Serena Mazzucchelli
University of Milan, Italy
Title: Metronomic treatment of breast cancer with Doxorubicin-loaded ferritin nanocages prevents chemoresistance and cardiotoxicity in comparison to liposomal Doxorubicin
Biography
Biography: Serena Mazzucchelli
Abstract
Metronomic chemotherapy (LDM) is based on frequent drug administrations at lower doses, resulting in neovascularization inhibition and induction of tumor dormancy. LDM application in clinical practice is limited by: 1) low drug accumulation at tumor site, 2) controversial effectiveness against chemoresistance in advanced metastatic cancers, and 3) acquired resistance after prolonged treatment.
Nanotechnology could offer groundbreaking solutions to improve the effectiveness of LDM chemotherapy, by taking advantage of the unique targeting efficiency of ferritin (HFn) nanocages. Here, we exploit the HFn mediated targeted delivery of doxorubicin (DOX) in an aggressive breast cancer mouse model with DOX inducible chemoresistance.
HFnDOX was recently demonstrated to overcome chemoresistance by actively promoting DOX nuclear translocation in vitro and was tested as a MTD treatment on a DOX sensitive tumor model with encouraging results. We find that LDM administration of HFnDOX strongly improves the antitumor potential of DOX chemotherapy arresting the tumor progression, demonstrating that HFn mediate the nuclear delivery of DOX and increase its accumulation both in tumor tissue and in cancer cell nuclei. Moreover, we find that HFnDOX antitumor effect is attributable to multiple nanodrug actions beyond cell killing, including inhibition of tumor angiogenesis and avoidance of chemoresistance. Otherwise, although an even better reduction of tumor progression was achieved with liposomal DOX (plDOX), a fivefold increase in MDR1 positive cells has been displayed, suggesting that plDOX is not suitable in view of a protracted LDM treatment, due to the onset of chemoresistance. Multiparametric assessment of hearts, including histology, ultrastructural analysis of tissue morphology, and measurement of markers of reactive oxygen species and hepatic/renal conditions, provided evidence that metronomic HFnDOX allowed us to overcome cardiotoxicity contrary to what is observed with DOX and plDOX.
Our results suggest that HFnDOX has tremendous potential for the development of “nanometronomic” chemotherapy toward safe and tailored oncological treatments.