Nanometronomics: doxorubicin-loaded H-ferritin allows for tailored treatment of breast cancer based on lower doses and higher safety

The standard clinical approach for cancer chemotherapy is based on the concept of maximum tolerated dose (MTD) of drug for a patient. This strategy, however, presents several disadvantages, including major systemic toxicity... [ view full abstract ]

The standard clinical approach for cancer chemotherapy is based on the concept of maximum tolerated dose (MTD) of drug for a patient. This strategy, however, presents several disadvantages, including major systemic toxicity and development of therapeutic resistance due to prolonged time between treatments. In addition, solid tumors are less effectively eradicated by MTD-based treatments because their proliferation is also sustained by the host microenvironment. Metronomic chemotherapy is based on more frequent and lower dose drug administrations compared to MTD [1]. Although initially intended to prevent angiogenesis, recent evidence suggests that potential new mechanisms of action are involved, including restoration of anticancer immune response and induction of tumor dormancy. For this reason, metronomic chemotherapy has gradually gained interest among clinicians for either primary systemic or maintenance therapy. However, low drug accumulation at the tumor and poor effectiveness against highly aggressive metastatic cancer limit the clinical application. To improve the efficacy of metronomic chemotherapy, we have investigated the potential of recombinant H-ferritin (HFn) nanocages targeted delivery of lower doses of chemotherapeutic drugs, such as doxorubicin (DOX). HFn was produced by genetic engineering and loaded with DOX [2]. Mice bearing a highly aggressive, DOX-resistant 4T1 breast cancer cells were treated in parallel with placebo, free DOX and HFn-DOX and monitored until day 21 at repeated doses as low as 1.24 mg/Kg, significantly lower than the minimal clinical dosage (2.4 mg/kg). Our results highlight that metronomic treatment with nanoformulated DOX is able to inhibit cancer growth with a lower dose and a significant improvement in DOX toxicity profile, even in a highly metastatic DOX-resistant breast cancer model in vivo. Histological analysis of cardiac tissues suggested that HFn-DOX allows overcoming cardiotoxicity, one of the most severe side effects of DOX. In conclusion, HFn-DOX has a tremendous potential for the development of novel nanometronomic chemotherapy for the next generation of safe and tailored oncological treatments.