Nucleolin-targeted Extracellular Vesicles as a Versatile Platform for Biologics Delivery to Breast Cancer

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Abstract

Small interfering RNAs (siRNA)/microRNAs (miRNA) have promising therapeutic potential, yet their clinical application has been hampered by the lack of appropriate delivery systems. Herein, we employed extracellular vesicles (EVs) as a targeted delivery system for small RNAs. EVs are cell-derived small vesicles that participate in cell-to-cell communication for protein and RNA delivery. We used the aptamer AS1411-modified EVs for targeted delivery of siRNA/microRNA to breast cancer tissues. Tumor targeting was facilitated via AS1411 binding to nucleolin, which is highly expressed on the surface membrane of breast cancer cells. This delivery vesicle targeted let-7 miRNA delivery to MDA-MB-231 cells in vitro as confirmed with fluorescent microscopic imaging and flow cytometry. Also, intravenously delivered AS1411-EVs loaded with miRNA let-7 labeled with the fluorescent marker, Cy5, selectively targeted tumor tissues in tumor-bearing mice and inhibited tumor growth. Importantly, the modified EVs were well tolerated and showed no evidence of nonspecific side effects or immune response. Thus, the RNAi nanoplatform is versatile and can deliver siRNA or miRNA to breast cancer cells both in vitro and in vivo. Our results suggest that the AS1411-EVs have a great potential as drug delivery vehicles to treat cancers.

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MicroRNAs: New Biomarkers for Diagnosis, Prognosis, Therapy Prediction and Therapeutic Tools for Breast Cancer

Gloria Bertoli, Claudia Cava, Isabella Castiglioni (2015)

Dysregulation of microRNAs (miRNAs) is involved in the initiation and progression of several human cancers, including breast cancer (BC), as strong evidence has been found that miRNAs can act as oncogenes or tumor suppressor genes. This review presents the state of the art on the role of miRNAs in the diagnosis, prognosis, and therapy of BC. Based on the results obtained in the last decade, some miRNAs are emerging as biomarkers of BC for diagnosis (i.e., miR-9, miR-10b, and miR-17-5p), prognosis (i.e., miR-148a and miR-335), and prediction of therapeutic outcomes (i.e., miR-30c, miR-187, and miR-339-5p) and have important roles in the control of BC hallmark functions such as invasion, metastasis, proliferation, resting death, apoptosis, and genomic instability. Other miRNAs are of interest as new, easily accessible, affordable, non-invasive tools for the personalized management of patients with BC because they are circulating in body fluids (e.g., miR-155 and miR-210). In particular, circulating multiple miRNA profiles are showing better diagnostic and prognostic performance as well as better sensitivity than individual miRNAs in BC. New miRNA-based drugs are also promising therapy for BC (e.g., miR-9, miR-21, miR34a, miR145, and miR150), and other miRNAs are showing a fundamental role in modulation of the response to other non-miRNA treatments, being able to increase their efficacy (e.g., miR-21, miR34a, miR195, miR200c, and miR203 in combination with chemotherapy).

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MicroRNA-221/222 confers tamoxifen resistance in breast cancer by targeting p27Kip1.

Tyler Miller, Kalpana Ghoshal, Bhuvaneswari Ramaswamy … (2008)

We explored the role of microRNAs (miRNAs) in acquiring resistance to tamoxifen, a drug successfully used to treat women with estrogen receptor-positive breast cancer. miRNA microarray analysis of MCF-7 cell lines that are either sensitive (parental) or resistant (4-hydroxytamoxifen-resistant (OHT(R))) to tamoxifen showed significant (>1.8-fold) up-regulation of eight miRNAs and marked down-regulation (>50%) of seven miRNAs in OHT(R) cells compared with parental MCF-7 cells. Increased expression of three of the most promising up-regulated (miR-221, miR-222, and miR-181) and down-regulated (miR-21, miR-342, and miR-489) miRNAs was validated by real-time reverse transcription-PCR. The expression of miR-221 and miR-222 was also significantly (2-fold) elevated in HER2/neu-positive primary human breast cancer tissues that are known to be resistant to endocrine therapy compared with HER2/neu-negative tissue samples. Ectopic expression of miR-221/222 rendered the parental MCF-7 cells resistant to tamoxifen. The protein level of the cell cycle inhibitor p27(Kip1), a known target of miR-221/222, was reduced by 50% in OHT(R) cells and by 28-50% in miR-221/222-overexpressing MCF-7 cells. Furthermore, overexpression of p27(Kip1) in the resistant OHT(R) cells caused enhanced cell death when exposed to tamoxifen. This is the first study demonstrating a relationship between miR-221/222 expression and HER2/neu overexpression in primary breast tumors that are generally resistant to tamoxifen therapy. This finding also provides the rationale for the application of altered expression of specific miRNAs as a predictive tamoxifen-resistant breast cancer marker.

