Active Targeting of Mesoporous Silica Drug Carriers Enhances γ-Secretase Inhibitor Efficacy in An In Vivo Model for Breast Cancer

Abstract

Aim: In this article, we use an alternative cancer model for the evaluation of nanotherapy, and assess the impact of surface functionalization and active targeting of mesoporous silica nanoparticles (MSNPs) on therapeutic efficacy in vivo. Materials & methods: We used the chorioallantoic membrane xenograft assay to investigate the biodistribution and therapeutic efficacy of folate versus polyethyleneimine-functionalized γ-secretase inhibitor-loaded MSNPs in breast and prostate tumor models. Results: γ-secretase inhibitor-loaded MSNPs inhibited tumor growth in breast and prostate cancer xenografts. Folate conjugation improved the therapeutic outcome in folic acid receptor-positive breast cancer, but not in prostate cancer lacking the receptor. Conclusion: The results demonstrate that therapeutic efficacy is linked to cellular uptake of MSNPs as opposed to tumor accumulation, and show that MSNP-based delivery of γ-secretase inhibitors is therapeutically effective in both breast and prostate cancer. In this article, we present a model system for a medium-to-high throughput, cost-effective, quantitative evaluation of nanoparticulate drug carriers.

Keywords::

• chorioallantoic membrane
• folic acid receptor
• mesoporous silica nanoparticle
• Notch signaling
• targeted cancer therapy

Financial & competing interests disclosure

The authors acknowledge funding from the Academy of Finland (projects #137101, #131034, #140193, #218062 and #264190), the Sigrid Juselius Foundation (to C Sahlgren), the Cancer Society of Finland (to C Sahlgren) and the German Research Foundation (WI3868/1–1 to R Wittig). The funding agencies had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Acknowledgments

The authors wish to thank Linus Silvander, inorganic chemistry, Department of Chemical Engineering, Åbo Akademi University (Turku, Finland), for scanning electron microscope imaging; Antonio Martín Rengel, Rey Juan Carlos Univeristy (Madrid, Spain), the Technological Support Center of Rey Juan Carlos University, Department of Chemical and Environmental Technology, for transmission electron microscope imaging; Andrea Böhmler, Eva Winkler, Petra Kruse (Institute for Laser Technologies in Medicine and Metrology Biology, Ulm, Germany) for expert technical assistance, Carmen Hauser (Institute for Laser Technologies in Medicine and Metrology Microscopy and Ulm University, Live Cell Imaging Core Facility, Germany) for valuable support in confocal fluorescence microscopy; as well as the Cell Imaging Core Facility at Turku Center for Biotechnology (Turku, Finland).

Additional information

Funding

The authors acknowledge funding from the Academy of Finland (projects #137101, #131034, #140193, #218062 and #264190), the Sigrid Juselius Foundation (to C Sahlgren), the Cancer Society of Finland (to C Sahlgren) and the German Research Foundation (WI3868/1–1 to R Wittig). The funding agencies had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.