H-Ferritin-nanocaged olaparib: a promising choice for both BRCA-mutated and sporadic triple negative breast cancer

S Mazzucchelli, M Truffi, F Baccarini, M Beretta, L Sorrentino, M Bellini, M A Rizzuto, R Ottria, A Ravelli, P Ciuffreda, D Prosperi, F Corsi

Research output: Contribution to journalArticle

Abstract

Poly(ADP-ribose) polymerase (PARP) inhibitors represent a promising strategy toward the treatment of triple-negative breast cancer (TNBC), which is often associated to genomic instability and/or BRCA mutations. However, clinical outcome is controversial and no benefits have been demonstrated in wild type BRCA cancers, possibly due to poor drug bioavailability and low nuclear delivery. In the attempt to overcome these limitations, we have developed H-Ferritin nanoformulated olaparib (HOla) and assessed its anticancer efficacy on both BRCA-mutated and non-mutated TNBC cells. We exploited the natural tumor targeting of H-Ferritin, which is mediated by the transferrin receptor-1 (TfR1), and its physiological tropism toward cell nucleus. TNBC cell lines over-expressing TfR-1 were successfully recognized by H-Ferritin, displaying a fast internalization into the cells. HOla induced remarkable cytotoxic effect in cancer cells, exhibiting 1000-fold higher anticancer activity compared to free olaparib (Ola). Accordingly, HOla treatment enhanced PARP-1 cleavage, DNA double strand breaks and Ola delivery into the nuclear compartment. Our findings suggest that H-Ferritin nanoformulation strongly enhances cytotoxic efficacy of Ola as a stand-alone therapy in both BRCA-mutated and wild type TNBC cells, by promoting targeted nuclear delivery.

Original languageEnglish
Pages (from-to)7505
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - Aug 8 2017

Keywords

  • Journal Article

Fingerprint Dive into the research topics of 'H-Ferritin-nanocaged olaparib: a promising choice for both BRCA-mutated and sporadic triple negative breast cancer'. Together they form a unique fingerprint.

  • Cite this

    Mazzucchelli, S., Truffi, M., Baccarini, F., Beretta, M., Sorrentino, L., Bellini, M., Rizzuto, M. A., Ottria, R., Ravelli, A., Ciuffreda, P., Prosperi, D., & Corsi, F. (2017). H-Ferritin-nanocaged olaparib: a promising choice for both BRCA-mutated and sporadic triple negative breast cancer. Scientific Reports, 7(1), 7505. https://doi.org/10.1038/s41598-017-07617-7