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A comprehensive overview of exosomes as drug delivery vehicles - endogenous nanocarriers for targeted cancer therapy.

Kasper Bendix Johnsen, Johann Mar Gudbergsson, Martin Najbjerg Skov … (2014)

Exosomes denote a class of secreted nanoparticles defined by size, surface protein and lipid composition, and the ability to carry RNA and proteins. They are important mediators of intercellular communication and regulators of the cellular niche, and their altered characteristics in many diseases, such as cancer, suggest them to be important both for diagnostic and therapeutic purposes, prompting the idea of using exosomes as drug delivery vehicles, especially for gene therapy. This review covers the current status of evidence presented in the field of exosome-based drug delivery systems. Components for successful exosome-based drug delivery, such as choice of donor cell, therapeutic cargo, use of targeting peptide, loading method and administration route are highlighted and discussed with a general focus pertaining to the results obtained in models of different cancer types. In addition, completed and on-going clinical trials are described, evaluating exosome-based therapies for the treatment of different cancer types. Due to their endogenous origin, exosome-based drug delivery systems may have advantages in the treatment of cancer, but their design needs further refinement to justify their usage on the clinical scale.

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Author and article information

Journal

Journal ID (nlm-ta): Theranostics

Journal ID (iso-abbrev): Theranostics

Journal ID (publisher-id): thno

Title: Theranostics

Publisher: Ivyspring International Publisher (Sydney )

ISSN (Electronic): 1838-7640

Publication date Collection: 2017

Publication date (Electronic): 22 March 2017

Volume: 7

Issue: 5

Pages: 1360-1372

Affiliations

[1 ]Institute of Biomedicine & Department of Cell Biology, Jinan University; National Engineering Research Center of Genetic Medicine; Guangdong Provincial Key Laboratory of Bioengineering Medicine, Guangzhou, China;

[2 ]Department of Chemistry, Jinan University, Guangzhou, China.

Author notes

✉ Corresponding authors: Xiaogang Wang, Department of Cell Biology & Institute of Biomedicine, Jinan University, 601 Huangpu Avenue. West, Guangzhou, 510632, China Phone: 86-020-85226059 Fax: 86-020-85226059 E-mail: txg_wang@ 123456jnu.edu.cn or An Hong, Department of Cell Biology & Institute of Biomedicine, Jinan University, 601 Huangpu Avenue. West, Guangzhou, 510632, China Phone: 86-020-85221983 Fax: 86-020-85221983 E-mail: tha@ 123456jnu.edu.cn

* These authors contributed equally to this work.

Competing Interests: The authors have declared that no competing interest exists.

Article

Publisher ID: thnov07p1360

DOI: 10.7150/thno.16532

PMC ID: 5399599

PubMed ID: 28435471

SO-VID: 2ed0e792-9096-490a-a4f5-5b67e5a990d2

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This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.

Nucleolin-targeted Extracellular Vesicles as a Versatile Platform for Biologics Delivery to Breast Cancer

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Abstract

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Most cited references 40

MicroRNAs: New Biomarkers for Diagnosis, Prognosis, Therapy Prediction and Therapeutic Tools for Breast Cancer

MicroRNA-221/222 confers tamoxifen resistance in breast cancer by targeting p27Kip1.

A comprehensive overview of exosomes as drug delivery vehicles - endogenous nanocarriers for targeted cancer therapy.

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