Everolimus Nanoformulation in Biological Nanoparticles Increases Drug Responsiveness in Resistant and Low-Responsive Breast Cancer Cell Lines.

Arianna Bonizzi,Fabio Corsi,Serena Mazzucchelli,Sara Negri,Marta Sevieri,Elena Grignani,Roberta Ottria,Luca Sorrentino,Leopoldo Sitia,Cristina Sottani,Marta Truffi,Raffaele Allevi

doi:10.3390/pharmaceutics11080384

Arianna Bonizzi, Fabio Corsi + Show 10 more

Open Access

https://doi.org/10.3390/pharmaceutics11080384

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Abstract

Everolimus (Eve) is an FDA approved drug that inhibits mammalian target of rapamycin (mTOR). It is employed in breast cancer treatment even if its responsiveness is controversial. In an attempt to increase Eve effectiveness, we have developed a novel Eve nanoformulation exploiting H-ferritin nanocages (HEve) to improve its subcellular delivery. We took advantage of the natural tumor targeting of H-Ferritin, which is mediated by the transferrin receptor-1 (TfR1). Breast cancer cells overexpressing TfR-1 were successfully recognized by H-Ferritin, displaying quick nanocage internalization. HEve has been tested and compared to Eve for in vitro efficacy in sensitive and resistant breast cancer cells. Nanoformulated Eve induced remarkable antiproliferative activity in vitro, making even resistant cell lines sensitive to Eve. Moreover, the antiproliferative activity of HEve is fully in accordance with cytotoxicity observed by cell death assay. Furthermore, the significant increase in anticancer efficacy displayed in HEve-treated samples is due to the improved drug accumulation, as demonstrated by UHPLC-MS/MS quantifications. Our findings suggest that optimizing Eve subcellular delivery, thanks to nanoformulation, determines its improved antitumor activity in a panel of Eve-sensitive or resistant breast cancer cell lines.

Highlights

Advanced breast cancer (BC) still represents a clinical challenge due to the high rate of chemoresistance and consequent cancer progression, both in hormone receptor-positive and negative subtypes [1]
Everolimus (Eve; RAD001, Afinitor®) is an FDA-approved rapamycin analog that acts inside the cytoplasmatic compartment, inhibiting the
Eve is currently approved for second-line treatment of metastatic BC, sometimes showing encouraging results, conflicting clinical data have been reported on its efficacy, in some hormone receptor-positive and in triple-negative BC

Summary

Introduction

Advanced breast cancer (BC) still represents a clinical challenge due to the high rate of chemoresistance and consequent cancer progression, both in hormone receptor-positive and negative subtypes [1]. Different drivers of resistance have been described for HER2-positive, triple-negative, and hormone receptor-positive cancers. A common shared feature has been identified downstream in the proliferative pathway of BC cells: the hyperactivation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway irrespectively from the growth factor receptors status [2]. Everolimus (Eve; RAD001, Afinitor®) is an FDA-approved rapamycin analog that acts inside the cytoplasmatic compartment, inhibiting the PI3K/AKT/mTOR pathway. Eve is currently approved for second-line treatment of metastatic BC, sometimes showing encouraging results, conflicting clinical data have been reported on its efficacy, in some hormone receptor-positive and in triple-negative BC. A relatively small advantage in progression-free survival is severely paid by patients with the well-known Eve-related toxicities, mainly stomatitis, affecting the quality of life [1,2]

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