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

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.

SUBMITTER: Bonizzi A

PROVIDER: S-EPMC6723888 | biostudies-other | 2019 Aug

REPOSITORIES: biostudies-other

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

Bonizzi Arianna A Truffi Marta M Sevieri Marta M Allevi Raffaele R Sitia Leopoldo L Ottria Roberta R Sorrentino Luca L Sottani Cristina C Negri Sara S Grignani Elena E Mazzucchelli Serena S Corsi Fabio F

Pharmaceutics 20190802 8

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 overexpressin ...[more]

PMID: 31382388

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Project description:Objectives:Due to the expanded bacterial genetic tolerance to antibiotics through different mechanisms, infectious diseases of MDR bacteria are difficult for treatment. Consequently, we synthesized drug conjugated nanoparticles to dissolve this problem. Moreover, the present study aims to display the cell death status treated with cefotaxime-CS-AgNPs and also, apoptosis pathways of human RPE-1 normal cells and human MCF-7 breast cancer cells. Methods:Here, we demonstrate the possibility to synthesize AgNPs and conjugate them with cefotaxime to survey the probability of cefotaxime-CS-AgNPs as an antimicrobial agent against cefotaxime-resistant strains E. coli and MRSA. Results:TEM showed the size of AgNPs, CS-AgNPs and cefotaxime-CS-AgNPs ranged from 7.42 to 18.3 nm, 8.05-23.89 nm and 8.48-25.3 nm, respectively, with a spherical shape. The cefotaxime-CS-AgNPs enhanced the high antimicrobial properties compared to AgNPs or pure antibiotic. The MIC of Cefotaxime-CS-AgNPs ranged from 3 µg/mL to 8 µg/mL against tested E. coli and MRSA bacteria. Consequently, the highest reduction in the MIC of cefotaxime-CS-AgNPs was noted against tested strains ranging from 22% to 96%. Comparing cefotaime-CS-AgNPs to AgNPs we showed that cefotaime-CS-AgNPs have no cytotoxic effect on normal cells at even 12 µg/mL for 24 hrs. The IC50 for the AgNPs and cefotaxime-CS-AgNPs was 12 µg/mL for human RPE-1 normal cells and human MCF-7 breast cancer cell lines. The pro-apoptotic genes p53, p21, and Bax of cancer cell lines significantly upregulated followed by downregulated by anti-apoptotic gene Bcl-2 after 48 hrs at 24 µg/mL, and this concentration represents the most effective dose. Conclusion:Results enhanced the conjugating utility in old unresponsive cefotaxime to AgNPs to restore its efficiency against previous strains and demonstrated potential therapeutic applications of cefotaxime-CS-AgNPs. Moreover, this research gives remarkable insights for designing nanoscale delivery and curative systems that have a pronounced cytotoxic activity on cancer cells and are safe to normal cells.

Dataset Information

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

Publications

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

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