YSA-conjugated mesoporous silica nanoparticles effectively target EphA2-overexpressing breast cancer cells
Neoadjuvant chemotherapy is commonly used to treat patients with locally advanced breast cancer and a common option for primary operable disease. However, systemic toxicity including cardiotoxicity and inefficient delivery are significant challenges form any chemotherapeutics. The development of targeted treatments that lower the risk of toxicity has, therefore, become an active area of research in the field of novel cancer therapeutics. Mesoporous silica nanoparticles (MSNs) have attracted significant attention as efficient drug delivery carriers, due to their high surface area and tailorable mesoporous structures. Eph receptors are the largest receptor tyrosine kinase family, which are divided into the A- and the B-type. Eph receptors play critical roles in embryonic development and human diseases including cancer. EphA2 is expressed in breast cancer cells and has roles in carcinogenesis, progression and prognosis of breast cancer.
A homing peptide with the sequence YSAYPDSVPMMSK (YSA) that binds specifically to EphA2 was used to functionalize MSN. We focus on a novel EphA2-targeted delivery MSN system for breast cancer cells.
We show that the EphA2 receptor is differentially expressed in breast cancer cells and highly expressed in the HER2-negative breast cancer cell line MCF7. Our results suggest that EphA2-targeted MSN for doxorubicin delivery (MSN–YSA–DOX) are more effective than MSN–DOX in treating breast cancer cell lines in vitro.
Our preliminary observations suggest that the EphA2-targeted MSN delivery system may provide a strategy for enhancing delivery of therapeutic agents to breast cancer cells expressing EphA2, and potentially reduce toxicity while enhancing therapeutic efficacy.
KeywordsEphA2 Drug delivery MSN
Compliance with ethical standards
Research involving human participants and/or animals
This article does not contain any studies with human participants or animals performed by any of the authors.
Conflict of interest
The author(s) declare that they have no conflict of interest.
- 3.Zhou Z, Kennell C, Jafari M, Lee JY, Ruiz-Torres SJ, Waltz SE, Lee JH (2017) Sequential delivery of erlotinib and doxorubicin for enhanced triple negative Breast cancer treatment using polymeric nanoparticle. Int J Pharm 530(1–2):300–307. https://doi.org/10.1016/j.ijpharm.2017.07.085 CrossRefPubMedPubMedCentralGoogle Scholar
- 7.Rocca A, Cecconetto L, Passardi A, Melegari E, Andreis D, Monti M, Maltoni R, Sarti S, Pietri E, Schirone A, Fabbri F, Donati C, Nanni O, Fedeli A, Faedi M, Amadori D (2017) Phase Ib dose-finding trial of lapatinib plus pegylated liposomal doxorubicin in advanced HER2-positive breast cancer. Cancer Chemother Pharmacol 79(5):863–871. https://doi.org/10.1007/s00280-017-3279-8 CrossRefPubMedPubMedCentralGoogle Scholar
- 9.Ansari L, Shiehzadeh F, Taherzadeh Z, Nikoofal-Sahlabadi S, Momtazi-Borojeni AA, Sahebkar A, Eslami S (2017) The most prevalent side effects of pegylated liposomal doxorubicin monotherapy in women with metastatic breast cancer: a systematic review of clinical trials. Cancer Gene Ther 24(5):189–193. https://doi.org/10.1038/cgt.2017.9 CrossRefPubMedGoogle Scholar
- 11.Gao Y, Gu S, Zhang Y, Xie X, Yu T, Lu Y, Zhu Y, Chen W, Zhang H, Dong H, Sinko PJ, Jia L (2016) The architecture and function of monoclonal antibody-functionalized mesoporous silica nanoparticles loaded with mifepristone: repurposing abortifacient for cancer metastatic chemoprevention. Small 12(19):2595–2608. https://doi.org/10.1002/smll.201600550 CrossRefPubMedGoogle Scholar
- 14.Kataoka H, Igarashi H, Kanamori M, Ihara M, Wang JD, Wang YJ, Li ZY, Shimamura T, Kobayashi T, Maruyama K, Nakamura T, Arai H, Kajimura M, Hanai H, Tanaka M, Sugimura H (2004) Correlation of EPHA2 overexpression with high microvessel count in human primary colorectal cancer. Cancer Sci 95(2):136–141CrossRefPubMedGoogle Scholar
