provide context for future development of MOFs as efficient drug delivery systems.

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Author and article information

Journal

Journal ID (nlm-ta): Ann Transl Med

Journal ID (iso-abbrev): Ann Transl Med

Journal ID (publisher-id): ATM

Title: Annals of Translational Medicine

Publisher: AME Publishing Company

ISSN (Print): 2305-5839

ISSN (Electronic): 2305-5847

Publication date (Print and electronic): December 2021

Publication date (Print): December 2021

Volume: 9

Issue: 24

Affiliations

[1 ]deptDepartment of Medical Oncology , Harbin Medical University Cancer Hospital , Harbin, China;

[2 ]deptDepartment of Pathophysiology , Harbin Medical University , Harbin, China;

[3 ]deptDepartment of Surgery , The Second Affiliated Hospital of Harbin Medical University , Harbin, China

Author notes

Contributions: (I) Conception and design: J Li; (II) Administrative support: F Lu; (III) Provision of study materials or patients: J Li; (IV) Collection and assembly of data: X Shao; (V) Data analysis and interpretation: B You; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Jingquan Li. Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, No. 150, Haping Road, Nangang District, Harbin 150081, China. Email: lijingquan@ 123456hrbmu.edu.cn .

Article

Publisher ID: atm-09-24-1761

DOI: 10.21037/atm-21-5978

PMC ID: 8756249

PubMed ID: 35071455

SO-VID: 691cace7-50d6-4b0e-bdff-7544a7ce3a79

License:

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0.