Nanometronomic treatment of 4T1 breast cancer with nanocaged doxorubicin prevents drug resistance and circumvents cardiotoxicity

Abstract

Chemotherapeutic treatment of breast cancer is based on maximum tolerated dose (MTD) approach. However, advanced stage tumors are not effectively eradicated by MTD owing to suboptimal drug targeting, onset of therapeutic resistance and neoangiogenesis. In contrast, “metronomic” chemotherapy is based on frequent drug administrations at lower doses, resulting in neovascularization inhibition and induction of tumor dormancy. Here we show the potential of H-ferritin (HFn)-mediated targeted nanodelivery of metronomic doxorubicin (DOX) in the setting of a highly aggressive and metastatic 4T1 breast cancer mouse model with DOX-inducible expression of chemoresistance. We find that HFn-DOX administered at repeated doses of 1.24 mg kg−1 strongly improves the antitumor potential of DOX chemotherapy arresting the tumor progression. We find that such a potent antitumor effect is attributable to multiple nanodrug actions beyond cell killing, including inhibition of tumor angiogenesis and avoidance of chemoresistance. Multiparametric assessment of heart tissues, including histology, ultrastructural analysis of tissue morphology, and measurement of markers of reactive oxygen species and hepatic/renal conditions, provided evidence that metronomic HFn-DOX allowed us to overcome cardiotoxicity. Our results suggest that HFn-DOX has tremendous potential for the development of “nanometronomic” chemotherapy toward safe and tailored oncological treatments.

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

“…Indeed, HFn were recovered attached to the cell membrane after only 15 min of incubation, while they were found almost completely internalized after 1–3 h. In addition, the fluorescence signal of HFn dramatically dropped at 48 h of incubation (Supplementary Fig. 2 ), in accordance with results from previous studies 22 , 23 . HFn internalization route was investigated by assessing the colocalization with specific markers of endocytic compartments, i.e.…”

“…HFn nanocages were demonstrated to be able to mediate the direct delivery of cytotoxic doxorubicin into the nuclear compartment of cancer cells through a self-triggered mechanism activated by enhanced ROS production 21 , 22 . In addition, the metronomic administration of doxorubicin-HFn nanodrug in a 4T1 mouse model of metastatic BC demonstrated potent antitumor efficacy associated with inhibition of angiogenesis, reduced chemoresistance and negligible cardiotoxicity 23 . With the present study, we aimed to develop a novel HFn-based nanoformulation of Ola (HOla) able to achieve tumor targeting, improve cellular uptake of the drug and its nuclear release.…”

Therapeutic Efficacy of the Novel Stimuli-Sensitive Nano-Ferritins Containing Doxorubicin in a Head and Neck Cancer Model

“…Therefore, treatment with HFt-MP-PAS40-Dox nanocarrier can represent a promising option for anthracycline therapeutic regimens in cardiosensitive subjects as it did not display apparent anthracycline-related cardiotoxicity. These results well agree with those reported by other groups using HFt-Dox as nanocarrier [ 3 , 24 ].…”

Thirty Years of Cancer Nanomedicine: Success, Frustration, and Hope

“…These materials are generally well-tolerated, less recognized by MPS, and are eventually able to increase tumor targeting. For instance, ferritin-based NCs showed an intrinsic tumor homing as well as an improved performance compared to the liposomal formulation, when loaded with doxorubicin [127]. Another pioneering approach exploited the use of engineered leukocytes membrane to enhance the NCs' accumulation in the proximity of inflamed tumor tissues [128].…”