- 15.Dunne PD, Dasgupta S, Blayney JK, McArt DG, Redmond KL, Weir JA, Bradley CA, Sasazuki T, Shirasawa S, Wang T, Srivastava S, Ong CW, Arthur K, Salto-Tellez M, Wilson RH, Johnston PG, Van Schaeybroeck S (2016) EphA2 expression is a key driver of migration and invasion and a poor prognostic marker in colorectal cancer. Clin Cancer Res 22(1):230–242. https://doi.org/10.1158/1078-0432.CCR-15-0603 CrossRefPubMedGoogle Scholar
- 17.Gokmen-Polar Y, Toroni RA, Hocevar BA, Badve S, Zhao Q, Shen C, Bruckheimer E, Kinch MS, Miller KD (2011) Dual targeting of EphA2 and ER restores tamoxifen sensitivity in ER/EphA2-positive breast cancer. Breast Cancer Res Treat 127(2):375–384. https://doi.org/10.1007/s10549-010-1004-y CrossRefPubMedGoogle Scholar
- 18.Fox BP, Kandpal RP (2011) A paradigm shift in EPH receptor interaction: biological relevance of EPHB6 interaction with EPHA2 and EPHB2 in breast carcinoma cell lines. Cancer Genom Proteom 8(4):185–193Google Scholar
- 19.Noblitt LW, Bangari DS, Shukla S, Knapp DW, Mohammed S, Kinch MS, Mittal SK (2004) Decreased tumorigenic potential of EphA2-overexpressing breast cancer cells following treatment with adenoviral vectors that express EphrinA1. Cancer Gene Ther 11(11):757–766. https://doi.org/10.1038/sj.cgt.7700761 CrossRefPubMedGoogle Scholar
- 22.Wang J, Teng Z, Tian Y, Fang T, Ma J, Sun J, Zhu F, Wu J, Wang X, Yang N, Zhou X, Yun S, Lu G (2013) Increasing cellular uptake of mesoporous silica nanoparticles in human embryonic kidney cell line 293T cells by using Lipofectamine 2000. J Biomed Nanotechnol 9(11):1882–1890CrossRefPubMedGoogle Scholar
- 23.Wang X, Teng Z, Wang H, Wang C, Liu Y, Tang Y, Wu J, Sun J, Wang H, Wang J, Lu G (2014) Increasing the cytotoxicity of doxorubicin in breast cancer MCF-7 cells with multidrug resistance using a mesoporous silica nanoparticle drug delivery system. Int J Clin Exp Pathol 7(4):1337–1347PubMedPubMedCentralGoogle Scholar
- 25.Cheng W, Nie J, Xu L, Liang C, Peng Y, Liu G, Wang T, Mei L, Huang L, Zeng X (2017) pH-Sensitive delivery vehicle based on folic acid-conjugated polydopamine-modified mesoporous silica nanoparticles for targeted cancer therapy. ACS Appl Mater Interf 9(22):18462–18473. https://doi.org/10.1021/acsami.7b02457 CrossRefGoogle Scholar
- 27.Wang J, Wang Y, Liu Q, Yang L, Zhu R, Yu C, Wang S (2016) Rational design of multifunctional dendritic mesoporous silica nanoparticles to load curcumin and enhance efficacy for breast cancer therapy. ACS Appl Mater Interf 8(40):26511–26523. https://doi.org/10.1021/acsami.6b08400 CrossRefGoogle Scholar
- 28.Ultimo A, Gimenez C, Bartovsky P, Aznar E, Sancenon F, Marcos MD, Amoros P, Bernardo AR, Martinez-Manez R, Jimenez-Lara AM, Murguia JR (2016) Targeting innate immunity with dsRNA-conjugated mesoporous silica nanoparticles promotes antitumor effects on breast cancer cells. Chemistry 22(5):1582–1586. https://doi.org/10.1002/chem.201504629 CrossRefPubMedGoogle Scholar
- 30.Li T, Chen X, Liu Y, Fan L, Lin L, Xu Y, Chen S, Shao J (2017) pH-Sensitive mesoporous silica nanoparticles anticancer prodrugs for sustained release of ursolic acid and the enhanced anti-cancer efficacy for hepatocellular carcinoma cancer. Eur J Pharm Sci 96:456–463. https://doi.org/10.1016/j.ejps.2016.10.019 CrossRefPubMedGoogle Scholar
- 33.Sun H, Zhang D, Yao Z, Lin X, Liu J, Gu Q, Dong X, Liu F, Wang Y, Yao N, Cheng S, Li L, Sun S (2017) Anti-angiogenic treatment promotes triple-negative breast cancer invasion via vasculogenic mimicry. Cancer Biol Therapy 18(4):205–213. https://doi.org/10.1080/15384047.2017.1294288 CrossRefGoogle Scholar
- 34.Oualla K, El-Zawahry HM, Arun B, Reuben JM, Woodward WA, Gamal El-Din H, Lim B, Mellas N, Ueno NT, Fouad TM (2017) Novel therapeutic strategies in the treatment of triple-negative breast cancer. Ther Adv Med Oncol 9(7):493–511. https://doi.org/10.1177/1758834017711380 CrossRefPubMedPubMedCentralGoogle Scholar