A genetically engineered apoferritin variant consisting of 24 heavy-chain subunits (HFn) was produced to achieve a cumulative delivery of an antitumor drug, which exerts its cytotoxic action by targeting the DNA at the nucleus of human cancer cells with subcellular precision. The rationale of our approach is based on exploiting the natural arsenal of defense of cancer cells to stimulate them to recruit large amounts of HFn nanoparticles loaded with doxorubicin inside their nucleus in response to a DNA damage, which leads to a programmed cell death. After demonstrating the selectivity of HFn for representative cancer cells compared to healthy fibroblasts, doxorubicin-loaded HFn was used to treat the cancer cells. The results from confocal microscopy and DNA damage assays proved that loading of doxorubicin in HFn nanoparticles increased the nuclear delivery of the drug, thus enhancing doxorubicin efficacy. Doxorubicin-loaded HFn acts as a "Trojan Horse": HFn was internalized in cancer cells faster and more efficiently compared to free doxorubicin, then promptly translocated into the nucleus following the DNA damage caused by the partial release in the cytoplasm of encapsulated doxorubicin. This self-triggered translocation mechanism allowed the drug to be directly released in the nuclear compartment, where it exerted its toxic action. This approach was reliable and straightforward providing an antiproliferative effect with high reproducibility. The particular self-assembling nature of HFn nanocage makes it a versatile and tunable nanovector for a broad range of molecules suitable both for detection and treatment of cancer cells.

Bellini, M., Mazzucchelli, S., Galbiati, E., Sommaruga, S., Fiandra, L., Truffi, M., et al. (2014). Protein nanocages for self-triggered nuclear delivery of DNA-targeted chemotherapeutics in Cancer Cells. JOURNAL OF CONTROLLED RELEASE, 196, 184-196 [10.1016/j.jconrel.2014.10.002].

Protein nanocages for self-triggered nuclear delivery of DNA-targeted chemotherapeutics in Cancer Cells

BELLINI, MICHELA
Primo
;
MAZZUCCHELLI, SERENA
Secondo
;
GALBIATI, ELISABETTA;Fiandra, L;RIZZUTO, MARIA ANTONIETTA;COLOMBO, MIRIAM;TORTORA, PAOLO;PROSPERI, DAVIDE
Ultimo
2014

Abstract

A genetically engineered apoferritin variant consisting of 24 heavy-chain subunits (HFn) was produced to achieve a cumulative delivery of an antitumor drug, which exerts its cytotoxic action by targeting the DNA at the nucleus of human cancer cells with subcellular precision. The rationale of our approach is based on exploiting the natural arsenal of defense of cancer cells to stimulate them to recruit large amounts of HFn nanoparticles loaded with doxorubicin inside their nucleus in response to a DNA damage, which leads to a programmed cell death. After demonstrating the selectivity of HFn for representative cancer cells compared to healthy fibroblasts, doxorubicin-loaded HFn was used to treat the cancer cells. The results from confocal microscopy and DNA damage assays proved that loading of doxorubicin in HFn nanoparticles increased the nuclear delivery of the drug, thus enhancing doxorubicin efficacy. Doxorubicin-loaded HFn acts as a "Trojan Horse": HFn was internalized in cancer cells faster and more efficiently compared to free doxorubicin, then promptly translocated into the nucleus following the DNA damage caused by the partial release in the cytoplasm of encapsulated doxorubicin. This self-triggered translocation mechanism allowed the drug to be directly released in the nuclear compartment, where it exerted its toxic action. This approach was reliable and straightforward providing an antiproliferative effect with high reproducibility. The particular self-assembling nature of HFn nanocage makes it a versatile and tunable nanovector for a broad range of molecules suitable both for detection and treatment of cancer cells.
Articolo in rivista - Articolo scientifico
Anticancer drugs; Apoferritin; Bionanoparticles; Drug delivery system; Nuclear targeting; Self-triggered translocation
English
2014
196
184
196
reserved
Bellini, M., Mazzucchelli, S., Galbiati, E., Sommaruga, S., Fiandra, L., Truffi, M., et al. (2014). Protein nanocages for self-triggered nuclear delivery of DNA-targeted chemotherapeutics in Cancer Cells. JOURNAL OF CONTROLLED RELEASE, 196, 184-196 [10.1016/j.jconrel.2014.10.002].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/64461
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